Embryology - User contributions [en-gb]

Talk:Musculoskeletal System - Skull Development

2024-05-23T10:39:34Z

Z8600021:

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==2024==

{{#pmid:38619396}}

Piezo1 and Piezo2 collectively regulate jawbone development.
Nie X, Abbasi Y, Chung MK.
Development. 2024 May 1;151(9):dev202386. doi: 10.1242/dev.202386. Epub 2024 May 9.

Piezo1 and Piezo2 are recently reported mechanosensory ion channels that transduce mechanical stimuli from the environment into intracellular biochemical signals in various tissues and organ systems. Here, we show that Piezo1 and Piezo2 display a robust expression during jawbone development. Deletion of Piezo1 in neural crest cells causes jawbone malformations in a small but significant number of mice. We further demonstrate that disruption of Piezo1 and Piezo2 in neural crest cells causes more striking defects in jawbone development than any single knockout, suggesting essential but partially redundant roles of Piezo1 and Piezo2. In addition, we observe defects in other neural crest derivatives such as malformation of the vascular smooth muscle in double knockout mice. Moreover, TUNEL examinations reveal excessive cell death in osteogenic cells of the maxillary and mandibular arches of the double knockout mice, suggesting that Piezo1 and Piezo2 together regulate cell survival during jawbone development. We further demonstrate that Yoda1, a Piezo1 agonist, promotes mineralization in the mandibular arches. Altogether, these data firmly establish that Piezo channels play important roles in regulating jawbone formation and maintenance.

==2022==

{{#pmid:35220463}}

Calvarial bone is one of the most complex sequences of developmental events in embryology, featuring a uniquely transient, pluripotent stem cell-like population known as the cranial neural crest (CNC). The skull is formed through intramembranous ossification with distinct tissue lineages (e.g. neural crest derived frontal bone and mesoderm derived parietal bone). Due to CNC's vast cell fate potential, in response to a series of inductive secreted cues including BMP/TGF-β, Wnt, FGF, Notch, Hedgehog, Hippo and PDGF signaling, CNC enables generations of a diverse spectrum of differentiated cell types in vivo such as osteoblasts and chondrocytes at the craniofacial level. In recent years, since the studies from a genetic mouse model and single-cell sequencing, new discoveries are uncovered upon CNC patterning, differentiation, and the contribution to the development of cranial bones. In this review, we summarized the differences upon the potential gene regulatory network to regulate CNC derived osteogenic potential in mouse and human, and highlighted specific functions of genetic molecules from multiple signaling pathways and the crosstalk, transcription factors and epigenetic factors in orchestrating CNC commitment and differentiation into osteogenic mesenchyme and bone formation. Disorders in gene regulatory network in CNC patterning indicate highly close relevance to clinical birth defects and diseases, providing valuable transgenic mouse models for subsequent discoveries in delineating the underlying molecular mechanisms. We also emphasized the potential regenerative alternative through scientific discoveries from CNC patterning and genetic molecules in interfering with or alleviating clinical disorders or diseases, which will be beneficial for the molecular targets to be integrated for novel therapeutic strategies in the clinic.

==2021==

Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw

Jeffry Cesario 1 , Sara Ha 1 , Julie Kim 1 , Niam Kataria 1 , Juhee Jeong 2
Affiliations expand
PMID: 34861428 DOI: 10.1016/j.gep.2021.119227
Abstract

Craniofacial development is controlled by a large number of genes, which interact with one another to form a complex gene regulatory network (GRN). Key components of GRN are signaling molecules and transcription factors. Therefore, identifying targets of core transcription factors is an important part of the overall efforts toward building a comprehensive and accurate model of GRN. LHX6 and LHX8 are transcription factors expressed in the oral mesenchyme of the first pharyngeal arch (PA1), and they are crucial regulators of palate and tooth development. Previously, we performed genome-wide transcriptional profiling and chromatin immunoprecipitation to identify target genes of LHX6 and LHX8 in PA1, and described a set of genes repressed by LHX. However, there has not been any discussion of the genes positively regulated by LHX6 and LHX8. In this paper, we revisited the above datasets to identify candidate positive targets of LHX in PA1. Focusing on those with known connections to craniofacial development, we performed RNA in situ hybridization to confirm the changes in expression in Lhx6;Lhx8 mutant. We also confirmed the binding of LHX6 to several putative enhancers near the candidate target genes. Together, we have uncovered novel connections between Lhx and other important regulators of craniofacial development, including Eya1, Barx1, Rspo2, Rspo3, and Wnt11.

Association between the developing sphenoid and adult morphology: A study using sagittal sections of the skull base from human embryos and fetuses

Masahito Yamamoto 1 , Zhe-Wu Jin 2 , Shogo Hayashi 3 , José Francisco Rodríguez-Vázquez 4 , Gen Murakami 5 , Shinichi Abe 1
Affiliations expand
PMID: 34268732 PMCID: PMC8602018 (available on 2023-12-01) DOI: 10.1111/joa.13515
Abstract

The developing sphenoid is regarded as a median cartilage mass (basisphenoid [BS]) with three cartilaginous processes (orbitosphenoid [OS], ala temporalis [AT], and alar process [AP]). The relationships of this initial configuration with the adult morphology are difficult to determine because of extensive membranous ossification along the cartilaginous elements. The purpose of this study was therefore to evaluate the anatomical connections between each element of the fetal sphenoid and adult morphology. Sagittal sections from 25 embryos and fetuses of gestational age 6-34 weeks and crown-rump length 12-295 mm were therefore examined and compared with horizontal and frontal sections from the other 25 late-term fetuses (217-340 mm). The OS was identified as a set of three mutually attached cartilage bars in early fetuses. At all stages, the OS-post was continuous with the anterolateral part of the BS. The BS included the notochord and Rathke's pouch remnant in embryos and early fetuses. The dorsum sellae was absent from embryos, but it protruded from the BS in early fetuses before a fossa for the hypophysis became evident. Although not higher than the hypophysis at midterm, the dorsum sellae elongated superiorly after gestational age 25 weeks. In early fetuses, the AP was located on the side immediately anterior to the otic capsule. The AT developed on the side immediately posterior to the extraocular rectus muscles. At late term, the greater wing was formed by membranous bones from the AT and AP. The AT and AP formed a complex bridge between the BS and the greater wing. A small cartilage, future medial pterygoid process (PTmed) was located inferior to the AT in early fetuses. At midterm, one endochondral bone and multiple membranous bones formed the PTmed. The lateral pterygoid process (PTlat) was formed by a single membranous bone plate. Therefore, we connected fetal elements and the adult morphology as follows. (1) Derivative of the OS makes not only the lesser wing but also the anterior margin of the body of the sphenoid. (2) Derivatives of the BS are the body of the sphenoid including the sella turcica and the dorsum sellae. (3) Most of the greater wing including the foramen rotundum and the foramen oval originate from the AT and AP and multiple membranous bones. (4) The PTmed originate from endochondral bones and multiple membranous bones, while the PTlat derive from a single membranous bone.

==2018==
===Johns Hopkins Fetal Skull Collection (1918–1951)===

{{Johns Hopkins Fetal Skull Collection table}}

==2017==

Childs Nerv Syst. 2017 Jun;33(6):909-914. doi: 10.1007/s00381-017-3406-1. Epub 2017 Apr 10.
A comprehensive review of the anterior fontanelle: embryology, anatomy, and clinical considerations.
D'Antoni AV1, Donaldson OI1, Schmidt C2, Macchi V3, De Caro R3, Oskouian RJ4, Loukas M5, Shane Tubbs R6.
Author information
Abstract
PURPOSE:
Fontanelles are a regular feature of infant development in which two segments of bone remain separated, leaving an area of fibrous membrane or a "soft spot" that acts to accommodate growth of the brain without compression by the skull. Of the six fontanelles in the human skull, the anterior fontanelle, located between the frontal and parietal bones, serves as an important anatomical diagnostic tool in the assessment of impairments of the skull and brain and allows access to the brain and ventricles in the infant.
METHODS:
Using a standard database search, we conducted a review of the anterior fontanelle, including its embryology, anatomy, pathology, and related surgical implications.
CONCLUSIONS:
The diagnostic value of the anterior fontanelle, through observation of its shape, size, and palpability, makes the area of significant clinical value. It is important that clinicians are aware of the features and associated pathologies of this area in their everyday practice.
KEYWORDS:
Cranial calvaria; Skull; Soft spot; Suture
PMID: 28396968 DOI: 10.1007/s00381-017-3406-1

==2016==

===The remodeling pattern of human mandibular alveolar bone during prenatal formation from 19 to 270mm CRL===
Ann Anat. 2016 Feb 24;205:65-74. doi: 10.1016/j.aanat.2016.01.005. [Epub ahead of print]

Radlanski RJ1, Renz H2, Tsengelsaikhan N2, Schuster F2, Zimmermann CA2.

Abstract

The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia.
Copyright © 2016 Elsevier GmbH. All rights reserved.
KEYWORDS:
3D-reconstructions; Alveolar bone; Dental primordia; Human; Mandible

PMID 26921449

==2015==

===Transcriptional analysis of human cranial compartments with different embryonic origins===
Arch Oral Biol. 2015 Sep;60(9):1450-60. doi: 10.1016/j.archoralbio.2015.06.008. Epub 2015 Jul 2.

Homayounfar N1, Park SS2, Afsharinejad Z3, Bammler TK3, MacDonald JW3, Farin FM3, Mecham BH4, Cunningham ML5.

Abstract

OBJECTIVE:
Previous investigations suggest that the embryonic origins of the calvarial tissues (neural crest or mesoderm) may account for the molecular mechanisms underlying sutural development. The aim of this study was to evaluate the differences in the gene expression of human cranial tissues and assess the presence of an expression signature reflecting their embryonic origins.
METHODS:
Using microarray technology, we investigated global gene expression of cells from the frontal and parietal bones and the metopic and sagittal intrasutural mesenchyme (ISM) of four human foetal calvaria. qRT-PCR of a selected group of genes was done to validate the microarray analysis. Paired comparison and correlation analyses were performed on microarray results.
RESULTS:
Of six paired comparisons, frontal and parietal compartments (distinct tissue types of calvaria, either bone or intrasutural mesenchyme) had the most different gene expression profiles despite being composed of the same tissue type (bone). Correlation analysis revealed two distinct gene expression profiles that separate frontal and metopic compartments from parietal and sagittal compartments. TFAP2A, TFAP2B, ICAM1, SULF1, TNC and FOXF2 were among differentially expressed genes.
CONCLUSION:
Transcriptional profiles of two groups of tissues, frontal and metopic compartments vs. parietal and sagittal compartments, suggest differences in proliferation, differentiation and extracellular matrix production. Our data suggest that in the second trimester of human foetal development, a gene expression signature of neural crest origin still exists in frontal and metopic compartments while gene expression of parietal and sagittal compartments is more similar to mesoderm.
Copyright © 2015 Elsevier Ltd. All rights reserved.
KEYWORDS:
Cranial suture; Differentiation; Extracellular matrix; Mesoderm; Neural crest; Proliferation
PMID 26188427

==2014==

===Direct Brain Recordings Reveal Impaired Neural Function in Infants With Single-Suture Craniosynostosis: A Future Modality for Guiding Management?===
J Craniofac Surg. 2014 Dec 19. [Epub ahead of print]

Hashim PW1, Brooks ED, Persing JA, Reuman H, Naples A, Travieso R, Terner J, Steinbacher D, Landi N, Mayes L, McPartland JC.

Abstract

BACKGROUND:
Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population.
METHODS:
Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing.
RESULTS:
Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls.
CONCLUSIONS:
Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.

PMID 25534054

==2012==

===Paleontological and developmental evidence resolve the homology and dual embryonic origin of a mammalian skull bone, the interparietal===

Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14075-80. doi: 10.1073/pnas.1208693109. Epub 2012 Aug 13.

Koyabu D, Maier W, Sánchez-Villagra MR.
Source
Palaeontological Institute and Museum, University of Zürich, 8006 Zürich, Switzerland. daisuke.koyabu@pim.uzh.ch

Abstract

The homologies of mammalian skull elements are now fairly well established, except for the controversial interparietal bone. A previous experimental study reported an intriguing mixed origin of the interparietal: the medial portion being derived from the neural crest cells, whereas the lateral portion from the mesoderm. The evolutionary history of such mixed origin remains unresolved, and contradictory reports on the presence or absence and developmental patterns of the interparietal among mammals have complicated the question of its homology. Here we provide an alternative perspective on the evolutionary identity of the interparietal, based on a comprehensive study across more than 300 extinct and extant taxa, integrating embryological and paleontological data. Although the interparietal has been regarded as being lost in various lineages, our investigation on embryos demonstrates its presence in all extant mammalian "orders." The generally accepted paradigm has regarded the interparietal as consisting of two elements that are homologized to the postparietals of basal amniotes. The tabular bones have been postulated as being lost during the rise of modern mammals. However, our results demonstrate that the interparietal consists not of two but of four elements. We propose that the tabulars of basal amniotes are conserved as the lateral interparietal elements, which quickly fuse to the medial elements at the embryonic stage, and that the postparietals are homologous to the medial elements. Hence, the dual developmental origin of the mammalian interparietal can be explained as the evolutionary consequence of the fusion between the crest-derived "postparietals" and the mesoderm-derived "tabulars."

PMID 22891324

===The BMP Ligand Gdf6 Prevents Differentiation of Coronal Suture Mesenchyme in Early Cranial Development===

PLoS One. 2012;7(5):e36789. Epub 2012 May 31.

Clendenning DE, Mortlock DP.
Source
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

Abstract

Growth Differentiation Factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules. Previous studies have shown that Gdf6 plays a role in formation of a diverse subset of skeletal joints. In mice, loss of Gdf6 results in fusion of the coronal suture, the intramembranous joint that separates the frontal and parietal bones. Although the role of GDFs in the development of cartilaginous limb joints has been studied, limb joints are developmentally quite distinct from cranial sutures and how Gdf6 controls suture formation has remained unclear. In this study we show that coronal suture fusion in the Gdf6-/- mouse is due to accelerated differentiation of suture mesenchyme, prior to the onset of calvarial ossification. Gdf6 is expressed in the mouse frontal bone primordia from embryonic day (E) 10.5 through 12.5. In the Gdf6-/- embryo, the coronal suture fuses prematurely and concurrently with the initiation of osteogenesis in the cranial bones. Alkaline phosphatase (ALP) activity and Runx2 expression assays both showed that the suture width is reduced in Gdf6+/- embryos and is completely absent in Gdf6-/- embryos by E12.5. ALP activity is also increased in the suture mesenchyme of Gdf6+/- embryos compared to wild-type. This suggests Gdf6 delays differentiation of the mesenchyme occupying the suture, prior to the onset of ossification. Therefore, although BMPs are known to promote bone formation, Gdf6 plays an inhibitory role to prevent the osteogenic differentiation of the coronal suture mesenchyme.

PMID 22693558

===The human calvaria: a review of embryology, anatomy, pathology, and molecular development===
Childs Nerv Syst. 2012 Jan;28(1):23-31. Epub 2011 Nov 27.

Tubbs RS, Bosmia AN, Cohen-Gadol AA.
Source
Department of Neurosurgery, Children's Hospital, Ambulatory Care Center, 1600 7th Avenue South, Birmingham, AL 35294, USA. shane.tubbs@chsys.org

Abstract

INTRODUCTION:
The human skull is a complex structure that deserves continued study. Few studies have directed their attention to the development, pathology, and molecular formation of the human calvaria.
MATERIALS AND METHODS:
A review of the medical literature using standard search engines was performed to locate studies regarding the human calvaria.
RESULTS:
The formation of the human calvaria is a complex interaction between bony and meningeal elements. Derailment of these interactions may result in deformation of this part of the skull.
CONCLUSIONS:
Knowledge of the anatomy, formation, and pathology of the human calvaria will be of use to the clinician that treats skull diseases. With an increased understanding of genetic and molecular biology, treatment paradigms for calvarial issues may change.

PMID 22120469

===Principles of cranial base ossification in humans and rats===
Acta Otolaryngol. 2012 Apr;132(4):349-54. doi: 10.3109/00016489.2011.642814. Epub 2011 Dec 27.

Santaolalla-Montoya F, Martinez-Ibargüen A, Sánchez-Fernández JM, Sánchez-del-Rey A.
Source
Otorhinolaryngology Department, School of Medicine, University of the Basque Country, Spain. Francisco.santaolalla@ehu.es
Abstract
CONCLUSIONS:
1. The principle of bilateral symmetry depends on the chordal cartilage that is the keystone in cranial base ossification in rats and humans, due to its anatomical situation and for the production of the chordin protein that regulates the bone morphogenetic protein BMP-7. 2. In humans and in rats, foramen lacerum closure follows a line of intramembranous ossification that depends on BMP-7, regulated by the first branchial pouch. 3. The cranial base ossification patterns and centres are similar in humans and in rats, except in the otic capsule, palate and the lateral pterygoid plate. 4. The neural crest may induce cranial ossification through the cranial nerves.
OBJECTIVES:
To study the patterns of cranial base ossification in humans and in rats, considering the chordal cartilage, and the otic, nasal and orbit capsules, as well as the participation of the branchial arches and pouches.
METHODS:
This was a light microscopy study of human fetal specimens obtained from spontaneous abortions with the following crown-rump-lengths (crl) 45, 74, 90, 134, 145 and 270 mm, and a 1-day-old neonate (360 mm crl), who had died of sudden death syndrome. We also examined Webster albino rat embryos of 16, 18 and 20 days of gestation and a postnatal series of rats 8 h and 1, 3, 4, 6, 7, 10 and 13 days old, as well as adult animals.
RESULTS:
In the 45 mm human fetus, the chordal cartilage with the nasal, otic and orbit capsules initiates cranial base ossification. Foramen lacerum closure begins in the 16-day-old rat embryo, following a line of membranous ossification between the external pterygoid process and the lateral alisphenoidal wing at ovalis foramen level. This is not a timing symmetrical process, which may persist until the 10th postnatal day in the rat. In the human fetus of 74 mm, the foramen lacerum space is closed by a membranous fusion ossification between the chordal cartilage and otic capsule, finishing at the 270 mm specimen. Endochondral ossification of the human otic capsule first appeared in the 145 mm (18 weeks) fetal specimen with four ossifying centres. The rat otic cartilaginous capsule showed rapid endochondral ossification, in the third and fourth postnatal day specimens.

PMID 22201370

http://informahealthcare.com/doi/abs/10.3109/00016489.2011.642814

==2011==

===Morphological and morphometric study on sphenoid and basioccipital ossification in normal human fetuses===

Congenit Anom (Kyoto). 2011 Sep;51(3):138-48. doi: 10.1111/j.1741-4520.2011.00322.x.

Zhang Q, Wang H, Udagawa J, Otani H.
Source
Department of Developmental Biology, Shimane University, Izumo, Japan.

Abstract

Congenital anomalies of the brain frequently correspond to cranial base anomalies, and a detailed description of morphology and individual variations in the developing cranial base is of clinical importance for diagnosing anomalies. Development of the human cranial base has been studied using dissection, computed tomography, and magnetic resonance imaging, each of which has advantages and disadvantages. We here examined development of the normal human fetal cranial base using bone staining, which allows for direct observation of the ossification centers and precise three-dimensional measurements. We observed alizarin red S-stained sphenoids and basiocciputs of 22 normal formalin-fixed human fetuses with crown-rump lengths (CRL) of 115-175 mm. We defined landmarks and measured sphenoids and basiocciputs using a fine caliper. Growth patterns of these ossifying bones were obtained, and we found similarities and differences among the growth patterns. We also observed individual variations in the ossification patterns, in particular, single- or double-ossification center patterns for the basisphenoid. The orbitosphenoid and basisphenoid widths and ratios of the widths to the total cranial base width were significantly different between the two pattern groups, whereas the other measurements and their ratios to the total cranial base did not differ between the groups. We measured the cerebrum and pons in different sets of 22 human fetuses with CRLs of 105-186 mm and found close relationships with the development of corresponding parts of the cranial base. The results contribute to the quantitative and qualitative information about the growth patterns and variations during human fetal cranial base development.
© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.

PMID 21848997

http://onlinelibrary.wiley.com/doi/10.1111/j.1741-4520.2011.00322.x/abstract;jsessionid=D215C1671CDF1C62716033D0D5E688F1.d04t04

===Modeling of the human fetal skull base growth: interest in new volumetrics morphometric tools===

Early Hum Dev. 2011 Apr;87(4):239-45. doi: 10.1016/j.earlhumdev.2011.01.022.

Herlin C, Largey A, deMatteï C, Daurès JP, Bigorre M, Captier G.
Source
Craniofacial and Plastic Pediatric Surgery Unit, Lapeyronie Hospital, Montpellier, 371 Av Doyen Gaston Giraud, 34 295 Montpellier, France. christian.herl@free.fr
Abstract
BACKGROUND:
Research on the skull base is important to improve our understanding of the growth and development of the modern human skull. To study the growth of the human fetal skull base, we assessed a new geometric morphometric tool, which does not require the use of bone landmarks.
MATERIAL AND METHODS:
Seven dry fetal skulls of an estimated gestational age ranging from 15 to 27 weeks were studied. Each skull was scanned using a standard CT scan and the image sets were post-processed to extract volumetric data by segmenting the skull base into predefined regions of interest. Our method of analysis was based on the inertial properties of reconstructed volumes.
RESULTS:
The volumetric study of the skulls highlighted an asynchronous speed of growth between the pre and post-chordal parts of the skull base whose preferential growth are in the vertical and horizontal planes. We also found different speeds of growth in the pre-chordal part depending on the type of ossification (endochondral or membranous). The overall shape of the skull base bones were preserved during the period studied except for the petrous pyramids. The expansion of bone parts was isometric with reference to a central point that was located at the intrasphenoidal synchondrosis. Finally, the analysis of the basicranial angles corroborated data from the literature in the sagittal plane and allowed their study also in the frontal and horizontal planes.
CONCLUSIONS:
This three-dimensional volumetric approach is a necessary complement to studies that are performed in the sagittal plane and are based on the identification of landmarks. The geometric morphometric method used by authors permitted to obtain original informations on the growth kinetics and bone tridimensional movements of the human fetal skull base.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID 21300487

==2010==

===Design and construction of a brain phantom to simulate neonatal MR images===
Comput Med Imaging Graph. 2010 Dec 10. [Epub ahead of print]

Kazemi K, Moghaddam HA, Grebe R, Gondry-Jouet C, Wallois F.

Department of Electrical and Electronics Engineering, Shiraz University of Technology, Shiraz, Iran; GRAMFC EA 4293, Faculty of Medicine, University of Picardie Jules Verne, 80036 Amiens, France.
Abstract
This paper presents the design and construction of a 3D digital neonatal neurocranial phantom and its application for the simulation of brain magnetic resonance (MR) images. Commonly used digital brain phantoms (e.g. BrainWeb) are based on the adult brain. With the growing interest in computer-aided methods for neonatal MR image processing, there is a growing demand a digital phantom and brain MR image simulator especially for the neonatal brains. This is due to the pronounced differences between adult and neonatal brains not only in terms of size but also, more importantly, in terms of geometrical proportions and the need to subdivide white matter into two different tissue types in neonates. Therefore the neonatal brain phantom created in the here presented work consists of 9 different tissue types: skin, fat, muscle, skull, dura mater, gray matter, myelinated white matter, nonmyelinated white matter and cerebrospinal fluid. Each voxel has a vector consisting of 9 components, one for each of these nine tissue types. This digital phantom can be used to map simulated magnetic resonance signal intensities resulting in simulated MR images of the newborns head. These images with controlled degradation of the image data present a representative, reproducible data set ideal for development and evaluation of neonatal MRI analysis methods, e.g. segmentation and registration algorithms.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21146956

===Fibroblast growth factor receptor signaling crosstalk in skeletogenesis===
Sci Signal. 2010 Nov 2;3(146):re9.

Miraoui H, Marie PJ.

Laboratory of Osteoblast Biology and Pathology, INSERM UMR606 and University Paris Diderot, Paris 75475, Cedex 10, France.
Abstract
Fibroblast growth factors (FGFs) play important roles in the control of embryonic and postnatal skeletal development by activating signaling through FGF receptors (FGFRs). Germline gain-of-function mutations in FGFR constitutively activate FGFR signaling, causing chondrocyte and osteoblast dysfunctions that result in skeletal dysplasias. Crosstalk between the FGFR pathway and other signaling cascades controls skeletal precursor cell differentiation. Genetic analyses revealed that the interplay of WNT and FGFR1 determines the fate and differentiation of mesenchymal stem cells during mouse craniofacial skeletogenesis. Additionally, interactions between FGFR signaling and other receptor tyrosine kinase networks, such as those mediated by the epidermal growth factor receptor and platelet-derived growth factor receptor α, were associated with excessive osteoblast differentiation and bone formation in the human skeletal dysplasia called craniosynostosis, which is a disorder of skull development. We review the roles of FGFR signaling and its crosstalk with other pathways in controlling skeletal cell fate and discuss how this crosstalk could be pharmacologically targeted to correct the abnormal cell phenotype in skeletal dysplasias caused by aberrant FGFR signaling.

PMID 21045207
The BMP antagonist noggin regulates cranial suture fusion STEPHEN M. WARREN, LISA J. BRUNET, RICHARD M. HARLAND, ARIS N.,ECONOMIDES & MICHAEL T. LONGAKER

"During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors ( fgfr ) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo , we suggest that syndromic fgfr -mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression."

==2009==

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Part -1===
J Pediatr Neurosci. 2009 Jul;4(2):86-99. doi: 10.4103/1817-1745.57327.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis is a disease characterized by untimely fusion of cranial sutures resulting in a variety of craniofacial deformities and neurological sequelae due to alteration in cranial volume and restriction of brain growth. This involves vault sutures predominantly, but cranial base is not immune. Association with a variety of syndromes makes the management decision complex. These children need careful evaluation by multiple specialists to have strategic treatment options. Parental counseling is an important and integral part of the treatment. Recent advancements in the surgical techniques and concept of team approach have significantly enhanced the safety and outcome of these children. We had an opportunity of treating 57 children with craniostenosis in the last 15 years at our craniofacial service. Out of them, 40 were nonsyndromic and 17 were syndromic variety. We describe our successful results along with individualized operative technical modifications adopted based on the current understanding of the disease.

PMID 21887189

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Parts -2===
J Pediatr Neurosci. 2009 Jul;4(2):100-7. doi: 10.4103/1817-1745.57328.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis associated with other syndromes poses several clinical and management challenges. Involvement of cranial, facial, and systemic defects with an underlying genetic abnormality needs comprehensive understanding, to plan appropriate and safe treatment modalities. Often, these children require staging involving several/multiple surgical procedures. Unsuccessful outcomes and retrusion of the deformities are common in comparison to the nonsyndromic variety. We present our experience in treating 17 children with syndromic craniostenosis with successful outcomes and minimal morbidity. We also describe the principles behind the staging. Technology adoption has improved the results as well as reduced the complications to an acceptable minimum.

PMID 21887190
==2008==

===Development and tissue origins of the mammalian cranial base===

Dev Biol. 2008 Oct 1;322(1):121-32. doi: 10.1016/j.ydbio.2008.07.016. Epub 2008 Jul 22.

McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay GM.
Source
Harvard School of Dental Medicine, Department of Developmental Biology, 190 Longwood Avenue, Boston, MA, 02115, USA. bmcbratneyowen@post.harvard.edu
Abstract
The vertebrate cranial base is a complex structure composed of bone, cartilage and other connective tissues underlying the brain; it is intimately connected with development of the face and cranial vault. Despite its central importance in craniofacial development, morphogenesis and tissue origins of the cranial base have not been studied in detail in the mouse, an important model organism. We describe here the location and time of appearance of the cartilages of the chondrocranium. We also examine the tissue origins of the mouse cranial base using a neural crest cell lineage cell marker, Wnt1-Cre/R26R, and a mesoderm lineage cell marker, Mesp1-Cre/R26R. The chondrocranium develops between E11 and E16 in the mouse, beginning with development of the caudal (occipital) chondrocranium, followed by chondrogenesis rostrally to form the nasal capsule, and finally fusion of these two parts via the midline central stem and the lateral struts of the vault cartilages. X-Gal staining of transgenic mice from E8.0 to 10 days post-natal showed that neural crest cells contribute to all of the cartilages that form the ethmoid, presphenoid, and basisphenoid bones with the exception of the hypochiasmatic cartilages. The basioccipital bone and non-squamous parts of the temporal bones are mesoderm derived. Therefore the prechordal head is mostly composed of neural crest-derived tissues, as predicted by the New Head Hypothesis. However, the anterior location of the mesoderm-derived hypochiasmatic cartilages, which are closely linked with the extra-ocular muscles, suggests that some tissues associated with the visual apparatus may have evolved independently of the rest of the "New Head".

PMID 18680740

===Three-dimensional ontogenetic shape changes in the human cranium during the fetal period===

J Anat. 2008 May;212(5):627-35. doi: 10.1111/j.1469-7580.2008.00884.x.

Morimoto N, Ogihara N, Katayama K, Shiota K.
Source
Laboratory of Physical Anthropology, Graduate School of Science, Kyoto University, Japan. morimoto@aim.uzh.ch <morimoto@aim.uzh.ch>
Abstract
Knowledge of the pattern of human craniofacial development in the fetal period is important for understanding the mechanisms underlying the emergence of variations in human craniofacial morphology. However, the precise character of the prenatal ontogenetic development of the human cranium has yet to be fully established. This study investigates ontogenetic changes in cranial shape in the fetal period, as exhibited in Japanese fetal specimens housed at Kyoto University. A total of 31 human fetal specimens aged from approximately 8 to 42 weeks of gestation underwent helical computed tomographic scanning, and 68 landmarks were digitized on the internal and external surfaces of the extracted crania. Ontogenetic shape change was then analyzed cross-sectionally and three-dimensionally using a geometric morphometric technique. The results of the present study are generally consistent with previously reported findings. It was found that during the prenatal ontogenetic process, the growth rate of the length of the cranium is greater than that of the width and height, and the growth rate of the length of the posterior cranial base is smaller than that of the anterior cranial base. Furthermore, it was observed that the change in shape of the human viscerocranium is smaller than that of the neurocranium during the fetal period, and that concurrently the basicranium extends by approximately 8 degrees due to the relative elevation of the basilar and lateral parts of occipital bone. These specific growth-related changes are the opposite of those reported for the postnatal period. Our findings therefore indicate that the allometric pattern of the human cranium is not a simple continuous transformation, but changes drastically from before to after birth.

PMID 18430090

==2000==

===MR, CT, and plain film imaging of the developing skull base in fetal specimens===

AJNR Am J Neuroradiol. 2000 Oct;21(9):1699-706.

Nemzek WR, Brodie HA, Hecht ST, Chong BW, Babcook CJ, Seibert JA.
Source
Department of Radiology, University of California, Davis Medical Center, Sacramento 95817, USA.
Abstract
BACKGROUND AND PURPOSE:
The developing fetal skull base has previously been studied via dissection and low-resolution CT. Most of the central skull base develops from endochondral ossification through an intermediary chondrocranium. We traced the development of the normal fetal skull base by using plain radiography, MR imaging, and CT.
METHODS:
Twenty-nine formalin-fixed fetal specimens ranging from 9 to 24 weeks' gestational age were examined with mammographic plain radiography, CT, and MR imaging. Skull base development and ossification were assessed.
RESULTS:
The postsphenoid cartilages enclose the pituitary and fuse to form the basisphenoid, from which the sella turcica and the posterior body of the sphenoid bone originate. The presphenoid cartilages will form the anterior body of the sphenoid bone. Portions of the presphenoid cartilage give rise to the mesethmoid cartilage, which forms the central portion of the anterior skull base. Ossification begins in the occipital bone (12 weeks) and progresses anteriorly. The postsphenoid (14 weeks) and then the presphenoid portion (17 weeks) of the sphenoid bone ossify. Ossification is seen laterally (16 weeks) in the orbitosphenoid, which contributes to the lesser wing of the sphenoid, and the alisphenoid (15 weeks), which forms the greater wing.
CONCLUSION:
MR imaging can show early progressive ossification of the cartilaginous skull base and its relation to intracranial structures. The study of fetal developmental anatomy may lead to a better understanding of abnormalities of the skull base.
PMID 11039353

==Historic==

===1937===

The Development of the Vertebrate Skull. G. R. de Beer, M.A., D.Sc., F.L.S. 552 pp., illust., $9.50. McAinsh, Toronto, 1937.

Anyone who has ever attempted even in a general way to compare the skull of man with that of lower mammals or reptiles and to determine the morphology of the different parts will realize the thorny and difficult field into which this book ventures. And it enters this field in no casual way but to a depth of 515 closely printed pages with abundant simple and clear illustrations. ,

The book is divided into three parts. The first deals with some general questions of the nature of cartilage and bone and goes on to review Goethe’s theory that the skull is made up of several fused vertebre. This theory of course has not stood the test of time but out of it arose the recognition of the segmental structure of the posterior end of. the skull.

Talk:Musculoskeletal System - Skull Development

2024-05-23T10:39:14Z

Z8600021:

{{Talk Page}}

==2024==

{{#pmid:38619396}}

Piezo1 and Piezo2 are recently reported mechanosensory ion channels that transduce mechanical stimuli from the environment into intracellular biochemical signals in various tissues and organ systems. Here, we show that Piezo1 and Piezo2 display a robust expression during jawbone development. Deletion of Piezo1 in neural crest cells causes jawbone malformations in a small but significant number of mice. We further demonstrate that disruption of Piezo1 and Piezo2 in neural crest cells causes more striking defects in jawbone development than any single knockout, suggesting essential but partially redundant roles of Piezo1 and Piezo2. In addition, we observe defects in other neural crest derivatives such as malformation of the vascular smooth muscle in double knockout mice. Moreover, TUNEL examinations reveal excessive cell death in osteogenic cells of the maxillary and mandibular arches of the double knockout mice, suggesting that Piezo1 and Piezo2 together regulate cell survival during jawbone development. We further demonstrate that Yoda1, a Piezo1 agonist, promotes mineralization in the mandibular arches. Altogether, these data firmly establish that Piezo channels play important roles in regulating jawbone formation and maintenance.

==2022==

{{#pmid:35220463}}

Calvarial bone is one of the most complex sequences of developmental events in embryology, featuring a uniquely transient, pluripotent stem cell-like population known as the cranial neural crest (CNC). The skull is formed through intramembranous ossification with distinct tissue lineages (e.g. neural crest derived frontal bone and mesoderm derived parietal bone). Due to CNC's vast cell fate potential, in response to a series of inductive secreted cues including BMP/TGF-β, Wnt, FGF, Notch, Hedgehog, Hippo and PDGF signaling, CNC enables generations of a diverse spectrum of differentiated cell types in vivo such as osteoblasts and chondrocytes at the craniofacial level. In recent years, since the studies from a genetic mouse model and single-cell sequencing, new discoveries are uncovered upon CNC patterning, differentiation, and the contribution to the development of cranial bones. In this review, we summarized the differences upon the potential gene regulatory network to regulate CNC derived osteogenic potential in mouse and human, and highlighted specific functions of genetic molecules from multiple signaling pathways and the crosstalk, transcription factors and epigenetic factors in orchestrating CNC commitment and differentiation into osteogenic mesenchyme and bone formation. Disorders in gene regulatory network in CNC patterning indicate highly close relevance to clinical birth defects and diseases, providing valuable transgenic mouse models for subsequent discoveries in delineating the underlying molecular mechanisms. We also emphasized the potential regenerative alternative through scientific discoveries from CNC patterning and genetic molecules in interfering with or alleviating clinical disorders or diseases, which will be beneficial for the molecular targets to be integrated for novel therapeutic strategies in the clinic.

==2021==

Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw

Jeffry Cesario 1 , Sara Ha 1 , Julie Kim 1 , Niam Kataria 1 , Juhee Jeong 2
Affiliations expand
PMID: 34861428 DOI: 10.1016/j.gep.2021.119227
Abstract

Craniofacial development is controlled by a large number of genes, which interact with one another to form a complex gene regulatory network (GRN). Key components of GRN are signaling molecules and transcription factors. Therefore, identifying targets of core transcription factors is an important part of the overall efforts toward building a comprehensive and accurate model of GRN. LHX6 and LHX8 are transcription factors expressed in the oral mesenchyme of the first pharyngeal arch (PA1), and they are crucial regulators of palate and tooth development. Previously, we performed genome-wide transcriptional profiling and chromatin immunoprecipitation to identify target genes of LHX6 and LHX8 in PA1, and described a set of genes repressed by LHX. However, there has not been any discussion of the genes positively regulated by LHX6 and LHX8. In this paper, we revisited the above datasets to identify candidate positive targets of LHX in PA1. Focusing on those with known connections to craniofacial development, we performed RNA in situ hybridization to confirm the changes in expression in Lhx6;Lhx8 mutant. We also confirmed the binding of LHX6 to several putative enhancers near the candidate target genes. Together, we have uncovered novel connections between Lhx and other important regulators of craniofacial development, including Eya1, Barx1, Rspo2, Rspo3, and Wnt11.

Association between the developing sphenoid and adult morphology: A study using sagittal sections of the skull base from human embryos and fetuses

Masahito Yamamoto 1 , Zhe-Wu Jin 2 , Shogo Hayashi 3 , José Francisco Rodríguez-Vázquez 4 , Gen Murakami 5 , Shinichi Abe 1
Affiliations expand
PMID: 34268732 PMCID: PMC8602018 (available on 2023-12-01) DOI: 10.1111/joa.13515
Abstract

The developing sphenoid is regarded as a median cartilage mass (basisphenoid [BS]) with three cartilaginous processes (orbitosphenoid [OS], ala temporalis [AT], and alar process [AP]). The relationships of this initial configuration with the adult morphology are difficult to determine because of extensive membranous ossification along the cartilaginous elements. The purpose of this study was therefore to evaluate the anatomical connections between each element of the fetal sphenoid and adult morphology. Sagittal sections from 25 embryos and fetuses of gestational age 6-34 weeks and crown-rump length 12-295 mm were therefore examined and compared with horizontal and frontal sections from the other 25 late-term fetuses (217-340 mm). The OS was identified as a set of three mutually attached cartilage bars in early fetuses. At all stages, the OS-post was continuous with the anterolateral part of the BS. The BS included the notochord and Rathke's pouch remnant in embryos and early fetuses. The dorsum sellae was absent from embryos, but it protruded from the BS in early fetuses before a fossa for the hypophysis became evident. Although not higher than the hypophysis at midterm, the dorsum sellae elongated superiorly after gestational age 25 weeks. In early fetuses, the AP was located on the side immediately anterior to the otic capsule. The AT developed on the side immediately posterior to the extraocular rectus muscles. At late term, the greater wing was formed by membranous bones from the AT and AP. The AT and AP formed a complex bridge between the BS and the greater wing. A small cartilage, future medial pterygoid process (PTmed) was located inferior to the AT in early fetuses. At midterm, one endochondral bone and multiple membranous bones formed the PTmed. The lateral pterygoid process (PTlat) was formed by a single membranous bone plate. Therefore, we connected fetal elements and the adult morphology as follows. (1) Derivative of the OS makes not only the lesser wing but also the anterior margin of the body of the sphenoid. (2) Derivatives of the BS are the body of the sphenoid including the sella turcica and the dorsum sellae. (3) Most of the greater wing including the foramen rotundum and the foramen oval originate from the AT and AP and multiple membranous bones. (4) The PTmed originate from endochondral bones and multiple membranous bones, while the PTlat derive from a single membranous bone.

==2018==
===Johns Hopkins Fetal Skull Collection (1918–1951)===

{{Johns Hopkins Fetal Skull Collection table}}

==2017==

Childs Nerv Syst. 2017 Jun;33(6):909-914. doi: 10.1007/s00381-017-3406-1. Epub 2017 Apr 10.
A comprehensive review of the anterior fontanelle: embryology, anatomy, and clinical considerations.
D'Antoni AV1, Donaldson OI1, Schmidt C2, Macchi V3, De Caro R3, Oskouian RJ4, Loukas M5, Shane Tubbs R6.
Author information
Abstract
PURPOSE:
Fontanelles are a regular feature of infant development in which two segments of bone remain separated, leaving an area of fibrous membrane or a "soft spot" that acts to accommodate growth of the brain without compression by the skull. Of the six fontanelles in the human skull, the anterior fontanelle, located between the frontal and parietal bones, serves as an important anatomical diagnostic tool in the assessment of impairments of the skull and brain and allows access to the brain and ventricles in the infant.
METHODS:
Using a standard database search, we conducted a review of the anterior fontanelle, including its embryology, anatomy, pathology, and related surgical implications.
CONCLUSIONS:
The diagnostic value of the anterior fontanelle, through observation of its shape, size, and palpability, makes the area of significant clinical value. It is important that clinicians are aware of the features and associated pathologies of this area in their everyday practice.
KEYWORDS:
Cranial calvaria; Skull; Soft spot; Suture
PMID: 28396968 DOI: 10.1007/s00381-017-3406-1

==2016==

===The remodeling pattern of human mandibular alveolar bone during prenatal formation from 19 to 270mm CRL===
Ann Anat. 2016 Feb 24;205:65-74. doi: 10.1016/j.aanat.2016.01.005. [Epub ahead of print]

Radlanski RJ1, Renz H2, Tsengelsaikhan N2, Schuster F2, Zimmermann CA2.

Abstract

The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia.
Copyright © 2016 Elsevier GmbH. All rights reserved.
KEYWORDS:
3D-reconstructions; Alveolar bone; Dental primordia; Human; Mandible

PMID 26921449

==2015==

===Transcriptional analysis of human cranial compartments with different embryonic origins===
Arch Oral Biol. 2015 Sep;60(9):1450-60. doi: 10.1016/j.archoralbio.2015.06.008. Epub 2015 Jul 2.

Homayounfar N1, Park SS2, Afsharinejad Z3, Bammler TK3, MacDonald JW3, Farin FM3, Mecham BH4, Cunningham ML5.

Abstract

OBJECTIVE:
Previous investigations suggest that the embryonic origins of the calvarial tissues (neural crest or mesoderm) may account for the molecular mechanisms underlying sutural development. The aim of this study was to evaluate the differences in the gene expression of human cranial tissues and assess the presence of an expression signature reflecting their embryonic origins.
METHODS:
Using microarray technology, we investigated global gene expression of cells from the frontal and parietal bones and the metopic and sagittal intrasutural mesenchyme (ISM) of four human foetal calvaria. qRT-PCR of a selected group of genes was done to validate the microarray analysis. Paired comparison and correlation analyses were performed on microarray results.
RESULTS:
Of six paired comparisons, frontal and parietal compartments (distinct tissue types of calvaria, either bone or intrasutural mesenchyme) had the most different gene expression profiles despite being composed of the same tissue type (bone). Correlation analysis revealed two distinct gene expression profiles that separate frontal and metopic compartments from parietal and sagittal compartments. TFAP2A, TFAP2B, ICAM1, SULF1, TNC and FOXF2 were among differentially expressed genes.
CONCLUSION:
Transcriptional profiles of two groups of tissues, frontal and metopic compartments vs. parietal and sagittal compartments, suggest differences in proliferation, differentiation and extracellular matrix production. Our data suggest that in the second trimester of human foetal development, a gene expression signature of neural crest origin still exists in frontal and metopic compartments while gene expression of parietal and sagittal compartments is more similar to mesoderm.
Copyright © 2015 Elsevier Ltd. All rights reserved.
KEYWORDS:
Cranial suture; Differentiation; Extracellular matrix; Mesoderm; Neural crest; Proliferation
PMID 26188427

==2014==

===Direct Brain Recordings Reveal Impaired Neural Function in Infants With Single-Suture Craniosynostosis: A Future Modality for Guiding Management?===
J Craniofac Surg. 2014 Dec 19. [Epub ahead of print]

Hashim PW1, Brooks ED, Persing JA, Reuman H, Naples A, Travieso R, Terner J, Steinbacher D, Landi N, Mayes L, McPartland JC.

Abstract

BACKGROUND:
Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population.
METHODS:
Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing.
RESULTS:
Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls.
CONCLUSIONS:
Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.

PMID 25534054

==2012==

===Paleontological and developmental evidence resolve the homology and dual embryonic origin of a mammalian skull bone, the interparietal===

Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14075-80. doi: 10.1073/pnas.1208693109. Epub 2012 Aug 13.

Koyabu D, Maier W, Sánchez-Villagra MR.
Source
Palaeontological Institute and Museum, University of Zürich, 8006 Zürich, Switzerland. daisuke.koyabu@pim.uzh.ch

Abstract

The homologies of mammalian skull elements are now fairly well established, except for the controversial interparietal bone. A previous experimental study reported an intriguing mixed origin of the interparietal: the medial portion being derived from the neural crest cells, whereas the lateral portion from the mesoderm. The evolutionary history of such mixed origin remains unresolved, and contradictory reports on the presence or absence and developmental patterns of the interparietal among mammals have complicated the question of its homology. Here we provide an alternative perspective on the evolutionary identity of the interparietal, based on a comprehensive study across more than 300 extinct and extant taxa, integrating embryological and paleontological data. Although the interparietal has been regarded as being lost in various lineages, our investigation on embryos demonstrates its presence in all extant mammalian "orders." The generally accepted paradigm has regarded the interparietal as consisting of two elements that are homologized to the postparietals of basal amniotes. The tabular bones have been postulated as being lost during the rise of modern mammals. However, our results demonstrate that the interparietal consists not of two but of four elements. We propose that the tabulars of basal amniotes are conserved as the lateral interparietal elements, which quickly fuse to the medial elements at the embryonic stage, and that the postparietals are homologous to the medial elements. Hence, the dual developmental origin of the mammalian interparietal can be explained as the evolutionary consequence of the fusion between the crest-derived "postparietals" and the mesoderm-derived "tabulars."

PMID 22891324

===The BMP Ligand Gdf6 Prevents Differentiation of Coronal Suture Mesenchyme in Early Cranial Development===

PLoS One. 2012;7(5):e36789. Epub 2012 May 31.

Clendenning DE, Mortlock DP.
Source
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

Abstract

Growth Differentiation Factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules. Previous studies have shown that Gdf6 plays a role in formation of a diverse subset of skeletal joints. In mice, loss of Gdf6 results in fusion of the coronal suture, the intramembranous joint that separates the frontal and parietal bones. Although the role of GDFs in the development of cartilaginous limb joints has been studied, limb joints are developmentally quite distinct from cranial sutures and how Gdf6 controls suture formation has remained unclear. In this study we show that coronal suture fusion in the Gdf6-/- mouse is due to accelerated differentiation of suture mesenchyme, prior to the onset of calvarial ossification. Gdf6 is expressed in the mouse frontal bone primordia from embryonic day (E) 10.5 through 12.5. In the Gdf6-/- embryo, the coronal suture fuses prematurely and concurrently with the initiation of osteogenesis in the cranial bones. Alkaline phosphatase (ALP) activity and Runx2 expression assays both showed that the suture width is reduced in Gdf6+/- embryos and is completely absent in Gdf6-/- embryos by E12.5. ALP activity is also increased in the suture mesenchyme of Gdf6+/- embryos compared to wild-type. This suggests Gdf6 delays differentiation of the mesenchyme occupying the suture, prior to the onset of ossification. Therefore, although BMPs are known to promote bone formation, Gdf6 plays an inhibitory role to prevent the osteogenic differentiation of the coronal suture mesenchyme.

PMID 22693558

===The human calvaria: a review of embryology, anatomy, pathology, and molecular development===
Childs Nerv Syst. 2012 Jan;28(1):23-31. Epub 2011 Nov 27.

Tubbs RS, Bosmia AN, Cohen-Gadol AA.
Source
Department of Neurosurgery, Children's Hospital, Ambulatory Care Center, 1600 7th Avenue South, Birmingham, AL 35294, USA. shane.tubbs@chsys.org

Abstract

INTRODUCTION:
The human skull is a complex structure that deserves continued study. Few studies have directed their attention to the development, pathology, and molecular formation of the human calvaria.
MATERIALS AND METHODS:
A review of the medical literature using standard search engines was performed to locate studies regarding the human calvaria.
RESULTS:
The formation of the human calvaria is a complex interaction between bony and meningeal elements. Derailment of these interactions may result in deformation of this part of the skull.
CONCLUSIONS:
Knowledge of the anatomy, formation, and pathology of the human calvaria will be of use to the clinician that treats skull diseases. With an increased understanding of genetic and molecular biology, treatment paradigms for calvarial issues may change.

PMID 22120469

===Principles of cranial base ossification in humans and rats===
Acta Otolaryngol. 2012 Apr;132(4):349-54. doi: 10.3109/00016489.2011.642814. Epub 2011 Dec 27.

Santaolalla-Montoya F, Martinez-Ibargüen A, Sánchez-Fernández JM, Sánchez-del-Rey A.
Source
Otorhinolaryngology Department, School of Medicine, University of the Basque Country, Spain. Francisco.santaolalla@ehu.es
Abstract
CONCLUSIONS:
1. The principle of bilateral symmetry depends on the chordal cartilage that is the keystone in cranial base ossification in rats and humans, due to its anatomical situation and for the production of the chordin protein that regulates the bone morphogenetic protein BMP-7. 2. In humans and in rats, foramen lacerum closure follows a line of intramembranous ossification that depends on BMP-7, regulated by the first branchial pouch. 3. The cranial base ossification patterns and centres are similar in humans and in rats, except in the otic capsule, palate and the lateral pterygoid plate. 4. The neural crest may induce cranial ossification through the cranial nerves.
OBJECTIVES:
To study the patterns of cranial base ossification in humans and in rats, considering the chordal cartilage, and the otic, nasal and orbit capsules, as well as the participation of the branchial arches and pouches.
METHODS:
This was a light microscopy study of human fetal specimens obtained from spontaneous abortions with the following crown-rump-lengths (crl) 45, 74, 90, 134, 145 and 270 mm, and a 1-day-old neonate (360 mm crl), who had died of sudden death syndrome. We also examined Webster albino rat embryos of 16, 18 and 20 days of gestation and a postnatal series of rats 8 h and 1, 3, 4, 6, 7, 10 and 13 days old, as well as adult animals.
RESULTS:
In the 45 mm human fetus, the chordal cartilage with the nasal, otic and orbit capsules initiates cranial base ossification. Foramen lacerum closure begins in the 16-day-old rat embryo, following a line of membranous ossification between the external pterygoid process and the lateral alisphenoidal wing at ovalis foramen level. This is not a timing symmetrical process, which may persist until the 10th postnatal day in the rat. In the human fetus of 74 mm, the foramen lacerum space is closed by a membranous fusion ossification between the chordal cartilage and otic capsule, finishing at the 270 mm specimen. Endochondral ossification of the human otic capsule first appeared in the 145 mm (18 weeks) fetal specimen with four ossifying centres. The rat otic cartilaginous capsule showed rapid endochondral ossification, in the third and fourth postnatal day specimens.

PMID 22201370

http://informahealthcare.com/doi/abs/10.3109/00016489.2011.642814

==2011==

===Morphological and morphometric study on sphenoid and basioccipital ossification in normal human fetuses===

Congenit Anom (Kyoto). 2011 Sep;51(3):138-48. doi: 10.1111/j.1741-4520.2011.00322.x.

Zhang Q, Wang H, Udagawa J, Otani H.
Source
Department of Developmental Biology, Shimane University, Izumo, Japan.

Abstract

Congenital anomalies of the brain frequently correspond to cranial base anomalies, and a detailed description of morphology and individual variations in the developing cranial base is of clinical importance for diagnosing anomalies. Development of the human cranial base has been studied using dissection, computed tomography, and magnetic resonance imaging, each of which has advantages and disadvantages. We here examined development of the normal human fetal cranial base using bone staining, which allows for direct observation of the ossification centers and precise three-dimensional measurements. We observed alizarin red S-stained sphenoids and basiocciputs of 22 normal formalin-fixed human fetuses with crown-rump lengths (CRL) of 115-175 mm. We defined landmarks and measured sphenoids and basiocciputs using a fine caliper. Growth patterns of these ossifying bones were obtained, and we found similarities and differences among the growth patterns. We also observed individual variations in the ossification patterns, in particular, single- or double-ossification center patterns for the basisphenoid. The orbitosphenoid and basisphenoid widths and ratios of the widths to the total cranial base width were significantly different between the two pattern groups, whereas the other measurements and their ratios to the total cranial base did not differ between the groups. We measured the cerebrum and pons in different sets of 22 human fetuses with CRLs of 105-186 mm and found close relationships with the development of corresponding parts of the cranial base. The results contribute to the quantitative and qualitative information about the growth patterns and variations during human fetal cranial base development.
© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.

PMID 21848997

http://onlinelibrary.wiley.com/doi/10.1111/j.1741-4520.2011.00322.x/abstract;jsessionid=D215C1671CDF1C62716033D0D5E688F1.d04t04

===Modeling of the human fetal skull base growth: interest in new volumetrics morphometric tools===

Early Hum Dev. 2011 Apr;87(4):239-45. doi: 10.1016/j.earlhumdev.2011.01.022.

Herlin C, Largey A, deMatteï C, Daurès JP, Bigorre M, Captier G.
Source
Craniofacial and Plastic Pediatric Surgery Unit, Lapeyronie Hospital, Montpellier, 371 Av Doyen Gaston Giraud, 34 295 Montpellier, France. christian.herl@free.fr
Abstract
BACKGROUND:
Research on the skull base is important to improve our understanding of the growth and development of the modern human skull. To study the growth of the human fetal skull base, we assessed a new geometric morphometric tool, which does not require the use of bone landmarks.
MATERIAL AND METHODS:
Seven dry fetal skulls of an estimated gestational age ranging from 15 to 27 weeks were studied. Each skull was scanned using a standard CT scan and the image sets were post-processed to extract volumetric data by segmenting the skull base into predefined regions of interest. Our method of analysis was based on the inertial properties of reconstructed volumes.
RESULTS:
The volumetric study of the skulls highlighted an asynchronous speed of growth between the pre and post-chordal parts of the skull base whose preferential growth are in the vertical and horizontal planes. We also found different speeds of growth in the pre-chordal part depending on the type of ossification (endochondral or membranous). The overall shape of the skull base bones were preserved during the period studied except for the petrous pyramids. The expansion of bone parts was isometric with reference to a central point that was located at the intrasphenoidal synchondrosis. Finally, the analysis of the basicranial angles corroborated data from the literature in the sagittal plane and allowed their study also in the frontal and horizontal planes.
CONCLUSIONS:
This three-dimensional volumetric approach is a necessary complement to studies that are performed in the sagittal plane and are based on the identification of landmarks. The geometric morphometric method used by authors permitted to obtain original informations on the growth kinetics and bone tridimensional movements of the human fetal skull base.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID 21300487

==2010==

===Design and construction of a brain phantom to simulate neonatal MR images===
Comput Med Imaging Graph. 2010 Dec 10. [Epub ahead of print]

Kazemi K, Moghaddam HA, Grebe R, Gondry-Jouet C, Wallois F.

Department of Electrical and Electronics Engineering, Shiraz University of Technology, Shiraz, Iran; GRAMFC EA 4293, Faculty of Medicine, University of Picardie Jules Verne, 80036 Amiens, France.
Abstract
This paper presents the design and construction of a 3D digital neonatal neurocranial phantom and its application for the simulation of brain magnetic resonance (MR) images. Commonly used digital brain phantoms (e.g. BrainWeb) are based on the adult brain. With the growing interest in computer-aided methods for neonatal MR image processing, there is a growing demand a digital phantom and brain MR image simulator especially for the neonatal brains. This is due to the pronounced differences between adult and neonatal brains not only in terms of size but also, more importantly, in terms of geometrical proportions and the need to subdivide white matter into two different tissue types in neonates. Therefore the neonatal brain phantom created in the here presented work consists of 9 different tissue types: skin, fat, muscle, skull, dura mater, gray matter, myelinated white matter, nonmyelinated white matter and cerebrospinal fluid. Each voxel has a vector consisting of 9 components, one for each of these nine tissue types. This digital phantom can be used to map simulated magnetic resonance signal intensities resulting in simulated MR images of the newborns head. These images with controlled degradation of the image data present a representative, reproducible data set ideal for development and evaluation of neonatal MRI analysis methods, e.g. segmentation and registration algorithms.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21146956

===Fibroblast growth factor receptor signaling crosstalk in skeletogenesis===
Sci Signal. 2010 Nov 2;3(146):re9.

Miraoui H, Marie PJ.

Laboratory of Osteoblast Biology and Pathology, INSERM UMR606 and University Paris Diderot, Paris 75475, Cedex 10, France.
Abstract
Fibroblast growth factors (FGFs) play important roles in the control of embryonic and postnatal skeletal development by activating signaling through FGF receptors (FGFRs). Germline gain-of-function mutations in FGFR constitutively activate FGFR signaling, causing chondrocyte and osteoblast dysfunctions that result in skeletal dysplasias. Crosstalk between the FGFR pathway and other signaling cascades controls skeletal precursor cell differentiation. Genetic analyses revealed that the interplay of WNT and FGFR1 determines the fate and differentiation of mesenchymal stem cells during mouse craniofacial skeletogenesis. Additionally, interactions between FGFR signaling and other receptor tyrosine kinase networks, such as those mediated by the epidermal growth factor receptor and platelet-derived growth factor receptor α, were associated with excessive osteoblast differentiation and bone formation in the human skeletal dysplasia called craniosynostosis, which is a disorder of skull development. We review the roles of FGFR signaling and its crosstalk with other pathways in controlling skeletal cell fate and discuss how this crosstalk could be pharmacologically targeted to correct the abnormal cell phenotype in skeletal dysplasias caused by aberrant FGFR signaling.

PMID 21045207
The BMP antagonist noggin regulates cranial suture fusion STEPHEN M. WARREN, LISA J. BRUNET, RICHARD M. HARLAND, ARIS N.,ECONOMIDES & MICHAEL T. LONGAKER

"During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors ( fgfr ) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo , we suggest that syndromic fgfr -mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression."

==2009==

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Part -1===
J Pediatr Neurosci. 2009 Jul;4(2):86-99. doi: 10.4103/1817-1745.57327.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis is a disease characterized by untimely fusion of cranial sutures resulting in a variety of craniofacial deformities and neurological sequelae due to alteration in cranial volume and restriction of brain growth. This involves vault sutures predominantly, but cranial base is not immune. Association with a variety of syndromes makes the management decision complex. These children need careful evaluation by multiple specialists to have strategic treatment options. Parental counseling is an important and integral part of the treatment. Recent advancements in the surgical techniques and concept of team approach have significantly enhanced the safety and outcome of these children. We had an opportunity of treating 57 children with craniostenosis in the last 15 years at our craniofacial service. Out of them, 40 were nonsyndromic and 17 were syndromic variety. We describe our successful results along with individualized operative technical modifications adopted based on the current understanding of the disease.

PMID 21887189

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Parts -2===
J Pediatr Neurosci. 2009 Jul;4(2):100-7. doi: 10.4103/1817-1745.57328.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis associated with other syndromes poses several clinical and management challenges. Involvement of cranial, facial, and systemic defects with an underlying genetic abnormality needs comprehensive understanding, to plan appropriate and safe treatment modalities. Often, these children require staging involving several/multiple surgical procedures. Unsuccessful outcomes and retrusion of the deformities are common in comparison to the nonsyndromic variety. We present our experience in treating 17 children with syndromic craniostenosis with successful outcomes and minimal morbidity. We also describe the principles behind the staging. Technology adoption has improved the results as well as reduced the complications to an acceptable minimum.

PMID 21887190
==2008==

===Development and tissue origins of the mammalian cranial base===

Dev Biol. 2008 Oct 1;322(1):121-32. doi: 10.1016/j.ydbio.2008.07.016. Epub 2008 Jul 22.

McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay GM.
Source
Harvard School of Dental Medicine, Department of Developmental Biology, 190 Longwood Avenue, Boston, MA, 02115, USA. bmcbratneyowen@post.harvard.edu
Abstract
The vertebrate cranial base is a complex structure composed of bone, cartilage and other connective tissues underlying the brain; it is intimately connected with development of the face and cranial vault. Despite its central importance in craniofacial development, morphogenesis and tissue origins of the cranial base have not been studied in detail in the mouse, an important model organism. We describe here the location and time of appearance of the cartilages of the chondrocranium. We also examine the tissue origins of the mouse cranial base using a neural crest cell lineage cell marker, Wnt1-Cre/R26R, and a mesoderm lineage cell marker, Mesp1-Cre/R26R. The chondrocranium develops between E11 and E16 in the mouse, beginning with development of the caudal (occipital) chondrocranium, followed by chondrogenesis rostrally to form the nasal capsule, and finally fusion of these two parts via the midline central stem and the lateral struts of the vault cartilages. X-Gal staining of transgenic mice from E8.0 to 10 days post-natal showed that neural crest cells contribute to all of the cartilages that form the ethmoid, presphenoid, and basisphenoid bones with the exception of the hypochiasmatic cartilages. The basioccipital bone and non-squamous parts of the temporal bones are mesoderm derived. Therefore the prechordal head is mostly composed of neural crest-derived tissues, as predicted by the New Head Hypothesis. However, the anterior location of the mesoderm-derived hypochiasmatic cartilages, which are closely linked with the extra-ocular muscles, suggests that some tissues associated with the visual apparatus may have evolved independently of the rest of the "New Head".

PMID 18680740

===Three-dimensional ontogenetic shape changes in the human cranium during the fetal period===

J Anat. 2008 May;212(5):627-35. doi: 10.1111/j.1469-7580.2008.00884.x.

Morimoto N, Ogihara N, Katayama K, Shiota K.
Source
Laboratory of Physical Anthropology, Graduate School of Science, Kyoto University, Japan. morimoto@aim.uzh.ch <morimoto@aim.uzh.ch>
Abstract
Knowledge of the pattern of human craniofacial development in the fetal period is important for understanding the mechanisms underlying the emergence of variations in human craniofacial morphology. However, the precise character of the prenatal ontogenetic development of the human cranium has yet to be fully established. This study investigates ontogenetic changes in cranial shape in the fetal period, as exhibited in Japanese fetal specimens housed at Kyoto University. A total of 31 human fetal specimens aged from approximately 8 to 42 weeks of gestation underwent helical computed tomographic scanning, and 68 landmarks were digitized on the internal and external surfaces of the extracted crania. Ontogenetic shape change was then analyzed cross-sectionally and three-dimensionally using a geometric morphometric technique. The results of the present study are generally consistent with previously reported findings. It was found that during the prenatal ontogenetic process, the growth rate of the length of the cranium is greater than that of the width and height, and the growth rate of the length of the posterior cranial base is smaller than that of the anterior cranial base. Furthermore, it was observed that the change in shape of the human viscerocranium is smaller than that of the neurocranium during the fetal period, and that concurrently the basicranium extends by approximately 8 degrees due to the relative elevation of the basilar and lateral parts of occipital bone. These specific growth-related changes are the opposite of those reported for the postnatal period. Our findings therefore indicate that the allometric pattern of the human cranium is not a simple continuous transformation, but changes drastically from before to after birth.

PMID 18430090

==2000==

===MR, CT, and plain film imaging of the developing skull base in fetal specimens===

AJNR Am J Neuroradiol. 2000 Oct;21(9):1699-706.

Nemzek WR, Brodie HA, Hecht ST, Chong BW, Babcook CJ, Seibert JA.
Source
Department of Radiology, University of California, Davis Medical Center, Sacramento 95817, USA.
Abstract
BACKGROUND AND PURPOSE:
The developing fetal skull base has previously been studied via dissection and low-resolution CT. Most of the central skull base develops from endochondral ossification through an intermediary chondrocranium. We traced the development of the normal fetal skull base by using plain radiography, MR imaging, and CT.
METHODS:
Twenty-nine formalin-fixed fetal specimens ranging from 9 to 24 weeks' gestational age were examined with mammographic plain radiography, CT, and MR imaging. Skull base development and ossification were assessed.
RESULTS:
The postsphenoid cartilages enclose the pituitary and fuse to form the basisphenoid, from which the sella turcica and the posterior body of the sphenoid bone originate. The presphenoid cartilages will form the anterior body of the sphenoid bone. Portions of the presphenoid cartilage give rise to the mesethmoid cartilage, which forms the central portion of the anterior skull base. Ossification begins in the occipital bone (12 weeks) and progresses anteriorly. The postsphenoid (14 weeks) and then the presphenoid portion (17 weeks) of the sphenoid bone ossify. Ossification is seen laterally (16 weeks) in the orbitosphenoid, which contributes to the lesser wing of the sphenoid, and the alisphenoid (15 weeks), which forms the greater wing.
CONCLUSION:
MR imaging can show early progressive ossification of the cartilaginous skull base and its relation to intracranial structures. The study of fetal developmental anatomy may lead to a better understanding of abnormalities of the skull base.
PMID 11039353

==Historic==

===1937===

The Development of the Vertebrate Skull. G. R. de Beer, M.A., D.Sc., F.L.S. 552 pp., illust., $9.50. McAinsh, Toronto, 1937.

Anyone who has ever attempted even in a general way to compare the skull of man with that of lower mammals or reptiles and to determine the morphology of the different parts will realize the thorny and difficult field into which this book ventures. And it enters this field in no casual way but to a depth of 515 closely printed pages with abundant simple and clear illustrations. ,

The book is divided into three parts. The first deals with some general questions of the nature of cartilage and bone and goes on to review Goethe’s theory that the skull is made up of several fused vertebre. This theory of course has not stood the test of time but out of it arose the recognition of the segmental structure of the posterior end of. the skull.

Talk:Musculoskeletal System - Skull Development

2024-05-23T10:37:52Z

Z8600021:

{{Talk Page}}

==2024==
{{#pmid:38619396}}

Piezo1 and Piezo2 are recently reported mechanosensory ion channels that transduce mechanical stimuli from the environment into intracellular biochemical signals in various tissues and organ systems. Here, we show that Piezo1 and Piezo2 display a robust expression during jawbone development. Deletion of Piezo1 in neural crest cells causes jawbone malformations in a small but significant number of mice. We further demonstrate that disruption of Piezo1 and Piezo2 in neural crest cells causes more striking defects in jawbone development than any single knockout, suggesting essential but partially redundant roles of Piezo1 and Piezo2. In addition, we observe defects in other neural crest derivatives such as malformation of the vascular smooth muscle in double knockout mice. Moreover, TUNEL examinations reveal excessive cell death in osteogenic cells of the maxillary and mandibular arches of the double knockout mice, suggesting that Piezo1 and Piezo2 together regulate cell survival during jawbone development. We further demonstrate that Yoda1, a Piezo1 agonist, promotes mineralization in the mandibular arches. Altogether, these data firmly establish that Piezo channels play important roles in regulating jawbone formation and maintenance.

==2022==

{{#pmid:35220463}}

Calvarial bone is one of the most complex sequences of developmental events in embryology, featuring a uniquely transient, pluripotent stem cell-like population known as the cranial neural crest (CNC). The skull is formed through intramembranous ossification with distinct tissue lineages (e.g. neural crest derived frontal bone and mesoderm derived parietal bone). Due to CNC's vast cell fate potential, in response to a series of inductive secreted cues including BMP/TGF-β, Wnt, FGF, Notch, Hedgehog, Hippo and PDGF signaling, CNC enables generations of a diverse spectrum of differentiated cell types in vivo such as osteoblasts and chondrocytes at the craniofacial level. In recent years, since the studies from a genetic mouse model and single-cell sequencing, new discoveries are uncovered upon CNC patterning, differentiation, and the contribution to the development of cranial bones. In this review, we summarized the differences upon the potential gene regulatory network to regulate CNC derived osteogenic potential in mouse and human, and highlighted specific functions of genetic molecules from multiple signaling pathways and the crosstalk, transcription factors and epigenetic factors in orchestrating CNC commitment and differentiation into osteogenic mesenchyme and bone formation. Disorders in gene regulatory network in CNC patterning indicate highly close relevance to clinical birth defects and diseases, providing valuable transgenic mouse models for subsequent discoveries in delineating the underlying molecular mechanisms. We also emphasized the potential regenerative alternative through scientific discoveries from CNC patterning and genetic molecules in interfering with or alleviating clinical disorders or diseases, which will be beneficial for the molecular targets to be integrated for novel therapeutic strategies in the clinic.

==2021==

Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw

Jeffry Cesario 1 , Sara Ha 1 , Julie Kim 1 , Niam Kataria 1 , Juhee Jeong 2
Affiliations expand
PMID: 34861428 DOI: 10.1016/j.gep.2021.119227
Abstract

Craniofacial development is controlled by a large number of genes, which interact with one another to form a complex gene regulatory network (GRN). Key components of GRN are signaling molecules and transcription factors. Therefore, identifying targets of core transcription factors is an important part of the overall efforts toward building a comprehensive and accurate model of GRN. LHX6 and LHX8 are transcription factors expressed in the oral mesenchyme of the first pharyngeal arch (PA1), and they are crucial regulators of palate and tooth development. Previously, we performed genome-wide transcriptional profiling and chromatin immunoprecipitation to identify target genes of LHX6 and LHX8 in PA1, and described a set of genes repressed by LHX. However, there has not been any discussion of the genes positively regulated by LHX6 and LHX8. In this paper, we revisited the above datasets to identify candidate positive targets of LHX in PA1. Focusing on those with known connections to craniofacial development, we performed RNA in situ hybridization to confirm the changes in expression in Lhx6;Lhx8 mutant. We also confirmed the binding of LHX6 to several putative enhancers near the candidate target genes. Together, we have uncovered novel connections between Lhx and other important regulators of craniofacial development, including Eya1, Barx1, Rspo2, Rspo3, and Wnt11.

Association between the developing sphenoid and adult morphology: A study using sagittal sections of the skull base from human embryos and fetuses

Masahito Yamamoto 1 , Zhe-Wu Jin 2 , Shogo Hayashi 3 , José Francisco Rodríguez-Vázquez 4 , Gen Murakami 5 , Shinichi Abe 1
Affiliations expand
PMID: 34268732 PMCID: PMC8602018 (available on 2023-12-01) DOI: 10.1111/joa.13515
Abstract

The developing sphenoid is regarded as a median cartilage mass (basisphenoid [BS]) with three cartilaginous processes (orbitosphenoid [OS], ala temporalis [AT], and alar process [AP]). The relationships of this initial configuration with the adult morphology are difficult to determine because of extensive membranous ossification along the cartilaginous elements. The purpose of this study was therefore to evaluate the anatomical connections between each element of the fetal sphenoid and adult morphology. Sagittal sections from 25 embryos and fetuses of gestational age 6-34 weeks and crown-rump length 12-295 mm were therefore examined and compared with horizontal and frontal sections from the other 25 late-term fetuses (217-340 mm). The OS was identified as a set of three mutually attached cartilage bars in early fetuses. At all stages, the OS-post was continuous with the anterolateral part of the BS. The BS included the notochord and Rathke's pouch remnant in embryos and early fetuses. The dorsum sellae was absent from embryos, but it protruded from the BS in early fetuses before a fossa for the hypophysis became evident. Although not higher than the hypophysis at midterm, the dorsum sellae elongated superiorly after gestational age 25 weeks. In early fetuses, the AP was located on the side immediately anterior to the otic capsule. The AT developed on the side immediately posterior to the extraocular rectus muscles. At late term, the greater wing was formed by membranous bones from the AT and AP. The AT and AP formed a complex bridge between the BS and the greater wing. A small cartilage, future medial pterygoid process (PTmed) was located inferior to the AT in early fetuses. At midterm, one endochondral bone and multiple membranous bones formed the PTmed. The lateral pterygoid process (PTlat) was formed by a single membranous bone plate. Therefore, we connected fetal elements and the adult morphology as follows. (1) Derivative of the OS makes not only the lesser wing but also the anterior margin of the body of the sphenoid. (2) Derivatives of the BS are the body of the sphenoid including the sella turcica and the dorsum sellae. (3) Most of the greater wing including the foramen rotundum and the foramen oval originate from the AT and AP and multiple membranous bones. (4) The PTmed originate from endochondral bones and multiple membranous bones, while the PTlat derive from a single membranous bone.

==2018==
===Johns Hopkins Fetal Skull Collection (1918–1951)===

{{Johns Hopkins Fetal Skull Collection table}}

==2017==

Childs Nerv Syst. 2017 Jun;33(6):909-914. doi: 10.1007/s00381-017-3406-1. Epub 2017 Apr 10.
A comprehensive review of the anterior fontanelle: embryology, anatomy, and clinical considerations.
D'Antoni AV1, Donaldson OI1, Schmidt C2, Macchi V3, De Caro R3, Oskouian RJ4, Loukas M5, Shane Tubbs R6.
Author information
Abstract
PURPOSE:
Fontanelles are a regular feature of infant development in which two segments of bone remain separated, leaving an area of fibrous membrane or a "soft spot" that acts to accommodate growth of the brain without compression by the skull. Of the six fontanelles in the human skull, the anterior fontanelle, located between the frontal and parietal bones, serves as an important anatomical diagnostic tool in the assessment of impairments of the skull and brain and allows access to the brain and ventricles in the infant.
METHODS:
Using a standard database search, we conducted a review of the anterior fontanelle, including its embryology, anatomy, pathology, and related surgical implications.
CONCLUSIONS:
The diagnostic value of the anterior fontanelle, through observation of its shape, size, and palpability, makes the area of significant clinical value. It is important that clinicians are aware of the features and associated pathologies of this area in their everyday practice.
KEYWORDS:
Cranial calvaria; Skull; Soft spot; Suture
PMID: 28396968 DOI: 10.1007/s00381-017-3406-1

==2016==

===The remodeling pattern of human mandibular alveolar bone during prenatal formation from 19 to 270mm CRL===
Ann Anat. 2016 Feb 24;205:65-74. doi: 10.1016/j.aanat.2016.01.005. [Epub ahead of print]

Radlanski RJ1, Renz H2, Tsengelsaikhan N2, Schuster F2, Zimmermann CA2.

Abstract

The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia.
Copyright © 2016 Elsevier GmbH. All rights reserved.
KEYWORDS:
3D-reconstructions; Alveolar bone; Dental primordia; Human; Mandible

PMID 26921449

==2015==

===Transcriptional analysis of human cranial compartments with different embryonic origins===
Arch Oral Biol. 2015 Sep;60(9):1450-60. doi: 10.1016/j.archoralbio.2015.06.008. Epub 2015 Jul 2.

Homayounfar N1, Park SS2, Afsharinejad Z3, Bammler TK3, MacDonald JW3, Farin FM3, Mecham BH4, Cunningham ML5.

Abstract

OBJECTIVE:
Previous investigations suggest that the embryonic origins of the calvarial tissues (neural crest or mesoderm) may account for the molecular mechanisms underlying sutural development. The aim of this study was to evaluate the differences in the gene expression of human cranial tissues and assess the presence of an expression signature reflecting their embryonic origins.
METHODS:
Using microarray technology, we investigated global gene expression of cells from the frontal and parietal bones and the metopic and sagittal intrasutural mesenchyme (ISM) of four human foetal calvaria. qRT-PCR of a selected group of genes was done to validate the microarray analysis. Paired comparison and correlation analyses were performed on microarray results.
RESULTS:
Of six paired comparisons, frontal and parietal compartments (distinct tissue types of calvaria, either bone or intrasutural mesenchyme) had the most different gene expression profiles despite being composed of the same tissue type (bone). Correlation analysis revealed two distinct gene expression profiles that separate frontal and metopic compartments from parietal and sagittal compartments. TFAP2A, TFAP2B, ICAM1, SULF1, TNC and FOXF2 were among differentially expressed genes.
CONCLUSION:
Transcriptional profiles of two groups of tissues, frontal and metopic compartments vs. parietal and sagittal compartments, suggest differences in proliferation, differentiation and extracellular matrix production. Our data suggest that in the second trimester of human foetal development, a gene expression signature of neural crest origin still exists in frontal and metopic compartments while gene expression of parietal and sagittal compartments is more similar to mesoderm.
Copyright © 2015 Elsevier Ltd. All rights reserved.
KEYWORDS:
Cranial suture; Differentiation; Extracellular matrix; Mesoderm; Neural crest; Proliferation
PMID 26188427

==2014==

===Direct Brain Recordings Reveal Impaired Neural Function in Infants With Single-Suture Craniosynostosis: A Future Modality for Guiding Management?===
J Craniofac Surg. 2014 Dec 19. [Epub ahead of print]

Hashim PW1, Brooks ED, Persing JA, Reuman H, Naples A, Travieso R, Terner J, Steinbacher D, Landi N, Mayes L, McPartland JC.

Abstract

BACKGROUND:
Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population.
METHODS:
Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing.
RESULTS:
Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls.
CONCLUSIONS:
Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.

PMID 25534054

==2012==

===Paleontological and developmental evidence resolve the homology and dual embryonic origin of a mammalian skull bone, the interparietal===

Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14075-80. doi: 10.1073/pnas.1208693109. Epub 2012 Aug 13.

Koyabu D, Maier W, Sánchez-Villagra MR.
Source
Palaeontological Institute and Museum, University of Zürich, 8006 Zürich, Switzerland. daisuke.koyabu@pim.uzh.ch

Abstract

The homologies of mammalian skull elements are now fairly well established, except for the controversial interparietal bone. A previous experimental study reported an intriguing mixed origin of the interparietal: the medial portion being derived from the neural crest cells, whereas the lateral portion from the mesoderm. The evolutionary history of such mixed origin remains unresolved, and contradictory reports on the presence or absence and developmental patterns of the interparietal among mammals have complicated the question of its homology. Here we provide an alternative perspective on the evolutionary identity of the interparietal, based on a comprehensive study across more than 300 extinct and extant taxa, integrating embryological and paleontological data. Although the interparietal has been regarded as being lost in various lineages, our investigation on embryos demonstrates its presence in all extant mammalian "orders." The generally accepted paradigm has regarded the interparietal as consisting of two elements that are homologized to the postparietals of basal amniotes. The tabular bones have been postulated as being lost during the rise of modern mammals. However, our results demonstrate that the interparietal consists not of two but of four elements. We propose that the tabulars of basal amniotes are conserved as the lateral interparietal elements, which quickly fuse to the medial elements at the embryonic stage, and that the postparietals are homologous to the medial elements. Hence, the dual developmental origin of the mammalian interparietal can be explained as the evolutionary consequence of the fusion between the crest-derived "postparietals" and the mesoderm-derived "tabulars."

PMID 22891324

===The BMP Ligand Gdf6 Prevents Differentiation of Coronal Suture Mesenchyme in Early Cranial Development===

PLoS One. 2012;7(5):e36789. Epub 2012 May 31.

Clendenning DE, Mortlock DP.
Source
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

Abstract

Growth Differentiation Factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules. Previous studies have shown that Gdf6 plays a role in formation of a diverse subset of skeletal joints. In mice, loss of Gdf6 results in fusion of the coronal suture, the intramembranous joint that separates the frontal and parietal bones. Although the role of GDFs in the development of cartilaginous limb joints has been studied, limb joints are developmentally quite distinct from cranial sutures and how Gdf6 controls suture formation has remained unclear. In this study we show that coronal suture fusion in the Gdf6-/- mouse is due to accelerated differentiation of suture mesenchyme, prior to the onset of calvarial ossification. Gdf6 is expressed in the mouse frontal bone primordia from embryonic day (E) 10.5 through 12.5. In the Gdf6-/- embryo, the coronal suture fuses prematurely and concurrently with the initiation of osteogenesis in the cranial bones. Alkaline phosphatase (ALP) activity and Runx2 expression assays both showed that the suture width is reduced in Gdf6+/- embryos and is completely absent in Gdf6-/- embryos by E12.5. ALP activity is also increased in the suture mesenchyme of Gdf6+/- embryos compared to wild-type. This suggests Gdf6 delays differentiation of the mesenchyme occupying the suture, prior to the onset of ossification. Therefore, although BMPs are known to promote bone formation, Gdf6 plays an inhibitory role to prevent the osteogenic differentiation of the coronal suture mesenchyme.

PMID 22693558

===The human calvaria: a review of embryology, anatomy, pathology, and molecular development===
Childs Nerv Syst. 2012 Jan;28(1):23-31. Epub 2011 Nov 27.

Tubbs RS, Bosmia AN, Cohen-Gadol AA.
Source
Department of Neurosurgery, Children's Hospital, Ambulatory Care Center, 1600 7th Avenue South, Birmingham, AL 35294, USA. shane.tubbs@chsys.org

Abstract

INTRODUCTION:
The human skull is a complex structure that deserves continued study. Few studies have directed their attention to the development, pathology, and molecular formation of the human calvaria.
MATERIALS AND METHODS:
A review of the medical literature using standard search engines was performed to locate studies regarding the human calvaria.
RESULTS:
The formation of the human calvaria is a complex interaction between bony and meningeal elements. Derailment of these interactions may result in deformation of this part of the skull.
CONCLUSIONS:
Knowledge of the anatomy, formation, and pathology of the human calvaria will be of use to the clinician that treats skull diseases. With an increased understanding of genetic and molecular biology, treatment paradigms for calvarial issues may change.

PMID 22120469

===Principles of cranial base ossification in humans and rats===
Acta Otolaryngol. 2012 Apr;132(4):349-54. doi: 10.3109/00016489.2011.642814. Epub 2011 Dec 27.

Santaolalla-Montoya F, Martinez-Ibargüen A, Sánchez-Fernández JM, Sánchez-del-Rey A.
Source
Otorhinolaryngology Department, School of Medicine, University of the Basque Country, Spain. Francisco.santaolalla@ehu.es
Abstract
CONCLUSIONS:
1. The principle of bilateral symmetry depends on the chordal cartilage that is the keystone in cranial base ossification in rats and humans, due to its anatomical situation and for the production of the chordin protein that regulates the bone morphogenetic protein BMP-7. 2. In humans and in rats, foramen lacerum closure follows a line of intramembranous ossification that depends on BMP-7, regulated by the first branchial pouch. 3. The cranial base ossification patterns and centres are similar in humans and in rats, except in the otic capsule, palate and the lateral pterygoid plate. 4. The neural crest may induce cranial ossification through the cranial nerves.
OBJECTIVES:
To study the patterns of cranial base ossification in humans and in rats, considering the chordal cartilage, and the otic, nasal and orbit capsules, as well as the participation of the branchial arches and pouches.
METHODS:
This was a light microscopy study of human fetal specimens obtained from spontaneous abortions with the following crown-rump-lengths (crl) 45, 74, 90, 134, 145 and 270 mm, and a 1-day-old neonate (360 mm crl), who had died of sudden death syndrome. We also examined Webster albino rat embryos of 16, 18 and 20 days of gestation and a postnatal series of rats 8 h and 1, 3, 4, 6, 7, 10 and 13 days old, as well as adult animals.
RESULTS:
In the 45 mm human fetus, the chordal cartilage with the nasal, otic and orbit capsules initiates cranial base ossification. Foramen lacerum closure begins in the 16-day-old rat embryo, following a line of membranous ossification between the external pterygoid process and the lateral alisphenoidal wing at ovalis foramen level. This is not a timing symmetrical process, which may persist until the 10th postnatal day in the rat. In the human fetus of 74 mm, the foramen lacerum space is closed by a membranous fusion ossification between the chordal cartilage and otic capsule, finishing at the 270 mm specimen. Endochondral ossification of the human otic capsule first appeared in the 145 mm (18 weeks) fetal specimen with four ossifying centres. The rat otic cartilaginous capsule showed rapid endochondral ossification, in the third and fourth postnatal day specimens.

PMID 22201370

http://informahealthcare.com/doi/abs/10.3109/00016489.2011.642814

==2011==

===Morphological and morphometric study on sphenoid and basioccipital ossification in normal human fetuses===

Congenit Anom (Kyoto). 2011 Sep;51(3):138-48. doi: 10.1111/j.1741-4520.2011.00322.x.

Zhang Q, Wang H, Udagawa J, Otani H.
Source
Department of Developmental Biology, Shimane University, Izumo, Japan.

Abstract

Congenital anomalies of the brain frequently correspond to cranial base anomalies, and a detailed description of morphology and individual variations in the developing cranial base is of clinical importance for diagnosing anomalies. Development of the human cranial base has been studied using dissection, computed tomography, and magnetic resonance imaging, each of which has advantages and disadvantages. We here examined development of the normal human fetal cranial base using bone staining, which allows for direct observation of the ossification centers and precise three-dimensional measurements. We observed alizarin red S-stained sphenoids and basiocciputs of 22 normal formalin-fixed human fetuses with crown-rump lengths (CRL) of 115-175 mm. We defined landmarks and measured sphenoids and basiocciputs using a fine caliper. Growth patterns of these ossifying bones were obtained, and we found similarities and differences among the growth patterns. We also observed individual variations in the ossification patterns, in particular, single- or double-ossification center patterns for the basisphenoid. The orbitosphenoid and basisphenoid widths and ratios of the widths to the total cranial base width were significantly different between the two pattern groups, whereas the other measurements and their ratios to the total cranial base did not differ between the groups. We measured the cerebrum and pons in different sets of 22 human fetuses with CRLs of 105-186 mm and found close relationships with the development of corresponding parts of the cranial base. The results contribute to the quantitative and qualitative information about the growth patterns and variations during human fetal cranial base development.
© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.

PMID 21848997

http://onlinelibrary.wiley.com/doi/10.1111/j.1741-4520.2011.00322.x/abstract;jsessionid=D215C1671CDF1C62716033D0D5E688F1.d04t04

===Modeling of the human fetal skull base growth: interest in new volumetrics morphometric tools===

Early Hum Dev. 2011 Apr;87(4):239-45. doi: 10.1016/j.earlhumdev.2011.01.022.

Herlin C, Largey A, deMatteï C, Daurès JP, Bigorre M, Captier G.
Source
Craniofacial and Plastic Pediatric Surgery Unit, Lapeyronie Hospital, Montpellier, 371 Av Doyen Gaston Giraud, 34 295 Montpellier, France. christian.herl@free.fr
Abstract
BACKGROUND:
Research on the skull base is important to improve our understanding of the growth and development of the modern human skull. To study the growth of the human fetal skull base, we assessed a new geometric morphometric tool, which does not require the use of bone landmarks.
MATERIAL AND METHODS:
Seven dry fetal skulls of an estimated gestational age ranging from 15 to 27 weeks were studied. Each skull was scanned using a standard CT scan and the image sets were post-processed to extract volumetric data by segmenting the skull base into predefined regions of interest. Our method of analysis was based on the inertial properties of reconstructed volumes.
RESULTS:
The volumetric study of the skulls highlighted an asynchronous speed of growth between the pre and post-chordal parts of the skull base whose preferential growth are in the vertical and horizontal planes. We also found different speeds of growth in the pre-chordal part depending on the type of ossification (endochondral or membranous). The overall shape of the skull base bones were preserved during the period studied except for the petrous pyramids. The expansion of bone parts was isometric with reference to a central point that was located at the intrasphenoidal synchondrosis. Finally, the analysis of the basicranial angles corroborated data from the literature in the sagittal plane and allowed their study also in the frontal and horizontal planes.
CONCLUSIONS:
This three-dimensional volumetric approach is a necessary complement to studies that are performed in the sagittal plane and are based on the identification of landmarks. The geometric morphometric method used by authors permitted to obtain original informations on the growth kinetics and bone tridimensional movements of the human fetal skull base.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID 21300487

==2010==

===Design and construction of a brain phantom to simulate neonatal MR images===
Comput Med Imaging Graph. 2010 Dec 10. [Epub ahead of print]

Kazemi K, Moghaddam HA, Grebe R, Gondry-Jouet C, Wallois F.

Department of Electrical and Electronics Engineering, Shiraz University of Technology, Shiraz, Iran; GRAMFC EA 4293, Faculty of Medicine, University of Picardie Jules Verne, 80036 Amiens, France.
Abstract
This paper presents the design and construction of a 3D digital neonatal neurocranial phantom and its application for the simulation of brain magnetic resonance (MR) images. Commonly used digital brain phantoms (e.g. BrainWeb) are based on the adult brain. With the growing interest in computer-aided methods for neonatal MR image processing, there is a growing demand a digital phantom and brain MR image simulator especially for the neonatal brains. This is due to the pronounced differences between adult and neonatal brains not only in terms of size but also, more importantly, in terms of geometrical proportions and the need to subdivide white matter into two different tissue types in neonates. Therefore the neonatal brain phantom created in the here presented work consists of 9 different tissue types: skin, fat, muscle, skull, dura mater, gray matter, myelinated white matter, nonmyelinated white matter and cerebrospinal fluid. Each voxel has a vector consisting of 9 components, one for each of these nine tissue types. This digital phantom can be used to map simulated magnetic resonance signal intensities resulting in simulated MR images of the newborns head. These images with controlled degradation of the image data present a representative, reproducible data set ideal for development and evaluation of neonatal MRI analysis methods, e.g. segmentation and registration algorithms.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21146956

===Fibroblast growth factor receptor signaling crosstalk in skeletogenesis===
Sci Signal. 2010 Nov 2;3(146):re9.

Miraoui H, Marie PJ.

Laboratory of Osteoblast Biology and Pathology, INSERM UMR606 and University Paris Diderot, Paris 75475, Cedex 10, France.
Abstract
Fibroblast growth factors (FGFs) play important roles in the control of embryonic and postnatal skeletal development by activating signaling through FGF receptors (FGFRs). Germline gain-of-function mutations in FGFR constitutively activate FGFR signaling, causing chondrocyte and osteoblast dysfunctions that result in skeletal dysplasias. Crosstalk between the FGFR pathway and other signaling cascades controls skeletal precursor cell differentiation. Genetic analyses revealed that the interplay of WNT and FGFR1 determines the fate and differentiation of mesenchymal stem cells during mouse craniofacial skeletogenesis. Additionally, interactions between FGFR signaling and other receptor tyrosine kinase networks, such as those mediated by the epidermal growth factor receptor and platelet-derived growth factor receptor α, were associated with excessive osteoblast differentiation and bone formation in the human skeletal dysplasia called craniosynostosis, which is a disorder of skull development. We review the roles of FGFR signaling and its crosstalk with other pathways in controlling skeletal cell fate and discuss how this crosstalk could be pharmacologically targeted to correct the abnormal cell phenotype in skeletal dysplasias caused by aberrant FGFR signaling.

PMID 21045207
The BMP antagonist noggin regulates cranial suture fusion STEPHEN M. WARREN, LISA J. BRUNET, RICHARD M. HARLAND, ARIS N.,ECONOMIDES & MICHAEL T. LONGAKER

"During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors ( fgfr ) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo , we suggest that syndromic fgfr -mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression."

==2009==

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Part -1===
J Pediatr Neurosci. 2009 Jul;4(2):86-99. doi: 10.4103/1817-1745.57327.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis is a disease characterized by untimely fusion of cranial sutures resulting in a variety of craniofacial deformities and neurological sequelae due to alteration in cranial volume and restriction of brain growth. This involves vault sutures predominantly, but cranial base is not immune. Association with a variety of syndromes makes the management decision complex. These children need careful evaluation by multiple specialists to have strategic treatment options. Parental counseling is an important and integral part of the treatment. Recent advancements in the surgical techniques and concept of team approach have significantly enhanced the safety and outcome of these children. We had an opportunity of treating 57 children with craniostenosis in the last 15 years at our craniofacial service. Out of them, 40 were nonsyndromic and 17 were syndromic variety. We describe our successful results along with individualized operative technical modifications adopted based on the current understanding of the disease.

PMID 21887189

===Pediatric craniofacial surgery for craniosynostosis: Our experience and current concepts: Parts -2===
J Pediatr Neurosci. 2009 Jul;4(2):100-7. doi: 10.4103/1817-1745.57328.

Anantheswar YN, Venkataramana NK.
Source
Department of Plastic Surgery, Manipal Hospital, Kengeri, Bangalore, India.

Abstract

Craniostenosis associated with other syndromes poses several clinical and management challenges. Involvement of cranial, facial, and systemic defects with an underlying genetic abnormality needs comprehensive understanding, to plan appropriate and safe treatment modalities. Often, these children require staging involving several/multiple surgical procedures. Unsuccessful outcomes and retrusion of the deformities are common in comparison to the nonsyndromic variety. We present our experience in treating 17 children with syndromic craniostenosis with successful outcomes and minimal morbidity. We also describe the principles behind the staging. Technology adoption has improved the results as well as reduced the complications to an acceptable minimum.

PMID 21887190
==2008==

===Development and tissue origins of the mammalian cranial base===

Dev Biol. 2008 Oct 1;322(1):121-32. doi: 10.1016/j.ydbio.2008.07.016. Epub 2008 Jul 22.

McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay GM.
Source
Harvard School of Dental Medicine, Department of Developmental Biology, 190 Longwood Avenue, Boston, MA, 02115, USA. bmcbratneyowen@post.harvard.edu
Abstract
The vertebrate cranial base is a complex structure composed of bone, cartilage and other connective tissues underlying the brain; it is intimately connected with development of the face and cranial vault. Despite its central importance in craniofacial development, morphogenesis and tissue origins of the cranial base have not been studied in detail in the mouse, an important model organism. We describe here the location and time of appearance of the cartilages of the chondrocranium. We also examine the tissue origins of the mouse cranial base using a neural crest cell lineage cell marker, Wnt1-Cre/R26R, and a mesoderm lineage cell marker, Mesp1-Cre/R26R. The chondrocranium develops between E11 and E16 in the mouse, beginning with development of the caudal (occipital) chondrocranium, followed by chondrogenesis rostrally to form the nasal capsule, and finally fusion of these two parts via the midline central stem and the lateral struts of the vault cartilages. X-Gal staining of transgenic mice from E8.0 to 10 days post-natal showed that neural crest cells contribute to all of the cartilages that form the ethmoid, presphenoid, and basisphenoid bones with the exception of the hypochiasmatic cartilages. The basioccipital bone and non-squamous parts of the temporal bones are mesoderm derived. Therefore the prechordal head is mostly composed of neural crest-derived tissues, as predicted by the New Head Hypothesis. However, the anterior location of the mesoderm-derived hypochiasmatic cartilages, which are closely linked with the extra-ocular muscles, suggests that some tissues associated with the visual apparatus may have evolved independently of the rest of the "New Head".

PMID 18680740

===Three-dimensional ontogenetic shape changes in the human cranium during the fetal period===

J Anat. 2008 May;212(5):627-35. doi: 10.1111/j.1469-7580.2008.00884.x.

Morimoto N, Ogihara N, Katayama K, Shiota K.
Source
Laboratory of Physical Anthropology, Graduate School of Science, Kyoto University, Japan. morimoto@aim.uzh.ch <morimoto@aim.uzh.ch>
Abstract
Knowledge of the pattern of human craniofacial development in the fetal period is important for understanding the mechanisms underlying the emergence of variations in human craniofacial morphology. However, the precise character of the prenatal ontogenetic development of the human cranium has yet to be fully established. This study investigates ontogenetic changes in cranial shape in the fetal period, as exhibited in Japanese fetal specimens housed at Kyoto University. A total of 31 human fetal specimens aged from approximately 8 to 42 weeks of gestation underwent helical computed tomographic scanning, and 68 landmarks were digitized on the internal and external surfaces of the extracted crania. Ontogenetic shape change was then analyzed cross-sectionally and three-dimensionally using a geometric morphometric technique. The results of the present study are generally consistent with previously reported findings. It was found that during the prenatal ontogenetic process, the growth rate of the length of the cranium is greater than that of the width and height, and the growth rate of the length of the posterior cranial base is smaller than that of the anterior cranial base. Furthermore, it was observed that the change in shape of the human viscerocranium is smaller than that of the neurocranium during the fetal period, and that concurrently the basicranium extends by approximately 8 degrees due to the relative elevation of the basilar and lateral parts of occipital bone. These specific growth-related changes are the opposite of those reported for the postnatal period. Our findings therefore indicate that the allometric pattern of the human cranium is not a simple continuous transformation, but changes drastically from before to after birth.

PMID 18430090

==2000==

===MR, CT, and plain film imaging of the developing skull base in fetal specimens===

AJNR Am J Neuroradiol. 2000 Oct;21(9):1699-706.

Nemzek WR, Brodie HA, Hecht ST, Chong BW, Babcook CJ, Seibert JA.
Source
Department of Radiology, University of California, Davis Medical Center, Sacramento 95817, USA.
Abstract
BACKGROUND AND PURPOSE:
The developing fetal skull base has previously been studied via dissection and low-resolution CT. Most of the central skull base develops from endochondral ossification through an intermediary chondrocranium. We traced the development of the normal fetal skull base by using plain radiography, MR imaging, and CT.
METHODS:
Twenty-nine formalin-fixed fetal specimens ranging from 9 to 24 weeks' gestational age were examined with mammographic plain radiography, CT, and MR imaging. Skull base development and ossification were assessed.
RESULTS:
The postsphenoid cartilages enclose the pituitary and fuse to form the basisphenoid, from which the sella turcica and the posterior body of the sphenoid bone originate. The presphenoid cartilages will form the anterior body of the sphenoid bone. Portions of the presphenoid cartilage give rise to the mesethmoid cartilage, which forms the central portion of the anterior skull base. Ossification begins in the occipital bone (12 weeks) and progresses anteriorly. The postsphenoid (14 weeks) and then the presphenoid portion (17 weeks) of the sphenoid bone ossify. Ossification is seen laterally (16 weeks) in the orbitosphenoid, which contributes to the lesser wing of the sphenoid, and the alisphenoid (15 weeks), which forms the greater wing.
CONCLUSION:
MR imaging can show early progressive ossification of the cartilaginous skull base and its relation to intracranial structures. The study of fetal developmental anatomy may lead to a better understanding of abnormalities of the skull base.
PMID 11039353

==Historic==

===1937===

The Development of the Vertebrate Skull. G. R. de Beer, M.A., D.Sc., F.L.S. 552 pp., illust., $9.50. McAinsh, Toronto, 1937.

Anyone who has ever attempted even in a general way to compare the skull of man with that of lower mammals or reptiles and to determine the morphology of the different parts will realize the thorny and difficult field into which this book ventures. And it enters this field in no casual way but to a depth of 515 closely printed pages with abundant simple and clear illustrations. ,

The book is divided into three parts. The first deals with some general questions of the nature of cartilage and bone and goes on to review Goethe’s theory that the skull is made up of several fused vertebre. This theory of course has not stood the test of time but out of it arose the recognition of the segmental structure of the posterior end of. the skull.

ANAT3411 Neuroanatomy

2024-02-09T02:55:26Z

Z8600021:

==Introduction==

The aim of this course is to provide students in the BSc and BMedSc programs with a basic understanding of the structural organisation of the human central nervous system in sufficient depth to form the basis for further clinical or research studies of the nervous system.

The following images are prepared for a Neurodevelopment class from UNSW Embryology. The listed cross-sections are recommended to be viewed in the order in which they are shown below. A direct link [[ANAT3411 Neuroanatomy|ANAT3411]] to this current page appears on the lefthand menu of every embryology page.

* '''Begin''' with a simplified introduction by looking through [[K12 Brain Awareness Week|Brain Awareness Week]].
* '''Then''' return to this page for the remainder of the class.

{| class="wikitable mw-collapsible mw-collapsed"
! UNSW Embryology Textbooks  
|-
| UNSW Students have online access to the these embryology textbook chapters through UNSW Library subscription (with student Zpass log-in).
|-
| [[File:The Developing Human, 10th edn.jpg|thumb|left|90px]]
'''APA Citation:''' {{MPT2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074364&pg=500 Nervous System]
|-
| [[File:Larsen's human embryology 5th ed.jpg|thumb|left|90px]]

'''APA Citation:''' {{SBBF2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=215 Development of the Central Nervous System]
* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=252 Development of the Peripheral Nervous System]

|}

==Embryo Images Links==

[https://web.archive.org/web/20050513205027/http://www.med.unc.edu/embryo_images/unit-bdyfm/bdyfm_htms/bdyfmtoc.htm Early Cell Populations and Establishment of Body Form]

[https://web.archive.org/web/20050320092125/http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nervtoc.htm Nervous System Development]

: Note the links above are external links to Archival Web resources.

==Stage 22 Spinal Cord==
Cross-section of the human embryonic spinal cord (end of week 8).

[[File:Human Stage22 spinal cord01.jpg|400px]] [[File:Human Stage22 spinal cord02.jpg|400px]]
===Virtual Slide===
{|
| rowspan=2|{{SlideStage22-33-rotate-spinalcord}}
| colspan="2"|These listed features link to zoomed views of the virtual slide with the named feature generally in the centre of the view.

Use the (-) at the top left of the screen to see where this feature is located.
|-
| valign=top|'''Spinal Cord Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-1384.5&lon=4177.5&layers=B roof plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2140.5&lon=3138.5&layers=B alar plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2438.5&lon=5322.5&layers=B alar plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3078.5&lon=4187.5&layers=B sulcus limitans]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3748.5&lon=3216.5&layers=B basal plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3924.5&lon=5278.5&layers=B basal plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4338&lon=4269.5&layers=B floor plate]
| valign=top|'''Other Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5255.5&lon=2431.5&layers=B dorsal root ganglion] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5431.5&lon=6042.5&layers=B dorsal root ganglion]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2688.5&lon=6571.5&layers=B dorsal root] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2252.5&lon=1886.5&layers=B dorsal root]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7718.50692&lon=1887.54152&layers=B spinal nerve] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7776.5&lon=6593.5&layers=B spinal nerve]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2924.5&lon=7408.5&layers=B dura mater]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4941.5&lon=4302.5&layers=B ventral spinal artery] (showing fetal nucleated red blood cell)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7338.69233&lon=4161.30767&layers=B notochord] (lying in the centre of the vertebral body)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=4&lat=-7235.19233&lon=4189.80767&layers=B vertebral body] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=5&lat=-4423&lon=951.35969&layers=B vertebral arch root] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-881.5&lon=3870.5&layers=B dorsal uniting ligament] (lying dorsal to the spinal cord and under the periderm)
|}
==Embryo Stage 13==

[[File:Stage13 bf2c.jpg|thumb|300px|link=Carnegie stage 13|[[Carnegie stage 13]] Week 4 (6 mm Embryo)]]
{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage 13 image 097.jpg|G6L]] Midline longitudinal
|
| [[File:Stage_13_image_048.jpg|120px]]
| [[File:Stage 13 image 097.jpg|120px]]
|-
| [[:File:Stage 13 image 098.jpg|G7L]] Lateral longitudinal
|
| [[File:Stage_13_image_049.jpg|120px]]
| [[File:Stage 13 image 098.jpg|120px]]
|-
| [[:File:Stage 13 image 052.jpg|A3L]] Rhombomeres and otic vesicle
| [[File:Stage 13 A3 plane.gif|link=File:Stage_13_image_003.jpg]]
| [[File:Stage_13_image_003.jpg|120px]]
| [[File:Stage 13 image 052.jpg|120px]]
|-
| [[:File:Stage 13 image 060.jpg|B4L]] Spinal cord and optic vesicle
| [[File:Stage 13 B4 plane.gif|link=File:Stage_13_image_011.jpg]]
| [[File:Stage_13_image_011.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
|-
| [[:File:Stage 13 image 061.jpg|B5L]] Spinal cord and diencephalon
| [[File:Stage 13 B5 plane.gif|link=File:Stage_13_image_012.jpg]]
| [[File:Stage_13_image_012.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
|}

{|
|-bgcolor="CEDFF2"
! colspan=2|Human Embryo (Stage 13)
|-
| [[File:Stage13 face ventral view01.jpg|200px]]
| [[File:Stage13_spinal_cord02.jpg|300px]]
|-
| Ventral view of upper half of embryo
| Early spinal cord regions
|-
| colspan=2|[[Carnegie stage 13]] occurs in week 4 to week 5, 28 - 32 days. The embryos have a crown rump length (CRL) of 4 - 6 mm and somite number 30 pairs. Scale bar 0.5 mm.
|}
==Embryo Stage 22==
[[File:Stage22_embryo_and_brain_01.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage_22 image 050.jpg|A1L]]
| [[File:Stage 22 A1 plane.gif|link=]]
| [[File:Stage_22_image_001.jpg|120px]]
| [[File:Stage_22 image 050.jpg|120px]]
|-
| [[:File:Stage_22 image 052.jpg|A3L]]
| [[File:Stage 22 A3 plane.gif|link=File:Stage_22_image_003.jpg]]
| [[File:Stage_22_image_003.jpg|120px]]
| [[File:Stage_22 image 052.jpg|120px]]
|-
| [[:File:Stage_22 image 053.jpg|A4L]]
| [[File:Stage 22 A4 plane.gif|link=File:Stage_22_image_004.jpg]]
| [[File:Stage_22_image_004.jpg|120px]]
| [[File:Stage_22 image 053.jpg|120px]]
|-
| [[:File:Stage_22 image 055.jpg|A6L]]
| [[File:Stage 22 A6 plane.gif|link=File:Stage_22_image_006.jpg]]
| [[File:Stage_22_image_006.jpg|120px]]
| [[File:Stage_22 image 055.jpg|120px]]
|-
| [[:File:Stage_22 image 057.jpg|B1L]]
| [[File:Stage 22 B1 plane.gif|link=File:Stage_22_image_008.jpg]]
| [[File:Stage_22_image_008.jpg|120px]]
| [[File:Stage_22 image 057.jpg|120px]]
|-
| [[:File:Stage_22 image 058.jpg|B2L]]
| [[File:Stage 22 B2 plane.gif|link=File:Stage_22_image_009.jpg]]
| [[File:Stage_22_image_009.jpg|120px]]
| [[File:Stage_22 image 058.jpg|120px]]
|-
| [[:File:Stage_22 image 059.jpg|B3L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_010.jpg]]
| [[File:Stage_22_image_010.jpg|120px]]
| [[File:Stage_22 image 059.jpg|120px]]
|-
| [[:File:Stage_22 image 060.jpg|B4L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_011.jpg]]
| [[File:Stage_22_image_011.jpg|120px]]
| [[File:Stage_22 image 060.jpg|120px]]
|-
| [[:File:Stage_22 image 061.jpg|B5L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_012.jpg]]
| [[File:Stage_22_image_012.jpg|120px]]
| [[File:Stage_22 image 061.jpg|120px]]
|-
| [[:File:Stage_22 image 062.jpg|B6L]]
| [[File:Stage 22 B6 plane.gif|link=File:Stage_22_image_013.jpg]]
| [[File:Stage_22_image_013.jpg|120px]]
| [[File:Stage_22 image 062.jpg|120px]]
|-
| [[:File:Stage_22 image 063.jpg|B7L]]
| [[File:Stage 22 B7 plane.gif|link=File:Stage_22_image_014.jpg]]
| [[File:Stage_22_image_014.jpg|120px]]
| [[File:Stage_22 image 063.jpg|120px]]
|-
| [[:File:Stage_22 image 064.jpg|C1L]]
| [[File:Stage 22 C1 plane.gif|link=File:Stage_22_image_015.jpg]]
| [[File:Stage_22_image_015.jpg|120px]]
| [[File:Stage_22 image 064.jpg|120px]]
|-
| [[:File:Stage_22 image 065.jpg|C2L]]
| [[File:Stage 22 C2 plane.gif|link=File:Stage_22_image_016.jpg]]
| [[File:Stage_22_image_016.jpg|120px]]
| [[File:Stage_22 image 065.jpg|120px]]
|-
| [[:File:Stage_22 image 066.jpg|C3L]]
| [[File:Stage 22 C3 plane.gif|link=File:Stage_22_image_017.jpg]]
| [[File:Stage_22_image_017.jpg|120px]]
| [[File:Stage_22 image 066.jpg|120px]]

|}

==Late Embryo Cortex==
[[File:Stage22 bf1c.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

[[File:Stage_22_image_217.jpg|600px]]

==Additional Information==
{{Med Prac additional Information}}

:'''Links:''' [[AE_Practical_-_Neural_Histology|Neural Histology]]

===Scanning Electron Microscopy===
{|
! Stage 10 - Neural Groove
|-
| [[File:Stage10_sem2.jpg|300px]]
| This is a dorsolateral view of the embryo. The amniotic sac has been removed to show the still open neural groove.

* '''Neural groove''' forming from neural plate on upper surface.
** large brain fold region to left of image.
** narrow spinal cord region to right of image.
* '''Heart bulge''' can be seen on lower ventral surface.
* '''Connecting stalk''' to the right of image.
* '''Amniotic membrane''' cut edge shown at edge of developing embryo.

|-
| [[File:Stage10_sem6.jpg|300px]]
| This is a dorsal view of the same embryo with the future head, and brain, now shown at the top of image.
|-
| [[File:Stage10_sem10.jpg|300px]]
| This is a lateral view of a later embryo showing the neural groove closing to form the neural tube.

Note the still open cranial (top) and caudal (bottom) neuropores. These are the last parts of the tube to close.
|}

{|
! Stage 11 - Cut through the neural tube
|-
| [[File:Stage11_sem11.jpg|300px]]
| This slightly older embryo has been broken in half close slightly away from the midline to show features of the neural tube.
* At the level of the hindbrain and spinal cord - (right of image) the floor, wall and roof of the neural tube can be seen. Notice also the rhombomere bulges at the level of the hindbrain.
* In the head region - (top of image) part of the lateral wall of the neural tube remains, at the level of midbrain. A segment of the forebrain has been removed to show the internal surface of this region.
|}

===Timeline Events===

[[File:Neural-development.jpg|600px]]

Simplified overview table showing broad events of neural development classified by proliferation, migration, differentiation and metabolism. Note the long time course of development and that it continues into the postnatal period.
===Neural Movies===
{|
| valign="bottom"|{{Neural stage 13 movie}}
| valign="bottom"|{{Neural stage 22 movie}}
| valign="bottom"|{{Neural plate movie}}
| valign="bottom"|{{Neural tube movie}}
| valign="bottom"|{{Neural Tube Closure 1 movie}}
| valign="bottom"|{{Sylvian fissure movie}}
| valign="bottom"|{{Adult brain movie}}
|}

{{Glossary}}

{{Footer}}

[[Category:Science-Undergraduate]][[Category:Neural]]

ANAT3411 Neuroanatomy

2024-02-09T02:53:14Z

Z8600021:

==Introduction==
Course convenor: Dr. Elizabeth Tancred

The aim of this course is to provide students in the BSc and BMedSc programs with a basic understanding of the structural organisation of the human central nervous system in sufficient depth to form the basis for further clinical or research studies of the nervous system.

The following images are prepared for Dr Tancred's Neurodevelopment class from UNSW Embryology. The listed cross-sections are recommended to be viewed in the order in which they are shown below. A direct link [[ANAT3411 Neuroanatomy|ANAT3411]] to this current page appears on the lefthand menu of every embryology page.

* '''Begin''' with a simplified introduction by looking through [[K12 Brain Awareness Week|Brain Awareness Week]].
* '''Then''' return to this page for the remainder of the class.

{| class="wikitable mw-collapsible mw-collapsed"
! UNSW Embryology Textbooks  
|-
| UNSW Students have online access to the these embryology textbook chapters through UNSW Library subscription (with student Zpass log-in).
|-
| [[File:The Developing Human, 10th edn.jpg|thumb|left|90px]]
'''APA Citation:''' {{MPT2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074364&pg=500 Nervous System]
|-
| [[File:Larsen's human embryology 5th ed.jpg|thumb|left|90px]]

'''APA Citation:''' {{SBBF2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=215 Development of the Central Nervous System]
* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=252 Development of the Peripheral Nervous System]

|}

==Embryo Images Links==

[https://web.archive.org/web/20050513205027/http://www.med.unc.edu/embryo_images/unit-bdyfm/bdyfm_htms/bdyfmtoc.htm Early Cell Populations and Establishment of Body Form]

[https://web.archive.org/web/20050320092125/http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nervtoc.htm Nervous System Development]

: Note the links above are external links to Archival Web resources.

==Stage 22 Spinal Cord==
Cross-section of the human embryonic spinal cord (end of week 8).

[[File:Human Stage22 spinal cord01.jpg|400px]] [[File:Human Stage22 spinal cord02.jpg|400px]]
===Virtual Slide===
{|
| rowspan=2|{{SlideStage22-33-rotate-spinalcord}}
| colspan="2"|These listed features link to zoomed views of the virtual slide with the named feature generally in the centre of the view.

Use the (-) at the top left of the screen to see where this feature is located.
|-
| valign=top|'''Spinal Cord Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-1384.5&lon=4177.5&layers=B roof plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2140.5&lon=3138.5&layers=B alar plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2438.5&lon=5322.5&layers=B alar plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3078.5&lon=4187.5&layers=B sulcus limitans]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3748.5&lon=3216.5&layers=B basal plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3924.5&lon=5278.5&layers=B basal plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4338&lon=4269.5&layers=B floor plate]
| valign=top|'''Other Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5255.5&lon=2431.5&layers=B dorsal root ganglion] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5431.5&lon=6042.5&layers=B dorsal root ganglion]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2688.5&lon=6571.5&layers=B dorsal root] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2252.5&lon=1886.5&layers=B dorsal root]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7718.50692&lon=1887.54152&layers=B spinal nerve] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7776.5&lon=6593.5&layers=B spinal nerve]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2924.5&lon=7408.5&layers=B dura mater]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4941.5&lon=4302.5&layers=B ventral spinal artery] (showing fetal nucleated red blood cell)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7338.69233&lon=4161.30767&layers=B notochord] (lying in the centre of the vertebral body)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=4&lat=-7235.19233&lon=4189.80767&layers=B vertebral body] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=5&lat=-4423&lon=951.35969&layers=B vertebral arch root] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-881.5&lon=3870.5&layers=B dorsal uniting ligament] (lying dorsal to the spinal cord and under the periderm)
|}
==Embryo Stage 13==

[[File:Stage13 bf2c.jpg|thumb|300px|link=Carnegie stage 13|[[Carnegie stage 13]] Week 4 (6 mm Embryo)]]
{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage 13 image 097.jpg|G6L]] Midline longitudinal
|
| [[File:Stage_13_image_048.jpg|120px]]
| [[File:Stage 13 image 097.jpg|120px]]
|-
| [[:File:Stage 13 image 098.jpg|G7L]] Lateral longitudinal
|
| [[File:Stage_13_image_049.jpg|120px]]
| [[File:Stage 13 image 098.jpg|120px]]
|-
| [[:File:Stage 13 image 052.jpg|A3L]] Rhombomeres and otic vesicle
| [[File:Stage 13 A3 plane.gif|link=File:Stage_13_image_003.jpg]]
| [[File:Stage_13_image_003.jpg|120px]]
| [[File:Stage 13 image 052.jpg|120px]]
|-
| [[:File:Stage 13 image 060.jpg|B4L]] Spinal cord and optic vesicle
| [[File:Stage 13 B4 plane.gif|link=File:Stage_13_image_011.jpg]]
| [[File:Stage_13_image_011.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
|-
| [[:File:Stage 13 image 061.jpg|B5L]] Spinal cord and diencephalon
| [[File:Stage 13 B5 plane.gif|link=File:Stage_13_image_012.jpg]]
| [[File:Stage_13_image_012.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
|}

{|
|-bgcolor="CEDFF2"
! colspan=2|Human Embryo (Stage 13)
|-
| [[File:Stage13 face ventral view01.jpg|200px]]
| [[File:Stage13_spinal_cord02.jpg|300px]]
|-
| Ventral view of upper half of embryo
| Early spinal cord regions
|-
| colspan=2|[[Carnegie stage 13]] occurs in week 4 to week 5, 28 - 32 days. The embryos have a crown rump length (CRL) of 4 - 6 mm and somite number 30 pairs. Scale bar 0.5 mm.
|}
==Embryo Stage 22==
[[File:Stage22_embryo_and_brain_01.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage_22 image 050.jpg|A1L]]
| [[File:Stage 22 A1 plane.gif|link=]]
| [[File:Stage_22_image_001.jpg|120px]]
| [[File:Stage_22 image 050.jpg|120px]]
|-
| [[:File:Stage_22 image 052.jpg|A3L]]
| [[File:Stage 22 A3 plane.gif|link=File:Stage_22_image_003.jpg]]
| [[File:Stage_22_image_003.jpg|120px]]
| [[File:Stage_22 image 052.jpg|120px]]
|-
| [[:File:Stage_22 image 053.jpg|A4L]]
| [[File:Stage 22 A4 plane.gif|link=File:Stage_22_image_004.jpg]]
| [[File:Stage_22_image_004.jpg|120px]]
| [[File:Stage_22 image 053.jpg|120px]]
|-
| [[:File:Stage_22 image 055.jpg|A6L]]
| [[File:Stage 22 A6 plane.gif|link=File:Stage_22_image_006.jpg]]
| [[File:Stage_22_image_006.jpg|120px]]
| [[File:Stage_22 image 055.jpg|120px]]
|-
| [[:File:Stage_22 image 057.jpg|B1L]]
| [[File:Stage 22 B1 plane.gif|link=File:Stage_22_image_008.jpg]]
| [[File:Stage_22_image_008.jpg|120px]]
| [[File:Stage_22 image 057.jpg|120px]]
|-
| [[:File:Stage_22 image 058.jpg|B2L]]
| [[File:Stage 22 B2 plane.gif|link=File:Stage_22_image_009.jpg]]
| [[File:Stage_22_image_009.jpg|120px]]
| [[File:Stage_22 image 058.jpg|120px]]
|-
| [[:File:Stage_22 image 059.jpg|B3L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_010.jpg]]
| [[File:Stage_22_image_010.jpg|120px]]
| [[File:Stage_22 image 059.jpg|120px]]
|-
| [[:File:Stage_22 image 060.jpg|B4L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_011.jpg]]
| [[File:Stage_22_image_011.jpg|120px]]
| [[File:Stage_22 image 060.jpg|120px]]
|-
| [[:File:Stage_22 image 061.jpg|B5L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_012.jpg]]
| [[File:Stage_22_image_012.jpg|120px]]
| [[File:Stage_22 image 061.jpg|120px]]
|-
| [[:File:Stage_22 image 062.jpg|B6L]]
| [[File:Stage 22 B6 plane.gif|link=File:Stage_22_image_013.jpg]]
| [[File:Stage_22_image_013.jpg|120px]]
| [[File:Stage_22 image 062.jpg|120px]]
|-
| [[:File:Stage_22 image 063.jpg|B7L]]
| [[File:Stage 22 B7 plane.gif|link=File:Stage_22_image_014.jpg]]
| [[File:Stage_22_image_014.jpg|120px]]
| [[File:Stage_22 image 063.jpg|120px]]
|-
| [[:File:Stage_22 image 064.jpg|C1L]]
| [[File:Stage 22 C1 plane.gif|link=File:Stage_22_image_015.jpg]]
| [[File:Stage_22_image_015.jpg|120px]]
| [[File:Stage_22 image 064.jpg|120px]]
|-
| [[:File:Stage_22 image 065.jpg|C2L]]
| [[File:Stage 22 C2 plane.gif|link=File:Stage_22_image_016.jpg]]
| [[File:Stage_22_image_016.jpg|120px]]
| [[File:Stage_22 image 065.jpg|120px]]
|-
| [[:File:Stage_22 image 066.jpg|C3L]]
| [[File:Stage 22 C3 plane.gif|link=File:Stage_22_image_017.jpg]]
| [[File:Stage_22_image_017.jpg|120px]]
| [[File:Stage_22 image 066.jpg|120px]]

|}

==Late Embryo Cortex==
[[File:Stage22 bf1c.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

[[File:Stage_22_image_217.jpg|600px]]

==Additional Information==
{{Med Prac additional Information}}

:'''Links:''' [[AE_Practical_-_Neural_Histology|Neural Histology]]

===Scanning Electron Microscopy===
{|
! Stage 10 - Neural Groove
|-
| [[File:Stage10_sem2.jpg|300px]]
| This is a dorsolateral view of the embryo. The amniotic sac has been removed to show the still open neural groove.

* '''Neural groove''' forming from neural plate on upper surface.
** large brain fold region to left of image.
** narrow spinal cord region to right of image.
* '''Heart bulge''' can be seen on lower ventral surface.
* '''Connecting stalk''' to the right of image.
* '''Amniotic membrane''' cut edge shown at edge of developing embryo.

|-
| [[File:Stage10_sem6.jpg|300px]]
| This is a dorsal view of the same embryo with the future head, and brain, now shown at the top of image.
|-
| [[File:Stage10_sem10.jpg|300px]]
| This is a lateral view of a later embryo showing the neural groove closing to form the neural tube.

Note the still open cranial (top) and caudal (bottom) neuropores. These are the last parts of the tube to close.
|}

{|
! Stage 11 - Cut through the neural tube
|-
| [[File:Stage11_sem11.jpg|300px]]
| This slightly older embryo has been broken in half close slightly away from the midline to show features of the neural tube.
* At the level of the hindbrain and spinal cord - (right of image) the floor, wall and roof of the neural tube can be seen. Notice also the rhombomere bulges at the level of the hindbrain.
* In the head region - (top of image) part of the lateral wall of the neural tube remains, at the level of midbrain. A segment of the forebrain has been removed to show the internal surface of this region.
|}

===Timeline Events===

[[File:Neural-development.jpg|600px]]

Simplified overview table showing broad events of neural development classified by proliferation, migration, differentiation and metabolism. Note the long time course of development and that it continues into the postnatal period.
===Neural Movies===
{|
| valign="bottom"|{{Neural stage 13 movie}}
| valign="bottom"|{{Neural stage 22 movie}}
| valign="bottom"|{{Neural plate movie}}
| valign="bottom"|{{Neural tube movie}}
| valign="bottom"|{{Neural Tube Closure 1 movie}}
| valign="bottom"|{{Sylvian fissure movie}}
| valign="bottom"|{{Adult brain movie}}
|}

{{Glossary}}

{{Footer}}

[[Category:Science-Undergraduate]][[Category:Neural]]

ANAT3411 Neuroanatomy

2024-02-09T02:52:23Z

Z8600021:

==Introduction==
Course convenor: Dr. Elizabeth Tancred

The aim of this course is to provide students in the BSc and BMedSc programs with a basic understanding of the structural organisation of the human central nervous system in sufficient depth to form the basis for further clinical or research studies of the nervous system.

The following images are prepared for Dr Tancred's Neurodevelopment class from UNSW Embryology. The listed cross-sections are recommended to be viewed in the order in which they are shown below. A direct link [[ANAT3411 Neuroanatomy|ANAT3411]] to this current page appears on the lefthand menu of every embryology page.

* '''Begin''' with a simplified introduction by looking through [[K12 Brain Awareness Week|Brain Awareness Week]].
* '''Then''' return to this page for the remainder of the class.

{| class="wikitable mw-collapsible mw-collapsed"
! UNSW Embryology Textbooks  
|-
| UNSW Students have online access to the these embryology textbook chapters through UNSW Library subscription (with student Zpass log-in).
|-
| [[File:The Developing Human, 10th edn.jpg|thumb|left|90px]]
'''APA Citation:''' {{MPT2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074364&pg=500 Nervous System]
|-
| [[File:Larsen's human embryology 5th ed.jpg|thumb|left|90px]]

'''APA Citation:''' {{SBBF2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=215 Development of the Central Nervous System]
* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=252 Development of the Peripheral Nervous System]

|}

==Embryo Images Links==

[https://web.archive.org/web/20050513205027/http://www.med.unc.edu/embryo_images/unit-bdyfm/bdyfm_htms/bdyfmtoc.htm Early Cell Populations and Establishment of Body Form]

[https://web.archive.org/web/20050320092125/http://www.med.unc.edu/embryo_images/unit-nervous/nerv_htms/nervtoc.htm Nervous System Development]

==Stage 22 Spinal Cord==
Cross-section of the human embryonic spinal cord (end of week 8).

[[File:Human Stage22 spinal cord01.jpg|400px]] [[File:Human Stage22 spinal cord02.jpg|400px]]
===Virtual Slide===
{|
| rowspan=2|{{SlideStage22-33-rotate-spinalcord}}
| colspan="2"|These listed features link to zoomed views of the virtual slide with the named feature generally in the centre of the view.

Use the (-) at the top left of the screen to see where this feature is located.
|-
| valign=top|'''Spinal Cord Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-1384.5&lon=4177.5&layers=B roof plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2140.5&lon=3138.5&layers=B alar plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2438.5&lon=5322.5&layers=B alar plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3078.5&lon=4187.5&layers=B sulcus limitans]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3748.5&lon=3216.5&layers=B basal plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3924.5&lon=5278.5&layers=B basal plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4338&lon=4269.5&layers=B floor plate]
| valign=top|'''Other Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5255.5&lon=2431.5&layers=B dorsal root ganglion] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5431.5&lon=6042.5&layers=B dorsal root ganglion]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2688.5&lon=6571.5&layers=B dorsal root] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2252.5&lon=1886.5&layers=B dorsal root]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7718.50692&lon=1887.54152&layers=B spinal nerve] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7776.5&lon=6593.5&layers=B spinal nerve]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2924.5&lon=7408.5&layers=B dura mater]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4941.5&lon=4302.5&layers=B ventral spinal artery] (showing fetal nucleated red blood cell)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7338.69233&lon=4161.30767&layers=B notochord] (lying in the centre of the vertebral body)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=4&lat=-7235.19233&lon=4189.80767&layers=B vertebral body] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=5&lat=-4423&lon=951.35969&layers=B vertebral arch root] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-881.5&lon=3870.5&layers=B dorsal uniting ligament] (lying dorsal to the spinal cord and under the periderm)
|}
==Embryo Stage 13==

[[File:Stage13 bf2c.jpg|thumb|300px|link=Carnegie stage 13|[[Carnegie stage 13]] Week 4 (6 mm Embryo)]]
{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage 13 image 097.jpg|G6L]] Midline longitudinal
|
| [[File:Stage_13_image_048.jpg|120px]]
| [[File:Stage 13 image 097.jpg|120px]]
|-
| [[:File:Stage 13 image 098.jpg|G7L]] Lateral longitudinal
|
| [[File:Stage_13_image_049.jpg|120px]]
| [[File:Stage 13 image 098.jpg|120px]]
|-
| [[:File:Stage 13 image 052.jpg|A3L]] Rhombomeres and otic vesicle
| [[File:Stage 13 A3 plane.gif|link=File:Stage_13_image_003.jpg]]
| [[File:Stage_13_image_003.jpg|120px]]
| [[File:Stage 13 image 052.jpg|120px]]
|-
| [[:File:Stage 13 image 060.jpg|B4L]] Spinal cord and optic vesicle
| [[File:Stage 13 B4 plane.gif|link=File:Stage_13_image_011.jpg]]
| [[File:Stage_13_image_011.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
|-
| [[:File:Stage 13 image 061.jpg|B5L]] Spinal cord and diencephalon
| [[File:Stage 13 B5 plane.gif|link=File:Stage_13_image_012.jpg]]
| [[File:Stage_13_image_012.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
|}

{|
|-bgcolor="CEDFF2"
! colspan=2|Human Embryo (Stage 13)
|-
| [[File:Stage13 face ventral view01.jpg|200px]]
| [[File:Stage13_spinal_cord02.jpg|300px]]
|-
| Ventral view of upper half of embryo
| Early spinal cord regions
|-
| colspan=2|[[Carnegie stage 13]] occurs in week 4 to week 5, 28 - 32 days. The embryos have a crown rump length (CRL) of 4 - 6 mm and somite number 30 pairs. Scale bar 0.5 mm.
|}
==Embryo Stage 22==
[[File:Stage22_embryo_and_brain_01.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage_22 image 050.jpg|A1L]]
| [[File:Stage 22 A1 plane.gif|link=]]
| [[File:Stage_22_image_001.jpg|120px]]
| [[File:Stage_22 image 050.jpg|120px]]
|-
| [[:File:Stage_22 image 052.jpg|A3L]]
| [[File:Stage 22 A3 plane.gif|link=File:Stage_22_image_003.jpg]]
| [[File:Stage_22_image_003.jpg|120px]]
| [[File:Stage_22 image 052.jpg|120px]]
|-
| [[:File:Stage_22 image 053.jpg|A4L]]
| [[File:Stage 22 A4 plane.gif|link=File:Stage_22_image_004.jpg]]
| [[File:Stage_22_image_004.jpg|120px]]
| [[File:Stage_22 image 053.jpg|120px]]
|-
| [[:File:Stage_22 image 055.jpg|A6L]]
| [[File:Stage 22 A6 plane.gif|link=File:Stage_22_image_006.jpg]]
| [[File:Stage_22_image_006.jpg|120px]]
| [[File:Stage_22 image 055.jpg|120px]]
|-
| [[:File:Stage_22 image 057.jpg|B1L]]
| [[File:Stage 22 B1 plane.gif|link=File:Stage_22_image_008.jpg]]
| [[File:Stage_22_image_008.jpg|120px]]
| [[File:Stage_22 image 057.jpg|120px]]
|-
| [[:File:Stage_22 image 058.jpg|B2L]]
| [[File:Stage 22 B2 plane.gif|link=File:Stage_22_image_009.jpg]]
| [[File:Stage_22_image_009.jpg|120px]]
| [[File:Stage_22 image 058.jpg|120px]]
|-
| [[:File:Stage_22 image 059.jpg|B3L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_010.jpg]]
| [[File:Stage_22_image_010.jpg|120px]]
| [[File:Stage_22 image 059.jpg|120px]]
|-
| [[:File:Stage_22 image 060.jpg|B4L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_011.jpg]]
| [[File:Stage_22_image_011.jpg|120px]]
| [[File:Stage_22 image 060.jpg|120px]]
|-
| [[:File:Stage_22 image 061.jpg|B5L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_012.jpg]]
| [[File:Stage_22_image_012.jpg|120px]]
| [[File:Stage_22 image 061.jpg|120px]]
|-
| [[:File:Stage_22 image 062.jpg|B6L]]
| [[File:Stage 22 B6 plane.gif|link=File:Stage_22_image_013.jpg]]
| [[File:Stage_22_image_013.jpg|120px]]
| [[File:Stage_22 image 062.jpg|120px]]
|-
| [[:File:Stage_22 image 063.jpg|B7L]]
| [[File:Stage 22 B7 plane.gif|link=File:Stage_22_image_014.jpg]]
| [[File:Stage_22_image_014.jpg|120px]]
| [[File:Stage_22 image 063.jpg|120px]]
|-
| [[:File:Stage_22 image 064.jpg|C1L]]
| [[File:Stage 22 C1 plane.gif|link=File:Stage_22_image_015.jpg]]
| [[File:Stage_22_image_015.jpg|120px]]
| [[File:Stage_22 image 064.jpg|120px]]
|-
| [[:File:Stage_22 image 065.jpg|C2L]]
| [[File:Stage 22 C2 plane.gif|link=File:Stage_22_image_016.jpg]]
| [[File:Stage_22_image_016.jpg|120px]]
| [[File:Stage_22 image 065.jpg|120px]]
|-
| [[:File:Stage_22 image 066.jpg|C3L]]
| [[File:Stage 22 C3 plane.gif|link=File:Stage_22_image_017.jpg]]
| [[File:Stage_22_image_017.jpg|120px]]
| [[File:Stage_22 image 066.jpg|120px]]

|}

==Late Embryo Cortex==
[[File:Stage22 bf1c.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

[[File:Stage_22_image_217.jpg|600px]]

==Additional Information==
{{Med Prac additional Information}}

:'''Links:''' [[AE_Practical_-_Neural_Histology|Neural Histology]]

===Scanning Electron Microscopy===
{|
! Stage 10 - Neural Groove
|-
| [[File:Stage10_sem2.jpg|300px]]
| This is a dorsolateral view of the embryo. The amniotic sac has been removed to show the still open neural groove.

* '''Neural groove''' forming from neural plate on upper surface.
** large brain fold region to left of image.
** narrow spinal cord region to right of image.
* '''Heart bulge''' can be seen on lower ventral surface.
* '''Connecting stalk''' to the right of image.
* '''Amniotic membrane''' cut edge shown at edge of developing embryo.

|-
| [[File:Stage10_sem6.jpg|300px]]
| This is a dorsal view of the same embryo with the future head, and brain, now shown at the top of image.
|-
| [[File:Stage10_sem10.jpg|300px]]
| This is a lateral view of a later embryo showing the neural groove closing to form the neural tube.

Note the still open cranial (top) and caudal (bottom) neuropores. These are the last parts of the tube to close.
|}

{|
! Stage 11 - Cut through the neural tube
|-
| [[File:Stage11_sem11.jpg|300px]]
| This slightly older embryo has been broken in half close slightly away from the midline to show features of the neural tube.
* At the level of the hindbrain and spinal cord - (right of image) the floor, wall and roof of the neural tube can be seen. Notice also the rhombomere bulges at the level of the hindbrain.
* In the head region - (top of image) part of the lateral wall of the neural tube remains, at the level of midbrain. A segment of the forebrain has been removed to show the internal surface of this region.
|}

===Timeline Events===

[[File:Neural-development.jpg|600px]]

Simplified overview table showing broad events of neural development classified by proliferation, migration, differentiation and metabolism. Note the long time course of development and that it continues into the postnatal period.
===Neural Movies===
{|
| valign="bottom"|{{Neural stage 13 movie}}
| valign="bottom"|{{Neural stage 22 movie}}
| valign="bottom"|{{Neural plate movie}}
| valign="bottom"|{{Neural tube movie}}
| valign="bottom"|{{Neural Tube Closure 1 movie}}
| valign="bottom"|{{Sylvian fissure movie}}
| valign="bottom"|{{Adult brain movie}}
|}

{{Glossary}}

{{Footer}}

[[Category:Science-Undergraduate]][[Category:Neural]]

ANAT3411 Neuroanatomy

2024-02-09T02:51:22Z

Z8600021:

==Introduction==
Course convenor: Dr. Elizabeth Tancred

The aim of this course is to provide students in the BSc and BMedSc programs with a basic understanding of the structural organisation of the human central nervous system in sufficient depth to form the basis for further clinical or research studies of the nervous system.

The following images are prepared for Dr Tancred's Neurodevelopment class from UNSW Embryology. The listed cross-sections are recommended to be viewed in the order in which they are shown below. A direct link [[ANAT3411 Neuroanatomy|ANAT3411]] to this current page appears on the lefthand menu of every embryology page.

* '''Begin''' with a simplified introduction by looking through [[K12 Brain Awareness Week|Brain Awareness Week]].
* '''Then''' return to this page for the remainder of the class.

{| class="wikitable mw-collapsible mw-collapsed"
! UNSW Embryology Textbooks  
|-
| UNSW Students have online access to the these embryology textbook chapters through UNSW Library subscription (with student Zpass log-in).
|-
| [[File:The Developing Human, 10th edn.jpg|thumb|left|90px]]
'''APA Citation:''' {{MPT2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074364&pg=500 Nervous System]
|-
| [[File:Larsen's human embryology 5th ed.jpg|thumb|left|90px]]

'''APA Citation:''' {{SBBF2015APAcitation}}

* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=215 Development of the Central Nervous System]
* [http://www.unsw.eblib.com.wwwproxy0.library.unsw.edu.au/patron/Read.aspx?p=2074524&pg=252 Development of the Peripheral Nervous System]

|}

==Embryo Images Links==

[https://web.archive.org/web/20050513205027/http://www.med.unc.edu/embryo_images/unit-bdyfm/bdyfm_htms/bdyfmtoc.htm Early Cell Populations and Establishment of Body Form]

==Stage 22 Spinal Cord==
Cross-section of the human embryonic spinal cord (end of week 8).

[[File:Human Stage22 spinal cord01.jpg|400px]] [[File:Human Stage22 spinal cord02.jpg|400px]]
===Virtual Slide===
{|
| rowspan=2|{{SlideStage22-33-rotate-spinalcord}}
| colspan="2"|These listed features link to zoomed views of the virtual slide with the named feature generally in the centre of the view.

Use the (-) at the top left of the screen to see where this feature is located.
|-
| valign=top|'''Spinal Cord Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-1384.5&lon=4177.5&layers=B roof plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2140.5&lon=3138.5&layers=B alar plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2438.5&lon=5322.5&layers=B alar plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3078.5&lon=4187.5&layers=B sulcus limitans]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3748.5&lon=3216.5&layers=B basal plate] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-3924.5&lon=5278.5&layers=B basal plate]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4338&lon=4269.5&layers=B floor plate]
| valign=top|'''Other Features'''
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5255.5&lon=2431.5&layers=B dorsal root ganglion] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-5431.5&lon=6042.5&layers=B dorsal root ganglion]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2688.5&lon=6571.5&layers=B dorsal root] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2252.5&lon=1886.5&layers=B dorsal root]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7718.50692&lon=1887.54152&layers=B spinal nerve] | [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7776.5&lon=6593.5&layers=B spinal nerve]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-2924.5&lon=7408.5&layers=B dura mater]
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-4941.5&lon=4302.5&layers=B ventral spinal artery] (showing fetal nucleated red blood cell)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-7338.69233&lon=4161.30767&layers=B notochord] (lying in the centre of the vertebral body)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=4&lat=-7235.19233&lon=4189.80767&layers=B vertebral body] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=5&lat=-4423&lon=951.35969&layers=B vertebral arch root] (cartilage stage)
* [https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/33-rotate-spinal-cord/Human_Stage22_spinal_cord.html?zoom=6&lat=-881.5&lon=3870.5&layers=B dorsal uniting ligament] (lying dorsal to the spinal cord and under the periderm)
|}
==Embryo Stage 13==

[[File:Stage13 bf2c.jpg|thumb|300px|link=Carnegie stage 13|[[Carnegie stage 13]] Week 4 (6 mm Embryo)]]
{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage 13 image 097.jpg|G6L]] Midline longitudinal
|
| [[File:Stage_13_image_048.jpg|120px]]
| [[File:Stage 13 image 097.jpg|120px]]
|-
| [[:File:Stage 13 image 098.jpg|G7L]] Lateral longitudinal
|
| [[File:Stage_13_image_049.jpg|120px]]
| [[File:Stage 13 image 098.jpg|120px]]
|-
| [[:File:Stage 13 image 052.jpg|A3L]] Rhombomeres and otic vesicle
| [[File:Stage 13 A3 plane.gif|link=File:Stage_13_image_003.jpg]]
| [[File:Stage_13_image_003.jpg|120px]]
| [[File:Stage 13 image 052.jpg|120px]]
|-
| [[:File:Stage 13 image 060.jpg|B4L]] Spinal cord and optic vesicle
| [[File:Stage 13 B4 plane.gif|link=File:Stage_13_image_011.jpg]]
| [[File:Stage_13_image_011.jpg|120px]]
| [[File:Stage 13 image 060.jpg|120px]]
|-
| [[:File:Stage 13 image 061.jpg|B5L]] Spinal cord and diencephalon
| [[File:Stage 13 B5 plane.gif|link=File:Stage_13_image_012.jpg]]
| [[File:Stage_13_image_012.jpg|120px]]
| [[File:Stage 13 image 061.jpg|120px]]
|}

{|
|-bgcolor="CEDFF2"
! colspan=2|Human Embryo (Stage 13)
|-
| [[File:Stage13 face ventral view01.jpg|200px]]
| [[File:Stage13_spinal_cord02.jpg|300px]]
|-
| Ventral view of upper half of embryo
| Early spinal cord regions
|-
| colspan=2|[[Carnegie stage 13]] occurs in week 4 to week 5, 28 - 32 days. The embryos have a crown rump length (CRL) of 4 - 6 mm and somite number 30 pairs. Scale bar 0.5 mm.
|}
==Embryo Stage 22==
[[File:Stage22_embryo_and_brain_01.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

{|
|-bgcolor="CEDFF2"
! width=150px|Series
! width=100px|Section Plane
! width=150px|Unlabeled
! width=150px|Labeled
|-
| [[:File:Stage_22 image 050.jpg|A1L]]
| [[File:Stage 22 A1 plane.gif|link=]]
| [[File:Stage_22_image_001.jpg|120px]]
| [[File:Stage_22 image 050.jpg|120px]]
|-
| [[:File:Stage_22 image 052.jpg|A3L]]
| [[File:Stage 22 A3 plane.gif|link=File:Stage_22_image_003.jpg]]
| [[File:Stage_22_image_003.jpg|120px]]
| [[File:Stage_22 image 052.jpg|120px]]
|-
| [[:File:Stage_22 image 053.jpg|A4L]]
| [[File:Stage 22 A4 plane.gif|link=File:Stage_22_image_004.jpg]]
| [[File:Stage_22_image_004.jpg|120px]]
| [[File:Stage_22 image 053.jpg|120px]]
|-
| [[:File:Stage_22 image 055.jpg|A6L]]
| [[File:Stage 22 A6 plane.gif|link=File:Stage_22_image_006.jpg]]
| [[File:Stage_22_image_006.jpg|120px]]
| [[File:Stage_22 image 055.jpg|120px]]
|-
| [[:File:Stage_22 image 057.jpg|B1L]]
| [[File:Stage 22 B1 plane.gif|link=File:Stage_22_image_008.jpg]]
| [[File:Stage_22_image_008.jpg|120px]]
| [[File:Stage_22 image 057.jpg|120px]]
|-
| [[:File:Stage_22 image 058.jpg|B2L]]
| [[File:Stage 22 B2 plane.gif|link=File:Stage_22_image_009.jpg]]
| [[File:Stage_22_image_009.jpg|120px]]
| [[File:Stage_22 image 058.jpg|120px]]
|-
| [[:File:Stage_22 image 059.jpg|B3L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_010.jpg]]
| [[File:Stage_22_image_010.jpg|120px]]
| [[File:Stage_22 image 059.jpg|120px]]
|-
| [[:File:Stage_22 image 060.jpg|B4L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_011.jpg]]
| [[File:Stage_22_image_011.jpg|120px]]
| [[File:Stage_22 image 060.jpg|120px]]
|-
| [[:File:Stage_22 image 061.jpg|B5L]]
| [[File:Stage 22 B5 plane.gif|link=File:Stage_22_image_012.jpg]]
| [[File:Stage_22_image_012.jpg|120px]]
| [[File:Stage_22 image 061.jpg|120px]]
|-
| [[:File:Stage_22 image 062.jpg|B6L]]
| [[File:Stage 22 B6 plane.gif|link=File:Stage_22_image_013.jpg]]
| [[File:Stage_22_image_013.jpg|120px]]
| [[File:Stage_22 image 062.jpg|120px]]
|-
| [[:File:Stage_22 image 063.jpg|B7L]]
| [[File:Stage 22 B7 plane.gif|link=File:Stage_22_image_014.jpg]]
| [[File:Stage_22_image_014.jpg|120px]]
| [[File:Stage_22 image 063.jpg|120px]]
|-
| [[:File:Stage_22 image 064.jpg|C1L]]
| [[File:Stage 22 C1 plane.gif|link=File:Stage_22_image_015.jpg]]
| [[File:Stage_22_image_015.jpg|120px]]
| [[File:Stage_22 image 064.jpg|120px]]
|-
| [[:File:Stage_22 image 065.jpg|C2L]]
| [[File:Stage 22 C2 plane.gif|link=File:Stage_22_image_016.jpg]]
| [[File:Stage_22_image_016.jpg|120px]]
| [[File:Stage_22 image 065.jpg|120px]]
|-
| [[:File:Stage_22 image 066.jpg|C3L]]
| [[File:Stage 22 C3 plane.gif|link=File:Stage_22_image_017.jpg]]
| [[File:Stage_22_image_017.jpg|120px]]
| [[File:Stage_22 image 066.jpg|120px]]

|}

==Late Embryo Cortex==
[[File:Stage22 bf1c.jpg|thumb|300px|link=Carnegie stage 22|[[Carnegie stage 22]] Week 8 (27 mm Embryo)]]

[[File:Stage_22_image_217.jpg|600px]]

==Additional Information==
{{Med Prac additional Information}}

:'''Links:''' [[AE_Practical_-_Neural_Histology|Neural Histology]]

===Scanning Electron Microscopy===
{|
! Stage 10 - Neural Groove
|-
| [[File:Stage10_sem2.jpg|300px]]
| This is a dorsolateral view of the embryo. The amniotic sac has been removed to show the still open neural groove.

* '''Neural groove''' forming from neural plate on upper surface.
** large brain fold region to left of image.
** narrow spinal cord region to right of image.
* '''Heart bulge''' can be seen on lower ventral surface.
* '''Connecting stalk''' to the right of image.
* '''Amniotic membrane''' cut edge shown at edge of developing embryo.

|-
| [[File:Stage10_sem6.jpg|300px]]
| This is a dorsal view of the same embryo with the future head, and brain, now shown at the top of image.
|-
| [[File:Stage10_sem10.jpg|300px]]
| This is a lateral view of a later embryo showing the neural groove closing to form the neural tube.

Note the still open cranial (top) and caudal (bottom) neuropores. These are the last parts of the tube to close.
|}

{|
! Stage 11 - Cut through the neural tube
|-
| [[File:Stage11_sem11.jpg|300px]]
| This slightly older embryo has been broken in half close slightly away from the midline to show features of the neural tube.
* At the level of the hindbrain and spinal cord - (right of image) the floor, wall and roof of the neural tube can be seen. Notice also the rhombomere bulges at the level of the hindbrain.
* In the head region - (top of image) part of the lateral wall of the neural tube remains, at the level of midbrain. A segment of the forebrain has been removed to show the internal surface of this region.
|}

===Timeline Events===

[[File:Neural-development.jpg|600px]]

Simplified overview table showing broad events of neural development classified by proliferation, migration, differentiation and metabolism. Note the long time course of development and that it continues into the postnatal period.
===Neural Movies===
{|
| valign="bottom"|{{Neural stage 13 movie}}
| valign="bottom"|{{Neural stage 22 movie}}
| valign="bottom"|{{Neural plate movie}}
| valign="bottom"|{{Neural tube movie}}
| valign="bottom"|{{Neural Tube Closure 1 movie}}
| valign="bottom"|{{Sylvian fissure movie}}
| valign="bottom"|{{Adult brain movie}}
|}

{{Glossary}}

{{Footer}}

[[Category:Science-Undergraduate]][[Category:Neural]]

Salamander Development

2024-01-25T01:37:37Z

Z8600021: Created page with "{{Header}} == Introduction == This {{Embryology}} category shows pages and files related to the development of the Salamander amphibian. See also the historic 1910 paler on Normal Plates of the Development of the Salamander Embryo and page on Axolotl Development. {{Animals}} ==Some Recent Findings== {| |-bgcolor="F5FAFF" | * '''Review - Salamanders as Key Models for Development and Regeneration Researc..."

{{Header}}
== Introduction ==
This {{Embryology}} category shows pages and files related to the development of the Salamander amphibian. See also the historic 1910 paler on [[Book - Normal Plates of the Development of Vertebrates 11|Normal Plates of the Development of the Salamander Embryo]] and page on [[Axolotl Development]].

{{Animals}}
==Some Recent Findings==
{|
|-bgcolor="F5FAFF"
|

* '''Review - Salamanders as Key Models for Development and Regeneration Research''{{#pmid:36272065|PMID36272065}}
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers  
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Salamander+Development ''Salamander Development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Salamander+Embryology ''Salamander Embryology''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Salamander+Limb+Development ''Salamander Limb Development'']

|}

==References==

<references/>

===Articles===
===Historic References===

{{Ref-Eycleshymer1910}}

{{Ref-Herrick1948}}

<br>

{{Animals}}

{{Glossary}}

{{Footer}}
[[Category:Salamander]]
[[Category:Animal Development]]

Template:Salamander

2024-01-25T01:32:16Z

Z8600021: Created page with "salamander<noinclude>Category:TemplateCategory:Term LinkCategory:Salamander</noinclude>"

[[Salamander Development|salamander]]<noinclude>[[Category:Template]][[Category:Term Link]][[Category:Salamander]]</noinclude>

Template:Animals

2024-01-25T01:31:37Z

Z8600021:

{|
|-bgcolor="F5FFFA"
| [[Animal Development|'''Animal Development''']]: {{axolotl}} | {{bat}} | {{cat}} | {{chicken}} | {{cow}} | {{dog}} | [[Dolphin Development|dolphin]] | {{echidna}} | {{fly}} | {{frog}} | {{Goat}} | {{Grasshopper}} | {{guinea pig}} | {{hamster}} | {{horse}} | {{kangaroo}} | {{koala}} | {{lizard}} | {{medaka}} | {{mouse}} | {{opossum}} | {{pig}} | {{platypus}} | {{rabbit}} | {{rat}} | {{salamander}} | {{sea squirt}} | {{sea urchin}} | {{sheep}} | {{worm}} | {{zebrafish}} | {{life cycles}} | [[:Template:Animal development period table|development timetable]] | {{development models}} | [[K12 Animal Development Times|K12]]
|-
|
{| class="wikitable mw-collapsible mw-collapsed"
! [[Historic Embryology Papers|'''Historic Embryology''']]  
|-
| [[Book - Normal Plates of the Development of Vertebrates 1|1897 Pig]] | [[Book - Normal Plates of the Development of Vertebrates 2|1900 Chicken]] | [[Book - Normal Plates of the Development of Vertebrates 3|1901 Lungfish]] | [[Book - Normal Plates of the Development of Vertebrates 4|1904 Sand Lizard]] | [[Book - Normal Plates of the Development of Vertebrates 5|1905 Rabbit]] | [[Book_-_Normal_Plates_of_the_Development_of_Vertebrates_6|1906 Deer]] | [[Book_-_Normal_Plates_of_the_Development_of_Vertebrates_7|1907 Tarsiers]] | [[Book - Normal Plates of the Development of Vertebrates 8|1908 Human]] | [[Book_-_Normal_Plates_of_the_Development_of_Vertebrates_9|1909 Northern Lapwing]] | [[Book_-_Normal_Plates_of_the_Development_of_Vertebrates_10|1909 South American and African Lungfish]] | [[Book_-_Normal_Plates_of_the_Development_of_Vertebrates_11|1910 Salamander]] | [[Book - The Frog Its Reproduction and Development|1951 Frog]] | [[Embryology History]] | [[Embryology_History#Historic_Disclaimer|Historic Disclaimer]]
|}
|}[[Category:Animal Development]]<noinclude>[[Category:Template]][[Category:Links Menu]]</noinclude>

Vision - Lens Development

2024-01-25T01:27:51Z

Z8600021:

{{Header}}
==Introduction==
[[File:Stage_22_image_155.jpg|thumb|300px|Human lens development ([[Carnegie stage 22]], [[Week 8]])]]
The lens or crystalline lens or aquula (Latin, ''aquula'' = a little stream) has a key role in focussing light (with the cornea) upon the neural retina. The lens embryonic origin is from surface ectoderm of the sensory placodes that form in the head region (More? [[Placodes]]).

The lens focusses by refracting light as it passes through the biconvex lens, which can be altered in shape (accommodation) by surrounding ciliary muscles. These ciliary muscles are activated (contracted) by parasympathetic innervation from the ciliary ganglion itself innervated by the oculomotor nerve (Cranial Nerve {{CN III}}).

The lens has recently been shown in the chicken model to not be required for specification of the iris and ciliary body.{{#pmid:17275804|PMID17275804}}

{{Vision Links}}
==Some Recent Findings==
{|
|-bgcolor="F5FAFF"
|

* '''Review - The cellular and molecular mechanisms of vertebrate lens development'''{{#pmid:25406393|PMID25406393}} "The ocular lens is a model system for understanding important aspects of embryonic development, such as cell specification and the spatiotemporally controlled formation of a three-dimensional structure. The lens, which is characterized by transparency, refraction and elasticity, is composed of a bulk mass of fiber cells attached to a sheet of lens epithelium. Although lens induction has been studied for over 100 years, recent findings have revealed a myriad of extracellular signaling pathways and gene regulatory networks, integrated and executed by the transcription factor Pax6, that are required for lens formation in vertebrates."

* '''Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development'''{{#pmid:25184676|PMID25184676}} "While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription."

* '''On the growth and internal structure of the human lens'''{{#pmid:20171212|PMID20171212}} "Growth of the human lens and the development of its internal features are examined using in vivo and in vitro observations on dimensions, weights, cell sizes, protein gradients and other properties. In vitro studies have shown that human lens growth is biphasic, asymptotic until just after birth and linear for most of postnatal life."

* '''Activated Ras alters lens and corneal development'''{{#pmid:20105280|PMID20105280}} "The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. ...Collectively, these results suggest that Ras activation a) induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b) is sufficient for initiation but not completion of lens fiber differentiation."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers  
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Lens+Embryology ''Lens Embryology'']

|}
==Development Overview==

surface ectoderm -> lens placode -> lens pit -> lens vesicle -> lens fibres -> lens capsule and embryonic/fetal nucleus.

==Week 4==
[[File:Stage11_sem8.jpg|thumb|Human Embryo [[Carnegie stage 11]]]]
[[File:Stage12 sem6.jpg|thumb|Human Embryo [[Carnegie stage 12]]]]
[[File:Stage11_histology-optic_pit.jpg|600px]]

Human Embryo [[Carnegie stage 11]] optic pit

==Week 5==

[[File:Stage13 bf8.jpg|thumb|Human Embryo [[Carnegie stage 13]]]]

[[File:Stage_13_image_058.jpg|300px]] [[File:Stage_13_image_059.jpg|300px]][[File:Stage_13_image_060.jpg|300px]][[File:Stage_13_image_061.jpg|300px]]

==Week 8==
{{Streeter1957 fig6 gallery}}
<br>
The images below link to virtual slides of the human developing eye at Carnegie stage {{CS22}}. Click on the image to open or select specific regions from the regions of interest links.

{|
| {{SlideStage22-08}}
| {{SlideStage22-08-eye}}
|
===Virtual Slide - Regions of Interest===
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=3&lat=-3544&lon=4688&layers=B Eye Overview]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=4&lat=-2030&lon=2572&layers=B Lens and Cornea]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-1208&lon=2473&layers=B Cornea and Anterior Chamber]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-2242&lon=2982&layers=B Lens - anterior]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-2670&lon=3082&layers=B Lens - posterior]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-2641&lon=2295&layers=B Lens -equator]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-2410&lon=1843&layers=B Iris and Lens]
|-
|}
<gallery>
File:Stage 22 image 209.jpg|
File:Stage_22_image_208.jpg|
File:Stage 22 image 207.jpg|
File:Stage 22 image 212.jpg|
File:Stage 22 image 211.jpg|
</gallery>

'''Links:''' Carnegie stage {{CS22}} | [[Embryo Virtual Slides]]

==Molecular Signaling==

[[File:Eye-neural crest signaling.jpg|600px]]

Wnt mediates lens repression by neural crest cells and Transforming growth factor-β<ref>Grocott T, Johnson S, Bailey AP, Streit A. '''Neural crest cells organize the eye via TGF-β and canonical Wnt signalling.''' Nat Commun. 2011 Apr;2:265. [http://www.ncbi.nlm.nih.gov/pubmed/21468017 PMID21468017] | [http://www.nature.com/ncomms/journal/v2/n4/full/ncomms1269.html Nat Commun.]</ref> (open image for full description)

:'''Links:''' [[Vision_-_Lens_Development|Lens Development]] | [[Neural Crest Development]] | [[Developmental_Signals_-_Wnt|Wnt]] | [[:File:Eye-neural crest signaling.jpg|Lens repression by neural crest cells]] | [[:File:Lens-neural crest signaling 01.jpg|Proposed model how NCCs organize the eye]] | [[:File:Lens-neural crest signaling 02.jpg|molecular model to explain TGF-β- and Wnt-mediated lens restriction]]

==References==

<references/>

===Reviews===

===Articles===

==Additional Images==
<gallery>
</gallery>

===Historic Images===
{{Historic Disclaimer}}

{{Streeter1957 fig6 gallery}}

{{Glossary}}

{{Footer}}

[[Category:Placode]]
[[Category:Lens]]

Sensory - Vision Development

2024-01-25T01:26:58Z

Z8600021:

{{Header}}
==Introduction==
[[File:Historic_retina_drawing.jpg|right|300px]]
[[File:Human-retina-01.jpg|thumb|300px|Adult Human Retina histology{{#pmid:12186651|PMID12186651}}]]
These notes introduce {{vision}} development of the eye: induction and regional specification of the eye structures, maturation and formation of retina and optic tectum neuronal connections.

The adult eye has contributions from several different embryonic layers eventually forming neuronal, supportive connective tissue, optical structures, and muscular tissues. Historically determined that at birth, the human eyeball volume is about 3.25 cc and the estimated weight is about 3.40 grams.<ref name=ScammonArmstrong1925>{{Ref-ScammonArmstrong1925}}</ref>

There are additional pages shown in the vision links, covering specific topics of vision development.

{{Vision Links}}
<br>
{{Senses Links}}

== Some Recent Findings ==
{|
|-bgcolor="F5FAFF"
|

* '''Vision-dependent specification of cell types and function in the developing cortex'''{{#pmid:35063073|PMID35063073}} "The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs."

* '''Endocrine regulation of multichromatic color vision.'''{{#pmid:31383755|PMID31383755}} "Vertebrate color vision requires spectrally selective opsin-based pigments, expressed in distinct cone photoreceptor populations. In primates and in fish, spectrally divergent opsin genes may reside in head-to-tail tandem arrays. Mechanisms underlying differential expression from such arrays have not been fully elucidated. Regulation of human red (LWS) vs. green (MWS) opsins is considered a stochastic event, whereby upstream enhancers associate randomly with promoters of the proximal or distal gene, and one of these associations becomes permanent. We demonstrate that, distinct from this stochastic model, the endocrine signal {{thyroid}} hormone (TH) regulates differential expression of the orthologous {{zebrafish}} lws1/lws2 array, and of the tandemly quadruplicated rh2-1/rh2-2/rh2-3/rh2-4 array. TH treatment caused dramatic, dose-dependent increases in abundance of lws1, the proximal member of the lws array, and reduced lws2 Fluorescent lws reporters permitted direct visualization of individual cones switching expression from lws2 to lws1 Athyroidism increased lws2 and reduced lws1, except within a small ventral domain of lws1 that was likely sustained by retinoic acid signaling. Changes in lws abundance and distribution in athyroid zebrafish were rescued by TH, demonstrating plasticity of cone phenotype in response to this signal. TH manipulations also regulated the rh2 array, with athyroidism reducing abundance of distal members. Interestingly, the opsins encoded by the proximal lws gene and distal rh2 genes are sensitive to longer wavelengths than other members of their respective arrays; therefore, endogenous TH acts upon each opsin array to shift overall spectral sensitivity toward longer wavelengths, underlying coordinated changes in visual system function during development and growth."

* '''Fetal ocular development in the {{second trimester}} of pregnancy documented by 7.0 T postmortem Magnetic Resonance Imaging'''{{#pmid:30947240|PMID30947240}} "Few investigators have analyzed fetal ocular growth with Magnetic Resonance Imaging (MRI) of high magnetic strength. Our purpose is to obtain normative biometrics for fetal ocular development in the second trimester of pregnancy. Sixty specimens with a gestational age (GA) of 12-23 weeks were scanned using a 7.0 T MRI scanner. The linear interocular and binocular distances (IOD and BOD, respectively), globe diameter (GD) and lens diameter (LD) were measured on the transverse section of the largest diameter of the eyeballs. The three dimensional (3D) visualization model of the eyeball was reconstructed with Amira software. Then, the globe and lens volumes (GV and LV, respectively) were obtained. All the measurements were plotted as a function of GA. The fetal ocular structures in the second trimester of pregnancy could be clearly delineated on 7.0 T postmortem MRI images. All the linear measurements logarithmically increased with GA, while, the volumetric measurements linearly increased with GA. Postmortem MRI of high magnetic strength can clearly document fetal ocular growth in the second trimester of pregnancy. These quantitative data may be a valuable reference for the assessment of normal fetal eyeball development in clinical settings and may be considered a supplement to anatomical investigations."

|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers  
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}

Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Vision+Development ''Vision Development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Vision+Embryology ''Vision Embryology'']

|}
{| class="wikitable mw-collapsible mw-collapsed"
! Older papers  
|-
| {{Older papers}}

* '''The relationship between eye movement and vision develops before birth''' {{#pmid:22496813|PMID22496813}} "While the visuomotor system is known to develop rapidly after birth, studies have observed spontaneous activity in vertebrates in visually excitable cortical areas already before extrinsic stimuli are present. Resting state networks and fetal eye movements were observed independently in utero, but no functional brain activity coupled with visual stimuli could be detected using fetal fMRI. This study closes this gap and links in utero eye movement with corresponding functional networks. BOLD resting-state fMRI data were acquired from seven singleton fetuses between gestational weeks 30-36 with normal brain development. During the scan time, fetal eye movements were detected and tracked in the functional MRI data. We show that already in utero spontaneous fetal eye movements are linked to simultaneous networks in visual- and frontal cerebral areas. In our small but in terms of gestational age homogenous sample, evidence across the population suggests that the preparation of the human visuomotor system links visual and motor areas already prior to birth."

* '''Activation of c-Jun N-Terminal Kinase (JNK) during Mitosis in Retinal Progenitor Cells'''{{#pmid:22496813|PMID22496813}} "Most studies of c-Jun N-terminal Kinase (JNK) activation in retinal tissue were done in the context of neurodegeneration. In this study, we investigated the behavior of JNK during mitosis of progenitor cells in the retina of newborn rats. ... The data show, for the first time, that JNK is activated in mitotic progenitor cells of developing retinal tissue, suggesting a new role of JNK in the control of progenitor cell proliferation in the retina."
* '''Rearrangement of retinogeniculate projection patterns after eye-specific segregation in mice'''{{#pmid:20544023|PMID20544023}} "When monocular enucleation was performed after eye-specific segregation, rearrangement of retinogeniculate axons in the dorsal lateral geniculate nucleus (dLGN) was observed within 5 days. ...We also examined the critical period for this rearrangement and found that the rearrangement became almost absent by the beginning of the critical period for ocular dominance plasticity in the primary visual cortex."

* '''The long noncoding RNA RNCR2 directs mouse retinal cell specification'''{{#pmid:20459797|PMID20459797}} "We find that the RNCR2 is selectively expressed in a subset of both mitotic progenitors and postmitotic retinal precursor cells. ShRNA-mediated knockdown of RNCR2 results in an increase of both amacrine cells and Müller glia, indicating a role for this lncRNA in regulating retinal cell fate specification."
|}
==Timeline==
{|
|
Embryonic Development
* Weeks 3 - 4 Eye Fields-Optic Vesicle
* Weeks 5 - 6 Optic Cup, Lens Vesicle, Choroid Fissure, Hyaloid Artery
* Weeks 7 - 8 Cornea, Anterior Chamber, Pupillary Membrane, Lens, Retina
* Weeks 9 - 15 Iris, Ciliary Body
* Weeks 8 - 10 Eyelids
| [[File:Eye_and_retina_cartoon.jpg|600px]]
|}

{{Eye Timeline table}}

See below the drawings of sections of the whole eye from week 8 of development.<ref name="Streeter1957">{{Ref-Streeter1957}}</ref>

Optic Nerve
* Carnegie stage {{CS19}} - Optic nerve small, slender. Lumen practically whole length of stalk. Few or no fibers.
* Carnegie stage {{CS20}} - Ependymal arrangement partially retained along stalk. Remnant of ependyma along whole length of stalk. Hyaloid groove at bulbar end. A few fibers arriving at brain.
* Carnegie stage {{CS21}} - Remnant of ependyma present.
* Carnegie stage {{CS22}} - Sheath layer beginning to form. Vascular canal present.
* Carnegie stage {{CS23}} - Early nerve sheath. Reticular spongioblastic framework, striate arrangement of nuclei, bundles of fibers. Definite nerve sheath.

<gallery caption="Eye and Optic Nerve">
File:Streeter1957 fig04-19.jpg|Carnegie stage {{CS19}}
File:Streeter1957 fig04-20.jpg|Carnegie stage {{CS20}}
File:Streeter1957 fig04-21.jpg|Carnegie stage {{CS21}}
File:Streeter1957 fig04-22.jpg|Carnegie stage {{CS22}}
File:Streeter1957 fig04-23.jpg|Carnegie stage {{CS23}}
</gallery>

==Lens==
[[File:Stage_22_image_155.jpg|thumb|Human Lens (Carnegie stage {{CS22}})]]
The lens or crystalline lens or aquula (Latin, aquula = a little stream) has a key role in focussing light (with the cornea) upon the neural retina. The lens embryonic origin is from surface ectoderm of the sensory placodes that form in the head region (More? Week 4 - Placodes). The lens focusses by refracting light as it passes through the biconvex lens, which can be altered in shape (accommodation) by surrounding ciliary muscles. These ciliary muscles are activated (contracted) by parasympathetic innervation from the ciliary ganglion itself innervated by the oculomotor nerve (Cranial Nerve III) (More? Cranial Nerves).

surface ectoderm -> lens placode -> lens pit -> lens vesicle -> lens fibres -> lens capsule and embryonic/fetal nucleus.

:'''Links:''' [[Vision - Lens Development]]

==Stage 22 Eye==
The images below link to virtual slides of the human developing eye at [[Carnegie stage 22]]. Click on the image to open or select specific regions from the regions of interest links.

{|
| {{SlideStage22-08}}
| {{SlideStage22-08-eye}}
|
===Virtual Slide - Regions of Interest===
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=3&lat=-3544&lon=4688&layers=B Eye Overview]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=4&lat=-2030&lon=2572&layers=B Lens and Cornea]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-1208&lon=2473&layers=B Cornea and Anterior Chamber]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-2242&lon=2982&layers=B Lens - anterior]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-2670&lon=3082&layers=B Lens - posterior]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-2641&lon=2295&layers=B Lens -equator]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-2410&lon=1843&layers=B Iris and Lens]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-5201&lon=3493&layers=B Retina - Neural and Pigmented]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-5001&lon=4868&layers=B Retina and Nerve fibre layer]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-4603&lon=5797&layers=B Optic Nerve Head and Hyaloid Vessel]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-3939&lon=4852&layers=B Hyaloid Vessel]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-4710&lon=5838&layers=B Optic Nerve Head]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=5&lat=-6861&lon=8849&layers=B Optic Nerve and Sphenoid (''alar orbitalis'')]
* [http://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=4&lat=-4163&lon=7997&layers=B Extraocular Muscle - Medial Rectus]
|-
|}

'''Links:''' [[Embryo Virtual Slides]]
==Retinotopic Map==

This neuroscience term describes how the developing retina is precisely "mapped" onto the visual cortex through a series of signaling and activity dependent mechanisms. This follows from Hubel and Wiesel (1981 Nobel Prize in Physiology or Medicine) key discoveries (1959-70) of how in development system matching occurs in the visual system. The topographic map establishes an ordered neuronal connection between sensory structures and the central nervous system.

The retinotectal map (eye to brain) of birds (lower vertebrates):

* temporal (posterior) retina is connected to the rostral (anterior) part of the contralateral optic tectum
* nasal (anterior) retina to the caudal (posterior) tectum
* ventral retina to the dorsal (medial) tectum
* dorsal ventral (lateral) tectum

Retinal waves a form of coordinated spontaneous activity that occurs in the developing retina. These waves of electrical activity (action potentials) are thought to have a role in establishing the initial retinotopic map by correlating/coordinating the activity of neighbouring retinal ganglion cells.

EphA/ephrin-A molecular signaling also thought to have a role in establishing the initial retinotopic map.

==Neural Crest==

{|
| [[File:Mouse eye neural crest.jpg|400px]]

Mouse eye neural crest{{#pmid:16403239|PMID16403239}}
| [[File:Mouse_eye_TGF-beta_model.jpg|400px]]

Mouse eye TGF-beta model{{#pmid:16403239|PMID16403239}}

|}

:'''Links:''' [[:File:Mouse eye neural crest.jpg|Image - Mouse eye neural crest]] | [[:File:Mouse_eye_TGF-beta_model.jpg|Image - Mouse eye TGF-beta model]] | [[Sensory - Vision Development|Vision Development]] | [[Neural Crest Development]] | [[Head Development]]

==Schlemm's canal ==

[[File:Mouse Schlemm's canal development 01.jpg|600px]]

Schematic showing the stages of Schlemm's canal development in the postnatal mouse by the novel process of canalogenesis.{{#pmid:25051267|PMID25051267}}
(Cartoons have been drawn for clarity and are not intended to suggest that most early sprouts arise from the LVP.)

==Extraocular Muscles==
Extraocular muscles are required to move the eye within the orbit. Their embryonic origin requires an interaction between the cranial mesoderm and the migrating neural crest cells.

The following is from a recent paper comparing human to zebrafish muscle development.{{#pmid:22132088|PMID22132088}}
{|
! About the Muscles
! Legend
|-
| valign=top width=400px valign=top|
* Five of the six muscles (inferior rectus, superior rectus, lateral rectus, medial rectus, and superior oblique) originate at a common tendinous ring of fibrous tissue (the Annulus of Zinn).
** The Annulus of Zinn surrounds the optic nerve, ophthalmic artery, and ophthalmic vein at their entrance through the apex of the orbit.
* The sixth muscle (inferior oblique) has a separate origin point on the orbital side of the bony maxilla at the anterior inferomedial strut.
| valign=top width=200px|
* '''IR''' - inferior rectus
* '''SR''' - superior rectus
* '''LR''' - lateral rectus
* '''MR''' - medial rectus
* '''SO''' - superior oblique
* '''IO''' - inferior oblique
| valign=top| [[File:Human_extraocular_muscles_01.jpg|200px]]
|}

:'''Links:''' [[Vision_-_Extraocular_Muscle_Development|Extraocular Muscles]]
==Additional Images==
<gallery>
File:Stage 22 image 212.jpg|Human stage 22 developing iris region
File:Stage 22 image 211.jpg|Human stage 22 developing iris region
File:Stage 22 image 209.jpg|Human stage 22 overview of optic nerve
File:Stage 22 image 208.jpg|Human stage 22 overview of eye
File:Stage 22 image 207.jpg|Human stage 22 lens and hyaloid vessels
File:Stage 22 image 206.jpg|Human stage 22 optic nerve (stalk)
File:Stage 22 image 154.jpg|Human stage 22 retina
File:Mouse-optic nerve axons.jpg|Mouse adult optic nerve axons
File:Pax6 eye phenotypes.jpg|Pax6 eye phenotypes
</gallery>

===Historic Images===
{{Historic Disclaimer}}
<gallery>
File:Rugh 093.jpg|Frog eye development.
File:Bailey456.jpg|Fig. 456. Location of optic areas before the closure of the neural groove.
File:Bailey457.jpg|Fig. 457. Location of areas shown in Fig. 456 after the formation of the neural canal.
File:Bailey458-459.jpg|Fig. 458. Location of the optic area after the beginning of the formation of the optic cup and optic stalk. Fig. 459. Dorsal view of head of chick of 58 hours' incubation.
File:Bailey460.jpg|Fig. 460. Section through head of chick of two days' incubation.
File:Bailey461.jpg|Fig. 461. Section through head of chick of three days' incubation.
File:Bailey462.jpg|Fig. 462. Later stage in development of optic cup and lens than is shown in Fig. 461.
File:Bailey463.jpg|Fig. 463. Developing lens and optic cup.
File:Bailey464.jpg|Fig. 464. Model showing lens and formation of optic cup.
File:Bailey465.jpg|Fig. 465. Stages in the development of the lens in the rabbit embryo.
File:Bailey466.jpg|Fig. 466. Section through optic cup and lens invagination of chick of fifty-four hours' incubation.
File:Bailey467.jpg|Fig. 467. Section through eye of human embryo of 13-14 weeks.
File:Bailey468.jpg|Fig. 468. Development of the retinal cells.
File:Bailey469.jpg|Fig. 469. Vertical section through retina of a four months' human embryo.
File:Bailey470.jpg|Fig. 470. Vertical section through retina of a five and one-half months' human embryo.
File:Brown001.jpg|Fig. 1. Section through head of pig, 2 mm long.
File:Brown002.jpg|Fig. 2. Section through head of chick, 2 mm long.
File:Brown003.jpg|Fig. 3. Section through head of Foetal Pig, 2 mm long.
File:Brown004.jpg|Fig. 4. Section through head of Foetal Pig, 3 mm long.
File:Brown005.jpg|Fig. 5. Section through head of Foetal Pig, 3 mm long.
File:Brown006.jpg|Fig. 6. Section through head of Foetal Pig, 4 mm long.
File:Brown007.jpg|Fig. 7. Section through head of Foetal Pig, 7 mm long.
File:Brown008.jpg|Fig. 8. Section through head of pig, 8 mm long.
File:Brown009.jpg|Fig. 9. Section through head of pig, 9 mm long.
File:Brown010.jpg
File:Brown011.jpg|Fig. 11. colobomba of the fundus in the adult and means a lack of development.
</gallery>

== References ==
<references/>

===Online Textbooks===
* Kolb H, Fernandez E, Nelson R, editors. '''Webvision: The Organization of the Retina and Visual System''' [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK11530/

* Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Development of the Vertebrate Eye. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10024/
** [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5455%20 Evolution of the mammalian middle ear bones from the reptilian jaw] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.5460 Chick embryo rhombomere neural crest cells] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.table.3135 Some derivatives of the pharyngeal arches] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2871 Formation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2884 Differentiation of the Neural Tube] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2894 Tissue Architecture of the Central Nervous System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2908 Neuronal Types] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=dbio.section.2937 Snapshot Summary: Central Nervous System and Epidermis]

* '''Neuroscience''' Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel; McNamara, James O.; Williams, S. Mark. Sunderland (MA): Sinauer Associates, Inc. ; c2001 [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.879 The Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.894 The Inner Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.893 The Middle Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.891 The External Ear] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1447 Early Brain Development] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1546 Construction of Neural Circuits] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.chapter.1640 Modification of Brain Circuits as a Result of Experience]

* '''Molecular Biology of the Cell''' (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.section.3963 Neural Development] | [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=mboc4.figgrp.3966 The three phases of neural development]

* '''Clinical Methods''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.1949 63. Cranial Nerves IX and X: The Glossopharyngeal and Vagus Nerves] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3847 The Tongue] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3777 126. The Ear and Auditory System] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3627#3654 An Overview of the Head and Neck - Ears and Hearing] | [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cm.chapter.3897 Audiometry]

* '''Health Services/Technology Assessment Text (HSTAT)''' Bethesda (MD): National Library of Medicine (US), 2003 Oct. [http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?db=Books&rid=hstat1a.section.25014#25029 Developmental Disorders Associated with Failure to Thrive]

* '''Eurekah Bioscience Collection''' [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.chapter.53006 Cranial Neural Crest and Development of the Head Skeleton]
* [http://www.ncbi.nlm.nih.gov/books/NBK11530 Webvision: The Organization of the Retina and Visual System]. Kolb H, Fernandez E, Nelson R, editors. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-.

===Reviews===

{{#pmid:23523800}}

{{#pmid:20855501}}

The International Journal of Developmental Biology [http://www.ijdb.ehu.es/web/contents.php?vol=48&issue=8-9 Vol. 48 Nos. 8/9 (2004) Eye Development]

===Articles===
{{#pmid:19541779}}

'''Bookshelf''' [http://www.ncbi.nlm.nih.gov/sites/entrez?db=Books&cmd=search&term=vision%20development vision development]

===Search Pubmed===

'''Search Pubmed:''' [http://www.ncbi.nlm.nih.gov/pubmed?term=vision%20development vision development] | [http://www.ncbi.nlm.nih.gov/pubmed?term=eye%20development eye development] | [http://www.ncbi.nlm.nih.gov/pubmed?term=eye%20embryology eye embryology] | [http://www.ncbi.nlm.nih.gov/pubmed?term=retina%20embryology retina embryology] | [http://www.ncbi.nlm.nih.gov/pubmed?term=lens%20embryology lens embryology]

'''Search Entrez:''' [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=vision%20development vision development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=eye%20development eye development] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=eye%20embryology eye embryology] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=retina%20embryology retina embryology] | [http://www.ncbi.nlm.nih.gov/sites/gquery?itool=toolbar&cmd=search&term=lens%20embryology lens embryology]

==Terms==
{{Vision terms}}

==External Links==
{{External Links}}

{{Glossary}}

{{Footer}}

[[Category:Vision]]

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Book - Manual of Human Embryology 4

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{{Human Embryology Manual 1 TOC}}
----
{{Ref-Keibelchapter4-1910}}
{{Historic Disclaimer}}
=IV. Young Human Ova and Embryos up to the Formation of the First Primitive Segment=
[[File:Franz Keibel.jpg|thumb|300px|link=Embryology History - Franz Keibel|Franz Keibel (1861 - 1929)]]
(a critical. account)

By [[Embryology History - Franz Keibel|Franz Keibel]], Freiburg i. Br.

By the term ovum is understood in human embryology not only the egg-cell but also later the entire structure developed from the egg-cell, the embryo or fetus surrounded by the amnion and chorion. In this sense the word is used here. I do not intend to enumerate and describe here all young and very young human ova that have been observed, but only those which may be regarded as normal or approximately so, and as such I can regard only those in which an embryo has been observed. The observations of Graf Spee and Peters on human ova, and of Selenka on those of monkeys, have shown that in man and the primates the chorion grows much more rapidly than the embryo, that, consequently, a relatively large ovum may contain a very small embryo, and that even in the youngest ova yet studied the amnion and the yolk sack are already formed. I shall show later that in all probability the embryo never lies free upon the surface of the ovum, as it does in the birds and in many mammals, but that from the beginning it is sunk in the interior of the ovum, and that the amniotic cavity arises as a cleft and not by the formation of folds, and is always closed. The extraordinary minuteness of the embryonic anlage is a sufficient explanation why in early times, when the methods of investigation were imperfect, it was overlooked or unrecognized ; many of these earlier described ova may have been normal or nearly so. But when no embryonic anlage is found in an ovum that has been investigated according to all the rules of modern technic, as is the case with that which G. Leopold<ref>G. Leopold : Ueber ein sehr junges menschliches Ei, Arb. Kgl. Frauenklinik, Dresden, vol. iv, Leipzig, 1906. </ref>has lately studied with so much care, that ovum is certainly to be regarded as pathological; and the occurrence of maternal blood in the interior of the ovum is further evidence in this direction, as Spee has pointed out in Schwalbe's Jahresbericht. Leopold's ovum does not, therefore, require consideration here ; on the other hand, some older observations may be noticed, such as those of Eeichert, Wharton Jones, and Breuss. The ovum of Reichert especially has played and is still playing, though improperly, an important role in human embryology.

Reicher<ref>Reichert : Beschreibung einer f riihzeitigen menschlichen Frucht im blaschenformijsren Bildungszustande, etc., Abh. Kgl. Akad. d. Wiss., Berlin, 1873.</ref> found the ovum in the uterus of a suicide and estimated its age at twelve to thirteen or thirteen to fourteen days. It was completely enclosed by the mucous membrane of the uterus. On the side of the capsule which was turned towards the uterus there was a transparent area measuring 3 mm., which Reichert termed the capsule sear, believing that at the sides of it the mucous membrane of the uterus had grown up to surround the ovum. The ovum itself was a lenticular vesicle, whose diameters were 5.5 and 3.3 mm. The surface of the vesicle which was turned towards the uterus, the basal surface, was almost flat, that turned toward the lumen of the uterus somewhat curved. The marginal zone was richly furnished with small villi, the largest of which were 0.2 mm. in length and were already partly provided with lateral branches. From the margin small villi, diminishing in size, extended for some distance upon the surface of the vesicle turned toward the uterus wall (the basal surface of Reichert) ; but at the centre of the surface an area of about 2.5 mm. diameter remained free from them. In the centre of this free area Reichert described a dull circular spot. The surface of the ovum turned toward the lumen of the uterus was free from villi. The statements that Reichert makes concerning the finer structure of the ovum are in part insufficient and in part quite erroneous. Thus the wall of the ovum could not have been, as he supposed, purely epithelial, nor the villi hollow epithelial structures, but the wall must have been formed of mesodermal tissue with an epithelial covering and the axes of the villi occupied by mesodermal tissue. Reichert, indeed, perceived this mesodermal tissue, but regarded it as coagulated material. Also what he says concerning the ingrowth of the villi into the uterine glands is undoubtedly incorrect. As regards the structure of the dull spot on the uterine surface of the ovum, he supposed that it was formed by a layer of small, finely granular, nucleated, polyhedral cells, situated within the epithelial wall. It was taken for the embryonic anlage, and His has estimated the diameter of this "embryonic spot" as 1.6 mm. That this spot really represents the uninjured embryonic anlage is improbable, and Kollmann's statement in his " Handatlas der Entwicklungsgeschichte des Menschen" (1907) — "From what we know from the mammals this spot would now be regarded as the embryonic shield " — is, as will be shown later, absolutely disproved. A definite opinion cannot be given on account of the insufficiency of Reichert's description; nevertheless, I regard as well founded the conclusion of Spee, that Reichert had destroyed the actual embryonic structure during his preparation of the ovum and that in its degree of development it would have occupied a place between the oviun of Peters, to be described in detail later, and the Van Herff ovum of Spee. Probably Reichert had casually obsen^ed the embrj'o; it may have been the spherical body on the basal wall which he mentions on p. 26.

Another ovum which deserves mention is that described by Wharton Jones<ref>Thomas Wharton Jones : On the First Changes in the Ova of the Mammifera in Consequence of Impregnation and on the Mode of Origin of the Chorion, Philosoph. Transact. Royal Soc. London, 1837, p. 2.</ref> in 1837; it was of the size of a pea. The fisrure drawn from the preparation in alcohol shows a diameter of 6.2 X 4.7 mm. The surface turned toward the lumen of the uterus was free from villi Imbedded in the cavity of the ovum was a spherical body, with a diameter of 1,5 mm., which His, probably correctly, identified as the embryonic structure, that is to say, the actual embryonic anlage together with the amnion, yolk sack, and belly stalk. His assumes that this embryonic structure may have been artificially displaced.

Next comes an ovimi described by Breuss<ref>K. Breuss : Ueber ein menschliches Ei aus der zweiten Woche der Graviditat, Wiener med. Wochenschrift, 1877, pp. 502-504. </ref> in 1877. It was expelled together with the entire lining of the uterus. The wall of the ovum, which had a diameter of 5 mm., consisted of two layers, the outer of which was epithelial and the inner formed of connective tissue. The villi were for the most part unbranched and were about 1 mm. in length and 0.07 mm. in diameter; they left free a roundish area 2 mm. in diameter. Vessels could not be distinguished in their interior. A projection which occurred in the interior of the ovum, consisting of nucleated cells and having a length of 1 mm. and a diameter of 0.5 mm., may have been the embiyonic structure. If it is assumed that the ovum was normal, we must suppose that Breuss overlooked the amniotic cavity and the cavity of the yolk sack, a supposition which I regard as possible.

Mention may also be made of two other ova, described by Allen Thomson.<ref>Allen Thomson: Edinburgh Med. and Surg. Journal, vol. ii, 1839; and Froriep's Neue Notizen, vol. xiii, 1840. </ref> In one of these the embryonic structure must be regarded either as pathological or as not corresponding to the degree of development of the oviun. Thomson estimates the age of the smaller of the two ova at twelve to thirteen days. It had a diameter of 6.6 mm., was everywhere surrounded with villi, and was almost completely filled by a vesicle which was apparently the yolk sack. Upon the yolk sack was an embryo 2.2 mm. long and with both its cranial and caudal ends separated from the sack. Thomson makes no mention of an amnion, but we may suppose that it was present and covered the embryo on the surface opposite the yolk sack; and a belly stalk must also have been present, since Thomson states that the embryo was attached by its dorsal surface to the external egg membrane, that is to say, to the chorion.

Although the ovum is larger than that of His, to be described below, the second observation of Thomson may be recorded here; it concerns an ovum measuring 13.2 mm. in diameter, whose age was estimated at fifteen days. It was oval in shape and was evenly surrounded with villi. In the interior was a large cavity filled with fluid; and at one spot was the embryo, closely attached to the chorion and with a yolk sack and the remains of the amnion. The embryo had a length of 2.2 mm. and its cranial and caudal ends projected somewhat beyond the yolk sack. Viewed from the surface turned toward the chorion, it showed distinctly the medullary folds, which manifested a tendency to fuse at the middle of their length; ventrally was the heart. The diameter of the yolk sack was also 2.2 mm.; nothing is said concerning an amnion, but a lobe which is shown in Thomson's figure at the head end of the embryo is apparently the remains of an amnion that had been destroyed during the preparation of the embryo. It is interesting to note that Kolliker<ref>A. Kolliker: Entwicklungsgeschichte des Menschen, 1879. </ref>in 1879 regarded this second ovum described by Thomson as not quite normal on account of the large space which separated the embryo and yolk sack on the one side from the inner surface of the chorion on the other. We now know that this is the normal condition in embryos of this stage; and it is rather the smaller of Thomson's ova, which Kolliker was inclined to regard as normal, that shows abnormal conditions, since the yolk sack never fills the chorion so completely either in human or mammalian ova of this stage.

In all the ova so far mentioned a correct identification of the embryo, the yolk sack, amnion, belly stalk, and chorion is possible only in the two described by Thomson, which contained embryos already rather well developed; and even in these the identifications were only general ones, as may be seen from Kolliker's conmients upon the ova. He regarded, on the basis of the information available at that time, the normal ovum as abnormal and the abnormal one as normal, and the same conclusion was reached by Ecker, another distinguished embryologist of the time. A definite idea of the relations of the amnion and the belly stalk was also impossible for Kolliker. A correct interpretation of the discoveries mentioned could not be given at the time of their publication and, indeed, in part, not for some time after. The investigators who sought such interpretations were led from the right path, and Reichert's ovum, as I have stated, gave rise to many false ideas, even up to recent times. Consequently, as Elze and I<ref>Franz Keibel and Curt Elze : Normentafel zur Entwicklungsgeschichte des Menschen, Jena, 1908. </ref> have already pointed out in our "Normentafel zur Entwicklungsgeschichte des Menschen," an observation by His<ref>W. His: Anatomie menschlicher Embryonen, Leipzig, 1882, part ii, pp. 32 and 87 et seq. See also Mall, Joum. of Morph., vol. xix, p. 151. </ref> marks an important advance. The ovum in question (No. XLIV [Bff.] of His's collection) had a greater diameter of 8 mm. and, at right angles to this, a diameter of 7 mm.; it was somewhat flattened and at one point the villi were somewhat fewer than elsewhere. " On opening it there was found, on one wall, a small body measuring 1.4 mm. in its longest diameter and consisting of an ellipsoidal opaque body with a transparent vesicle attached to it. The opaque body, which seemed from partial foldings of its surface to be hollow, had a greater diameter of 0.85 mm. and a diameter at right angles to this of 0.6 mm. The transparent vesicle surrounded by its border one end of the ellipsoid. The connection with the chorion was by means of a short stalk, which stood in relation to both the vesicle and the ellipsoid." " I regard," His says in another place, " the more solid body as the umbilical vesicle and the transparent part as the amnion, and conclude from this that the embryonic anlage, so far as it is present, lies at the boundary between the two. With this idea the manner in which the structure is attached to the chorion agrees. That is to say, the place of attachment lies on the boundary between the vesicle and the opaque body." His's interpretation, we can say to-day with all certainty, is in agreement with the actual facts, and His was the first to give a perfectly correct interpretation of a human ovum of this stage. He further reported concerning this oviun that to the lower pole of the yolk sack there were attached threads of that looser tissue "which traverses the cavity of the ovum, one of these threads being especially distinguished by its tougher consistency and its opacity."

Later observations of young human embryos, carried out with the methods of modem technic, and especially with the aid of well stained and perfect series of sections, have, as has been already stated, confirmed His's views and have led to further, partly unexpected, results. It was the observations of Graf Spee, especially, that opened the way, and, later, H. Peters rendered great sendee; but for the sake of continuity the ova in question will not be described in the order in which they were discovered, but according to their degree of development. Consequently I shall begin with the ovum described by Bryce and Teacher.<ref>{{Ref-BryceTeacher1908}}</ref>

The ovum was obtained from an abortion, and although the presen'ation of the embryo proper is not perfect yet it is of the greatest importance; Fig. 10 shows the ovum as it lay in the uterine mucous membrane, according to a diagram by Bryce. With the exception of a small area it is completely surrounded by decidua, and the opening in the decidua (capsularis) is closed by coatated fibrin containing leucocytes. A large opening with fungoid tissue (the closing coagulum of Bonnet) is wanting.

The ovum, surrounded with blood, lies in a relativelj laige chamber, with whose walls it is not united; the maternal and fetal tissues are quite separate. The uinermost layer of the decidua, which forms the capsule of the ovum, is in an advanced stage of coagulation necrosis and, together with some deposits of fibrin, fonns around the ovum a capsule of dead tissue, which is interrupted only at one or two places, where blood-vessels open into the egg chamber, and at one where a hemorrhage has broken through into it.

<div id="Fig010"></div>
[[File:Keibel_Mall_010.jpg|800px]]

'''Fig. 10.''' Diagram of the ovum of Teacher and Bryce. after Bryce.

The wall of the ovum consists of an inner layer (the cytotropboblast, the layer of Langhans's cells), whose cells are poorly separated from one another and externally pass over into a very irregnilarly arranged plasmoditropboblast ; tbis has a distinctly plasmodial character and forms a loose network, whose spaces are filled with maternal blood. The cytotropboblast is nowhere continued into the plasmoditropboblBBtic trabecule.
The cavity of the ovum is oCoupied hj a delicate tissue which has the characters of mesenchyme. This primitive mesoblast shows no traces of a splitting into a parietal and a visceral layer; there is, accordingly, no Coelom. Alao, projections of the mesoblast toward the cytotropboblast (mesodermic villi) are not yet present.

The embryonic structures (the embryo together with the amnion and yolk sack) are represented by two vesicles which have an excentric position, and are completely separated from the cytotrophoblaat by the mesenchymstous tissue.

The cavity of the larger vesicle is supposed to be the amniotic cavity and that of the smaller the cavity of the yolk sack. The cells which enclose the amniotic cavity are cubical and those enclosing the yolk sack are flattened, but in neither vesicle do they show individual differentiation.

The egg-chamber is oval in form, the longest axis, lying parallel to the surface of the uterus, measuring 1.95 mm.; perpendicular to this and also parallel to the uterine surface the lumen of the egg-capsule measures 1.1 mm. and its depth (perpendicular to the surface of the uterus) is 0.95 mm. Since the wall of the ovum itself is folded the measurements of the cavity can be stated only approximately as 0.77 and 0.63 mm. The relative sizes of the amniotic cavity and of the yolk sack may be perceived from Fig. 10 ; unfortunately these structures were not intact.

The estimate of the age of the ovum made by Teacher and Bryce is very interesting and important, since it is based on exact data concerning the menstruation and the cohabitations. They estimate the age at thirteen to fourteen days, the ovum haWng been expelled sixteen and one-half days after the fertilizuig coitus. The cause of the abortion is supposed to have been a later coitus. If this estimate be correct the other ova to be described later on are all older than has hitherto been supposed. The table given by Bryce and Teacher may be reproduced here.

===Table I===

(From Bryce and Teacher.)

Chronological table of twelve well-described early pregnancies. Fertilization is assumed to be effected about 24 hours after insemination, and 24 to 48 hours are allowed for the completion of abortion. The leading data are supplied by the histories of Nos. 1, 4, 6, 8, 9, 10; and the position of the remainder is adjusted according to their dimensions and state of development. The ages according to the convention of His are shown in the colunm headed, " Days elapsed from omitted period."

[[File:Keibel Mall table01.jpg|800px]]

===Table II===

(From Bryce and Teacher.)

Showing the relation of the dates of fertilisation and of imbedding to the menstrual cycle, calculated from the data given in Table I. The higher figure in the age column is arbitrarily chosen in each instance, and allowance is made for the special circumstances of each case.

[[File:Keibel Mall table02.jpg|800px]]

We now come to the ovum described by Hubert Peters<ref>Hubert Peters: Ueber die Einbettung des menschlichen Eies und das friiheste bisher bekannte menschlichen Placentationsstadium, Leipzig und Wien, 1899. </ref>; it was obtained at the autopsy of a woman who had poisoned herself with caustic potash. Death had occurred within three hours after the taking of the poison and the autopsy was performed on the same day, a few hours after death. The ovum, together with the entire egg capsule, fixed by Prosector Kretz in Muller's fluid and hardened in alcohol, was successfully stained and microtomized by Hochstetter; it found in Peters an exceedingly careful observer. The uterus, from which the ovum was taken, was the size of a goose's egg and thick-walled, and felt somewhat more doughy and softer than a normal utenis. "The decidua of the corpus uteri was traversed by numerous furrows which crossed one another at various angles and occasionally formed grooves, so that the mucous membrane between these bounding furrows formed root-like or occasionally rounded projections toward the uterine lumen. In the middle of the posterior wall Prosector Kretz noticed a small area which was of the size of a hemp seed, which was somewhat paler but not prominent"; it contained the ovum. This was ellipsoidal in form, its diameters being 1.6 X ^-8 X ^-9 nam., these measurements, however, being of the cavity of the egg capsule. The part of the decidua in which the ovum lay presented, as the study of the sections showed, a slight, rounded elevation toward the cavity of the uterus. " While the decidua stretched as a very thin sheet, in the form of a capsulaxis, over the lateral portions of the ovum, the summit of the ovum was quite free from maternal tissue and projected freely into the lumen of the uterus by means of a blood-granulation mass which rested upon it " ; this mass Peters terms the fungoid tissue (Gewebspilz). If the interpretation which Peters gives of the fungoid tissue is correct and it is not a post-mortem phenomenon or a result of the poisoning, we have for the first time a human ovum that is not yet quite covered by a capsularis. Later Spee {Verh. Anat, Ges., 1902 (discussion of Marchand's paper) ; compare Schwalbe's Jahresber,, n. F., vol. viii. No. 2, p. 298) stated that occasionally young ova were to be found in which the egg capsule had an opening toward the uterus at the place where the scar tissue occurred, and at the corresponding place the ovum of Bryce and Teacher showed, as has been mentioned, only a small opening and no well-marked fungoid tissue. Upon the mesoblast layer of the ovum, which shows indications of the first few and as yet but slightly developed villi, follows a layer of epithelial cells, which reaches in places a thickness of more than 0.5 mm. and is traversed in a honeycomb manner by smaller and larger blood lacun®, but still remaining continuous at the periphery. Peters interprets this rightly, as I believe, as an " ectoblast shell " and names it the trophoblast, adopting the term which Hubrecht had proposed as a result of his observations on the hedgehog. Its further significance will be fully considered in the chapter on placentation and it will there also be compared with the corresponding structures of other mammals (cheiroptera) and with what is found in older human ova (Kastschenko, Merttens, Von Herff). As in the ovum of Bryce and Teacher differentiation of the cells of the trophoblast investment was evident, and the cytotrophoblast (Langhans's cells) and the spongiotrophoblast were distinguishable.<ref>Those portions of the trophoblast which come into relation with the tissues of the uterine wall and take an active part in the implantation of the ovum and in the excavation of the egg chamber have been termed trophoderm by Minot (Charles S. Minot: The Implantation of the Human Ovum in the Uterus, Trans. Americ. Gynaecol. Soc., 1904). </ref>

The embryonic anlage in this remarkable ovum was extraordinarily small, the embryo measuring, as estimated from the sections, 190 fi in length. I quote, as Peters has done, the description which Graf Spee has given of the cavity of the ovum. " The entire cavity of the ovum enclosed by the chorionic ectoblast [trophoblast shell, cytotrophoblast, and spongiotrophoblast] is filled up to the cavities of the embryonic anlage with mesoblast. This latter is very irregular as regards its possession of mesoderm cells. These are more numerous in the mesoderm layer resting upon the chorion, this consisting of two or at the most four cell-layers, presenting a greater thickness only in the region where the embryonic anlage oCours." Exception must be made of those places where there oCour the mesodermic rudiments of the villi, already mentioned. " The more central portions of the egg cavity are very poor in cellular elements. Only scattered tracts of spindle-shaped mesoderm cells traverse it. In the intervals there is a feebly staining fibrogranular mass which occupies most of the cavity. The cellular tracts frequently unite with the mesoderm enclosing the embryonic anlage and with that of the opposite wall of the ovum." Spee has found similar cords in all younger human ova.

" The embryonic anlage (cut obliquely in the preparations) shows two very small epithelial cavities (amnion and yolk sack), completely surrounded by mesoderm and contained within a thickening of the chorionic mesoblast. The amniotic cavity is completely closed. Its wall is differentiated into a very thin amniotic membrane, lying nearer the surface of the ovum, and a plate consisting of high cylindrical cells, the germinal disc (germinal shield, embryonic shield). Between these and the wall of the yolk sack, composed of entoderm cells occasionally diflficult to recognize, a layer of mesoderm is interposed. At one (the cranial) end (section 49 [44, 43f]) the cellular portion of the mesoblast does not appear to reach the median line. It lies on the yolk sack and is separated from the ectodermal territory by a * membrana prima.' This membrana prima (Hensen) always develops as a fine contour at the boundary between the ectoblast and mesoblast. It extends across the middle line in the preparations. . . . The series of sections clearly reveals the relations of most portions of the embryonic anlage. One end of the series only presents difficulties in the way of observation, partly on account of the unfavorable plane of the sections and partly, perhaps, on account of some complications in this region; for instance, it is impossible to determine the continuity of the ectoblast and mesoblast in some sections, and the condition of the yolk sack cannot be made out in this region." Spee considers this to be the caudal end. " An isolated cord connecting the embryonic structures with the chorion cannot be said to exist, since almost the entire embryonic anlage seems to be imbedded in a thickening of the chorionic mesoderm. Whether the first small rudiment of an entoblastic diverticulum (the allantoic duct) has begun to bud out and is represented by a ring of epithelium-like cells arranged around a lumen, is altogether uncertain." Grosser figures a section through the ovum in situ (see Fig. 96, from Peters's figure) in the chapter on the development of the egg membranes and the placenta. I have reconstructed the embryonic structures from plates left by Selenka and found neither an allantoic nor an amniotic duct. The surface of the yolk sack appeared warty, as if the blood and vessels were beginning to form upon it; naturally, the wax plates and the model give no definite information on this point.

The ovum which Graf Spee has described, unfortunately only briefly {Verh. deutsch. Ges, Gynak., 1905, pp. 421-423; compare Schwalbe's Jahresb., n. F., vol. xi. No. 2, p. 241), comes nearest to that of Peters. In a woman poisoned by oxalic acid one of the swollen areas of the mucous membrane on the ventral wall of the uterus immediately in front of the opening of the right tube was markedly prominent and its depressed summit showed a distinctive coloration. In it was found, in an egg capsule of 1.5 X 2.5 mm. diameter, an ovum poorly provided with villi and with a very small embryonic anlage that was surrounded by a quantity of blood. The summit of the egg capsule showed an implantation opening, which was 0.8 mm. in diameter and covered by a very flat blood-dot; in its neighborhood the villi were more numerous than elsewhere. Very near is also an ovum studied quite recently by Ph. Jung"; it was obtained from an abrasio mucossB. The preparation is splendidly preserved and apparently normal. Jung confirms in general the observations of Peters and Spee; comparatively little attention was devoted to the embryonic structures, and it is very desirable that these should be thoroughly studied. The cavity of the ovum measured 2.5 X 2.2 mm.

The Von Herff ovum described by Graf Spee" takes its place in the series here. It was expelled after a menopause of five weeks on the second day after a severe attack of influenza, probably as a result of the illness, and was apparently normal; it was throughout richly supplied with villi. Spee's remark that the diameters of the egg capsule, which he believes must have been really about 7 and 5i mm., were actually greater than these, is based upon the fact that the capsule was strongly distended with blood. Since, however, the periphery of the ovum must have reached the maternal tissues such a condition cannot be regarded as normal, but must have arisen shortly before or during the abortion. Spee estimates the diameter of the space within the chorion at barely 4 mm. The thickness of the chorion was 0.9 mm.; the villi measured 0.16-0.18 mm. at the base and were separated from each other by intervals of 0.2-0.78 mm. where the distance could be determined. The villi were covered by a double layer of cells, the Langhaus layer and the syncytium, the latter, although not so well developed as in later stages, being nevertheless quite distinct. Both layers are regarded as differentiations of the ectoblastic trophoblast shell, as cytotrophoblast (the Langhans layer) and spongioblast (the syncytium).

"Ph. Jung: Beitrage zur friihesten Eieinbettung beim menschlichen Weibe, with 20 figs, on 7 plates, Berlin, 1908.
" Graf von Spee : Neue Beobaehtungen iiber sehr f riihe Entwicklungsstuf en des menschlichen Eies, Arch. f. Anat. u. Physiol., Anat. Abt., 1896.

The embryonic structure had the form of an elongated thick papilla, attached at only one of its extremities to the chorion and elsewhere projecting quite freely into the interior of the cavity of the ovum (that is to say, into the periembryonic mesoderm space, the exocoelom of Selenka). Its long axis cuts the chorion at a very acute angle. A superficial furrow marks off on the papilla two elliptical portions. The larger of these forms the free pole of the papilla and proved to be the relatively very large yolk sack; the smaller one contains, on the surface which lies close to the chorion, a completely closed cavity, which was the amniotic cavity with its ectoblastic lining, but for the rest it is a compact cord composed of mesoderm, which extends from the mesoblastic covering of the yolk sack to the chorion, surrounding almost three-fourths of the amnion, so that this structure seems to be sunken into it. This part is the actual belly stalk and the sole connection with the chorion. In it there was an allantoic duct extending from the yolk sack. The portion of the ectoblastic lining of the medullo-amniotic cavity that rests on the yolk sack consisted of cylindrical cells and formed a thick plate, evidently the embryonic shield (the germinal disk). The plane of the embnonic shield is somewhat peqiendieular, that is to say, radial, to the surface of the chonon, the head end being nearest it. In the model the embryonic shield presents an oval outline and a median furrow lying between lateral portions which are convex dorsally and are somewhat unequal in size in the transverse direction. At the same time the dorsal surface of the shield is adapted to the form of the amniotic cavity and is, on the whole, concave. Spee gives the following measurements:

" Direct measurements of the embrj-onic papilla : Longest diameter, 1.84 mm. ; diameter through the constricted portion, 0.475 mm. Almost perpendicular to these the longest diameter of the yolk sack is 1.054 mm. The amnion together with the belly stalk measures 0.76 mm. ; the greatest length of the two latter structures is 0.76 mm.; the greatest breadth of the yolk sack, 1.083 mm.; its thickness about the same.

" Measurements taken on the model (divided by 100 and so reduced to the actual size): Length of the germinal disk, 0.37 mm.; its breadth, 0.23 mm. (this is the ectoblast plate of the germinal disk) ; height of the amniotic cavity, up to 0.34 mm.; thickness of the belly stalk together with the amnion, 0.62 mm.; length of the allantoic duct, 0.35 mm."

An amniotic duct or cord was not present. The entire anlage of the germinal disk (embryonic shield) was apparently, according to Spee, only a portion of the primitive streak region, notwithstanding that the typical fusion of the ectoblast and mesoblast could not be recognized in the sections, probably as a result of the preparation. No trace could be found of a differentiation of the medullary plates or of the chorda. " The primitive streak resrion extends right up to the cranial end of the germinal disk" (the embrj'onic shield).

The walls of the yolk sack seem to have advanced further in development than any other part of the embryonic anlage. The lining of its cavity is throughout single-layered and formed by cubical cells. Its mesoblastic covering forms irregular elevations and knobs, which project like small papillaB, especially over the pole that is turned away from the embryonic shield. In each papilla a blood island was interposed between the mesoblast and entoblast and produced a bulging of the mesoblast, but very little irr^rdarity of the entoblast. The formation of blood islands ceased at a much less distance from the embryonic shield in this ovum than in Von Spec's Glaevecke embryo, to be described later. The youngest stages of the blood islands lay nearest the embryonic shield; the oldest, at the distal pole of the yolk sack.

Near to this Von Herff ovum — indeed, aCoording to the opinion of its finder somewhat younger — is that which Beneke" found in a curetting done for therapeutic reasons. The curetting was made March 30, 1903, the last menstruation having lasted from March 5 to 10. No cohabitation had oCourred after March 22. The cavity of this ovum was 3.8 mm. long, 2.2 mm. broad, and 1.2 mm. highj and the embryo itself had a length of 1.74 mm.," its greatest thickness in the dorsoventral diameter being 0.6 mm. The meduUo-amniotic cavity was elongated caudally in a fusiform manner and was connected with the chorionic ectoblast by a cord of epithelial cells. It is stated that a typical medullary epithelium was already present in the anterior part of the germinal disk, and mention is made of a head process and of a chorda-like mass of cells. A neurenteric canal was present, but an allantoic duct was " not distinct." Although the statements in the brief description are not always as clear as could be desired, yet it seems to me, from the presence of a canalis neurentericus, of an amniotic duct or cord, and of an anlage of the medulla at the anterior end, that the embryo is more developed than that of the Herff ovum described by Spec.

A thorough study of the ovum is expected and when its results appear more definite conclusions will be possible; a thorough description may also make clear the meaning of certain peculiar structures that have been taken for blood-vessels, but which I shall not discuss here.

The embryonic anlage of an ovum described by Carlo Giacomini<ref>Carlo Giacomini: Un novo humano di 11 giorni, Giomale della Reale Academia di Medicina di Torino, vol. iii, anno 60, Fasc. 10-11, Torino, 1897. </ref>was probably in about the same stage of development as the Spee embryo Von Herff; but on aCoount of its poor preservation it would not have deserved mention here were it not that Giacomini states that it was expelled eleven days after a single cohabitation, so that its age may be estimated at nine or ten days, an estimate that does not agree with the conclusions of Bryce and Teacher that have been thoroughly discussed and reproduced above. The oCourrence may also be noted of a small duct that opened on the surface of the chorion near the point of fixation of the embryonic structures and has been identified by Marchand<ref>F. Marchand: Beobachtungen an jungen menschlichen Eiem, Anat. Hefte, vol. xxi, 1903.</ref> as the remains of an amniotic duct. A young ovum described by Mall<ref>{{Ref-Mall1900}} Also {{Ref-Mall1908}}</ref> may also be mentioned here, although since it possessed a well-developed
"Beneke: Ein sehr junges menschliches Ei (Ost.-Westpreuss. Gesellsch. f. Gynakol.), Deutsche med. Wochenschrift, Jahrg. xxx, 1904; and Mitteilungen und Demonstrationen mit dem Universalprojektionsapparat iiber ein sehr junges menschliches Ei, Marburger Sb., 1908, pp. 29-38. Surely a misprint.

Allantoic duct, it may have been somewhat older. Its diameter favors this view. Its long diameter was 10 mm. and its short one 7 mm., and, like the Reichert ovwn, it had villi only around its greatest circumference, two areas being thus bare. The villi were 0.5-0.7 mm. long and were branched. Mall now regards the ovum, probably correctly, as being pathological.

A very interesting ovum, similar, but probably in a slightly older stage of development, is described by Siegenbeek van Heukelom,<ref>Siegenbeek van Heukelom : Ueber die menschliche Plazentation, Arch, f . Anat. u. Physiol., Anat. Abt., 1898.</ref> who unfortunately considers the embryonic structures only casually.

It was obtained from a woman who received some bums during an epileptic attack and died six hours later. An autopsy was performed fourteen hours after death. With the exception of the bums the body showed no noteworthy departures from the normal. The entire uterus was placed in 3 per cent, formalin for some days and was then washed and fixed in alcohol. Since the ovum was collapsed as the result of a slight tear, accurate measurements could not be made; but Van Heukelom estimates its meridian at about 16i mm., which would give a diameter of 5.1 mm. The ovum was completely covered with villi; the insertion of thirtyone of these could be counted in a meridional section, fifteen occurring on the basal portion of the section (the portion nearest the uterine wall), twelve at the opposite pole, and two on each side at the equator. The villi of the embryonic pole were better developed than those of the opposite pole, and those at the -equator were " especially heavy and thick." They varied greatly in length, some being small and short, the majority 0.75 mm. long and those at the equator as much as 1 mm. Some were little branched, others, especially the basal and equatorial ones, had many offsets, and some divided into numerous branches. The epithelial covering of the villi was composed of two layers; the outer showed no cell limits, so that we have to deal again with the Langhans layer and the syncytium, a cytotrophoblast and a spongiotrophoblast. All the large branches of the villi were connected peripherally by means of epithelial trabeculaB (ectoblast trabeculflB, cell columns) to form an epithelial shell (ectoblast or trophoblast shell) provided with large and small spaces. This shell was often very thin, consisting of only a single cell layer; at other times it was very thick and in its thicker parts there were peculiar blood lacuna, resting directly upon the maternal compacta. The remaining conditions resembled in essence those of the Von Herff ovum of Spec. At the basal wall of the ovum was the embryonic papilla (the embryonic structures) united to the chorion at a very acute angle by a stalk. A distinct allantoic duct was present and the amniotic cavity was lower than in the Von Herff ovum described by Spee. Only one of the sections through the embryonic shield is figured, and this is reproduced here as Fig. 11. In it, in the region of the primitive streak, a mass of cells is seen projecting beyond the surface of the shield; Van Heukelom suggested that this might be Hensen's node, a suggestion which I, as well as the author, would mark with a large note of interrogation. Nothing is said of an amniotic duct.

Somewhat older again is the ovum that I<ref>Franz Keibel : Ein sehr junges menschliches Ei, Arch, f . Anat u. Physiol., Anat. Abt., 1890.</ref> described in 1890; it contained an embryonic shield with a well-developed primitive streak and was the first of this stage to be described. The ovum was expelled in an abortion with the egg capsule, which was lenticular in shape and measured 12 X ^i X 7 mm. ; it had a scar measuring 2i mm. Like all human ova of this period it was easily separated from the capsule, and measured SiX^iX^ mm. It had two areas free from villi : a larger one, measuring 6i X ^f ^^n., at the pole opposite the embryonic anlage, that is, the pole toward the lumen of the uterus; and a smaller one at the embryonic pole, situated exeentrically in front of the point of attachment of the belly stalk and measuring 2 mm. in diameter. The tissue of the Reichert scar showed neither glands nor blood-vessels, nor was it bounded by epithelium. The structure of the chorion and villi was the same as in the Spee ovum Von Herff, except that the syncytium was more strongly developed. The embryonic shield was about 1 mm. long and showed in the sections a well-developed primitive streak. The yolk sack liad a diameter of 1 mm. ajid showed numerous blood and bloodvessel aniagen. The endotlielial walls of the blood-vessels were already clearly distinguishable from the blood-corpuscles. There was an allantoic duct.

<div id="Fig011"></div>
[[File:Keibel_Mall_011.jpg|800px]]

'''Fig. 11.''' Section through the basal portion of (ha ovum described by Siegenbeek van Heukelom.

The ova described by Merttens,<ref>J. Merttens: Beitrage zur normalen und patholog. Anat. der menschl. Placenta, Zeitschr. f. Geburtsh. u. G>-nakol., vol. xxx, 1894, and vol. ixsi, 1895. "0. I^opold: Uterus und Kind, Leipzig, 1897.</ref> by Leopold in his Atlas, by Marchand and by Rossi need be mentioned here only in so far as they present especially striking peculiarities. Merttens had for study only four sections found aCoidentally in the investigation of a uterine curetting. Leopold in his ovum obtained by operation and estimated by him, " with doubtful accuracy," aCoording to Spee, to be seven to eight days old — it was undoubtedly older — found no distinct embryonic papilla, either on aCoount o£ unsatisfactory preservation, as Van Heukelom Euggesta, or, as Spee believes, because the ovuni was abnormal. At all events the ovum, whose diameter was 4 X 3-7 mm., need not be further considered here. Couceming the ova described by Marchand (1898) I may remark briefly that that author describes {Marburger 56., 1898, pp. 150-153), in an imperfectly preserved o\-um of the size of a pea, at that portion of the surface of the chorion where the remains of the embryonic anlage oCourred, a funnel-like depression of the surface of the chorion which led into a canal filled with syncytium; this he interpreted as the remains of an amniotic duct.<ref>In a later publication (Anat. Hefte, 1903, p. 223) he says: "We have to do therefore with a narrow canal traversing the choritn, which from Its opening at the surface is lined or, more properly, filled by a prolongation of the so-called surface epithelium, and ends blindly a short distance below the inner surface, just where the remains of the embryonic anlage occur." He ascribes the same significance to a depression on the surface of the chorion of an ovum of 14 X 3 mm diameters, which was laterally compressed by a blood-clot.</ref>

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[[File:Keibel_Mall_012.jpg|thumb|'''Fig. 12.''' Figure of the Embryonic Shield of the Frassi Ovum]]

From two later publications by Marchand (" Beobachtungen an jungren menschlichen Eiem,'' Anat. Hefte, No. 67, vol. xxi, 1902, pp. 217-278; and " Einige '* Beobachtungen an jungen menschlichen Eiem," Verh. Anat. Ges., 1902) it may be noted that he found in one ovum<ref>"The ovum was obtained from the body of a woman who had died as the result of a gunshot wound. It was studied in situ, but the ovum and egg capsule were folded; the latter, according to Marchand, had a length of about 1.5 cm, and a breadth and depth of about 5-6 mm. The entire ovum was covered with branched villi. The embryo was completely disintegrated</ref> that the intervillous space was not filled with maternal blood, not withstanding that the blood-vessels of the neighboring portions of the mucous membrane were esoessively engorged. The intervillous space seemed to be separated from the cavity of the egg chamber peripherally by strong ectoblastic proliferations; blood vessels opening into the cavity of the egg chamber could not be found. From this it would follow that the blood must normally enter the intervillous space only at a later period of development; a precocious entrance of the blood may, according to Marchand, lead to an abortion. Also, according to Rossi Doria,<ref>Tullio Jiossi Doria : Ueber die Einbettung des menschliehen Eies, studiert an einem kleinen Ei der zweiten Woche, Arch. f. Gynakol., 1905, vol. Issvi, pp. 433-505.</ref> who described an ovum of less than 9X8 mm. contained in a completely closed egg capsule, an actual circulation of the blood does not take place at the beginning of the second week of development, because at that time the maternal blood has not yet gained access to the intervillous space; he regards the so-called prickle processes on the surface of the syncytium as a deposit formed from degenerated blood-corpuscles and the " scar " of the egg capsule as formed by regressive changes of the summit of the reflexa. Nothing is stated concerning the embryonic anlage, and the entire ovum was apparently little favorable for the settlement of important questions. We may now consider an ovum obtained by operation and studied by Frassi<ref>L. Frassi : Ueber ein junges menschliches Ei in situ, Arch, f . mikr. Anat., vol. Ixx, 1907; and Weitere Ergebnisse des Studiums eines jungen menschlichen Eies in situ, ibid., vol. Ixxi, 1908. </ref> under my direction. The entire uterus, removed per vaginam, was at once placed in a warm 5 per cent, solution of formalin; it remained there forty-eight hours and was then washed for twelve hours and finally passed through alcohols of gradually increasing strength. Only then was it opened, cut into portions, and these imbedded in celloidin, in which condition it came into the hands of Frassi. The ovum, together with the portion of the uterus that contained it, was cut into serial sections. The ovum and embryonic structures were undoubtedly normal.

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[[File:Keibel_Mall_013.jpg|thumb|'''Fig. 13.''' Section of tbe embryonic anlage of the Frassi ovum.]]

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[[File:Keibel_Mall_014.jpg|thumb|'''Fig. 14.''' Section of tbe embryonic anlage of the Frassi ovum through the dorsal opening of the neurenteric canal.]]

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[[File:Keibel_Mall_014a.jpg|thumb|'''Fig. 14a,''' Section of tbe embryonic anlage of the Frassi ovum through the epithelium of yolk sack.]]

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[[File:Keibel_Mall_015.jpg|thumb|'''Fig. 15''' Section of tbe embryonic anlage of the Frassi ovum.]]

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[[File:Keibel_Mall_016.jpg|thumb|'''Fig. 16''' Section of tbe embryonic anlage of the Frassi ovum.]]

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[[File:Keibel_Mall_017.jpg|thumb|'''Fig. 17''' Section of tbe embryonic anlage of the Frassi ovum.]]

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[[File:Keibel_Mall_018.jpg|thumb|'''Fig. 18''' Section through portion of the wall of the yolk sack of the Frassi ovum.]]
The diameter of the egg capsule parallel to the surface of the uterine lumen, in the plane of the sections, was 13 mm., perpendicular to this surface it was 5 mm. at the middle of the ovum; the corresponding diameters of the cavity of the ovum were 9.4 and 3.2 mm. A scar could not be detected in the decidua capsularis. The ovum was completely covered with villi, which were especially developed in the equatorial zone; their length varied between 0.5 and 1.9 mm. Both blood-vessels and glands opened into the intervillous space, but with regard to the latter it could be perceived that they had been laterally eroded, so that their communication with the space was secondary. It is remarkable that practically no blood was contained in the intervillous space, notwithstanding that bloodvessels opened into it; it must be that the blood had completely escaped during the operation. The Langhans layer, syncytium, and cell columns were present; and of these the Langhans layer and the cell columns may be regarded as cytotrophoblast and the syncytium as spongiotropboblast. The embryonic shield was cut somewhat obliquely; it showed the anlage of a well-developed primitive streak, at the anterior end of which was a neurenteric canal and at the posterior end the cloacal membrane. The section shown in Fig. 14 passed directly through the neurenteric canal. In front of the primitive streak is a flat medullary groove, bounded by still indistinct medullary folds. Anlagen of blood and blood-vessels occurred on the yolk sack. Anlagen of blood-vessels could be seen with certainty in the mesoderm of the chorion only in the nei^borhood of the insertion of the belly stalk; none could be detected in the mesodermal axes of the villi. Models were made of the embryonic structures as well as of the embryonic shield, but only those of the shield need be figured here, together with some of the sections.

The measurements, made on the model, were:
# Length of the embryonic shield 1.17 mm.
# Breadth of the embryonic shield 0.6 mm.
# Length of the primitive streak 0.5 mm.
# Diameter of the yolk sack,
::a. Greatest 1.9 mm.
::b. Least 0.9 mm.

The embryonic structures were attached to the inner surface of the chorion by a typical belly stalk, in which vessels could be made out.
We come now to the ovum Gle (Glaevecke), the careful study of which by Graf Spee has done so much to advance our knowledge of human embryology. It was an aborted ovum that was expelled, together with the entire uterine mucous membrane, five weeks after the cessation of the menses. The diameter of the egg capsule parallel to the surface of the decidua was 10 X 11 mm., and perpendicular to this, the thickness of the decidua basalis being included, 7.2 mm. The ovum was everywhere, but not very thickly, covered with villi. It was somewhat oval, its diameters being 8.5 X 10 X 6.5 mm. ; the last diameter is that perpendicular to the decidua basalis. The villi were covered by a Langhans layer (cytoltrophoblast) and a syncytium layer (spongiotrophobiast), and the cavity of the ovum had a horizontal diameter of 7.5 X 8 mm.

Fig. 19 shows the embryonic structure after a model by Graf Spee (from Kollmans "Atlas"), and Fig. 20 a median sagittal section of them. The amnion is represented as opened in Fig. 19. The primitive streak, which occupied halt of the germinal disk in the stage of development last described, is now limited to its posterior end, and thb is bent strongly downward. At the anterior end of the streak was a well-developed canatis neurentericus, and in front of this the medullary groove bounded by well-formed medullary folds.

The greatest direct length of the embryonic structures, measured from the anterior curve of the amnion to the attachment to the chorion before the embryo had been placed in alcohol, was 2 mm., and that of the germinal disk from the anterior curve of the amnion to the hind end of the primitive streak was 1.54 mm. Throughout this length the disk rested like a lid upon the yolk sack. Tbe average diameters of the germinal disk (i.e., the distance in a direct line between the lines of reflection of the germinal layers into the amnion and yolk sack) were: anteriorly, 0.704-0.741 mm.; at the middle and posteriorly, 0.665 mm.; in the region of the canalis neurentericus and primitive streak, 0.589 mm. ; and in the region of the twliy stalk, about 0.4 mm. The medullary plate, disregarding its curvature, presented its greatest diameter of 0.5170.57 mm. anteriorly; at its narrowest portion, about the middle of the germinal di^, it was 0.494 to 0,38 mm. in breadth. The hei^t of the belly stalk together with the amnion was 0.722 mm., the width of tbe ectoblast plate exclusive of the amnion was 0.361 mm., and that of the subjacent mesoderm mass was 0.209 mm. The lumen of the neurenteric canal was 0.024 mm. in diameter and that of tbe circular swelling seen surrounding it on surface view was 0.13 mm.

<div id="Fig019"></div><div id="Fig020"></div>
[[File:Keibel_Mall_019.jpg|300px]][[File:Keibel_Mall_020.jpg|400px]]
'''Fig. 19'' '''Fig. 20''

Of this important embryo some figures are here reproduced, some of tbe yet intact embryo as published by Spec in his paper of 1889 and some of sections of it. Fig 21a shows the embryonic stnicture seen from tbe side as an opaque object: K, the embryonic shield (germinal disk); D, a constriction of the yolk sack; to the left one sees the caudal end of the embryonic shield bent down at right angles to the rest of the shield. Fig. 21b shows the dorsal surface of the embryo, and in Fig. 21c it is diowii from the right and dorsally; both these drawings were made under direct illumination, the amnion being intaet bnt cleared with turpentine, while the germinal disk still remained opaque. The reflection of the amnion into the embryonic shield is indicated by g; at the hiuder end of the shield is the primitive streak (Psl) and in front of this is the opening of the neurenteric canal. In Fig. 21c the portion of the streak that is bent venlrally is also visible.
Figs. 22 and 22a represent a section passing tfarough the neurenteric canal ; the amnion, the yolk sack, and the relations of the germinal layers are shown. The distal portion of the yolk sack shows blood-vessels in course of development; the round spaces shown in that r^on represent vascular canals lined with endothelium and, for the most part, completely filled with young blood-corpuscles, not shown in the figure. The diameters of the vessels increase toward the distal surface of the yolk sack; on the right side the yolk sack was torn. Fig. 22& shows the middle portion of the section represented in Fig. 22 more strongly magnified.

<div id="Fig021"></div>
[[File:Keibel_Mall_021.jpg|800px]]

'''Fig. 21.''' Three Views of the Glaevecke Embryo of Graf Spee

Fig. 23 is of a section through the region of the medullary groove. The chorda is included in the entoblast. The mesoblast shows to Ihe left a small cavity (h) resembling the cavity of a primitive segment in process of formation, and to the right is a narrow cleft in communication with the estra:-«mbryonic crelom.

Fig. 24 shows a section through the broadest portion of the head plate; it shows already a tendency toward the closure of the intestine. The primitive streak and primitive groove are represented more highly enlarged in Fig. 25. At the primitive streak the ectoblast bends down to unite with the layer of mesoblast subjacent to it. The nuclei of Ihe mesoblast are separated into two layers by a strip (Z) destitute of nuclei and also by a contour line that quickly disappears. The single layer that lies next to the entoblast cannot be distinguished from that layer in the middle of Ihe section, and in this region the entoblast appears thickened. P'ig. 26 shows Ihe half of a section passing through the medullary groove, greatly enlarged; at P it^shows the appearance of the pericardial cleft.

The embryo described by Elemod, a model of which has been reproduced by Friedr. Ziegler, is very similar to the Glaevecke embryo of Spec, but was not as well preser\-ed. It was obtained from a woman who had cohabited only during the night of November 6-7. The menslnaation expected on November 22 was omitted, the abortion occurred November 28.

<div id="Fig022-26"></div>
[[File:Keibel_Mall_022-026.jpg|800px]]

'''Fig. 22-26.'''

In the fresh condition the entire ovum with its villi measured 10.0 X 8.2 X 6.0 mm. The villi had a length of 1.2-2.0 mm., their diameter being 0.3-0.8 mm. The embryonic shield was biscuit-shaped and measured in length from head cap of the amnion to the projecting caudal end 1.3 mm.; its breadth was 0.23 mm. in front and 0.18 mm. posteriorly. The closed amnion was continued into an amniotic duct. Further it may be remarked that Etemod describes the remains of a chorda canal in both the caudal and cranial ends of the chorda anlage, which is flattened and contained within the entoderm. Etemod's statements concerning the heart and the blood-vessels will be considered in the chapter dealing with those structures.
Since Spec's Glaevecke embryo showed indications of the commencing formation of the embryonic coelom and the primitive segments, it represents the final stage of the period of development we are here considering.

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Book - Manual of Human Embryology 3

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=III. Segmentation=
[[File:Franz Keibel.jpg|thumb|300px|link=Embryology History - Franz Keibel|Franz Keibel (1861 - 1929)]]
By [[Embryology History - Franz Keibel|Franz Keibel]], Freiburg i. Br.

The segmentation stages of the human ovum have not yet been observed. We may with certainty assume that the early stages of fertilization are passed through during the passage of the ovum through the tube, but whether the entire segmentation takes place during this passage, or in what stage of segmentation the ovum reaches the uterus, cannot even be conjectured. In mammals there are apparently differences in this respect. The time, also, that the human ovima requires for the passage of the tube is very difficult to estimate; according to the data obtained from other manunals it cannot well be believed that the uterus is reached before the fifth day. Similarly, it is unknown whether the ovum becomes imbedded in the mucous membrane immediately after it has reached the uterus. That it is possible by good fortune and persistency yet to observe segmenting human ova in the tube is shown by the observations of Letheby <ref>H. Letheby: An Account of Two Cases in which Ovules or Their Remains Were Discovered in the Fallopian Tubes of Unimpregnated Women who Had Died during the Period of Menstruation, Philos. Transact. Royal Soc. London, 1852 (altogether unsatisfactory). See also Jroriep's Neue Notizen, 1852, No. 603. ' Th. L. W. Bischoff : Beitrage zur Lehre von der Menstruation und Bef nichtung, Zeitschrift fiir rationelle Medizin, neue Folge, vol. iv, 1854.</ref> and Hyrtl (in a work by Bischoff and in Froriep's "Neue Not.," 1852, No. 603), who discovered ova in the tube, althouja:h they were not able to make observations of the segmentation, partly on account of the imperfections of their technic and partly because the ova were unfertilized. The relative certainty with which experienced embryologists are able to-day to obtain the segmentation stages of even large mammals is an encouragement for further efforts in this direction. The force which propels the ovum through the tube into the uterus is the ciliary action of the tubal epithelium, and injury to this epithelium mav be the cause of the retention of the ovum in the tube or in a diverticulum of it and so the cause of a tubal pregnancy. If the ciliary current is not impaired, the ova are readily driven over any diverticula that may exist (Kromer<ref>P. Kromer: Untersuchungen iiber den Bau der menschlichen Tube, Leipzig, 1906. </ref>).

[[File:Keibel_Mall_009.jpg|thumb|Fig. 9. Ovum from a Monkey]]

It may be regarded as quite eertaia not only that the human ovum undergoes a segmentation quite similar to that of the other mammals, but also that it is a secondary total segmentation. The ancestors of the human species, like those of other mammals, must have once possessed yolk-laden meroblastic ova. A separation of the segmentation cells ccording to their developmental potencies has been variously postulated for the earlier stages of the mammalian segmentation, but conclusive evidence for this is lacking, the observations hitherto made not being capable of such an interpretation. This is true also of the observations which have been supposed to indicate the existence of a gastrulation process in the later stages, but this question will be considered in the chapter dealing with the formation of the germ layers and the gastrulation problem. Finally, it may be noted here that Hubrecht has recently succeeded in finding the ovum of a monkey in segmentation. It has been figured in ia KsmeDtatioD. from the tuba of the posthumous paper by Selenka which I have X wo (" MenschenafEen," 5 Lief., Zur vergleich ended Keimesgeschichte der Primaten, Wiesbaden, 1903) and is reproduced here (Fig. 9), since it is the only primate ovum in a segmentation stage at present known. Selenka states concerning this ovum, which was found in serial sections of a tube of a ''Macaacus nemestrinus'' from Java: "At about the middle of the oviduct was the ovum, having a diameter of 0.04 mm. and loosely attached to the somewhat frayed out ciliated cells. The largest of the approximately ripe ovarial ova were of about the same size. Four segmentation cells of about equal size are clearly to be distinguished; two of these (the central and left upper ones in the figure) are irregularly oval, the other two are almost spherical. The cells are naked; no trace of an enclosing membrane is to be observed. The shrinkage which tie tissues of the oviduct show suggests the idea that the segmenting ovum no longer retains its natural condition. It is, however, of importance to note what the preparation reveals: The segmentation begins in a manner rimilar to that of other higher mammals, and it is probable that it is completed as soon as the ovum has entered the uterine enlargement" This last conclusion I cannot accept.

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=The organs of special sense =

==The Eye==

The receptive mechanisms of all the general and special sense organs are derived from the ectoderm. With the single exception of the {{eye}}, all develop as direct specializations of the ectoderm in the form of the various neuro-epithelia. The eye is peculiar among the sense organs in that its receptive cells are not derived directly from surface ectoderm, but only indirectly from the ectoderm after it has become folded in to form the neural canal. The neuro-epithelium of the eye develops as a direct outgrowth from the central nervous system. The retina is a modified part of the brain; the optic nerves correspond to central nervous system fiber tracts. Of the accessory optic structures, the lens, the epithelium of the lids and conjunctiva, the eyelashes, the Meibomian glands and the epithelium of the lacrymal apparatus arc of ectodermic origin; the coats of the eye, the sclera and chorioid, and parts of their modified anterior extensions, the cornea, ciliary body and iris, are of mesodermic origin. In the sensory divisions of the other spinal and cranial nerves, with the exception of the olfactory, the cell bodies of the neurones which serve to connect the receptive mechanisms with the brain and cord are located in parts (the sensory ganglia of the cranial and spinal nerves) which have become separated from the crests of the neural folds as the latter fuse to form the neural canal. In the eye the cell bodies of these neurones are located in the retina, but the area of ectoderm from which the retina develops first occupies a position along the neural crest analogous to that occupied by the anlagen of the spinal and cranial ganglia. In the case of the retina this area, instead of becoming split off in the closure of the neural canal, becomes folded into the canal and later pushed out toward the surface in the optic evagination (Figs. 450, 457, 458).

<div id="Fig456"></div>
[[File:Bailey456.jpg|600px]]

'''Fig. 456. Diagram showing location of optic areas before the closure of the neural groove.''' (Modified from Lange)

The first indication of eye formation is found in the chick at the beginning of the second day of incubation ; in the human embryo, at what has been estimated as about the second or third week. At this stage the neural canal is not yet completely closed in and its anterior end shows three primary brain vesicles (p. 440, Fig. 497). The anlagen of the eyes first appear as bilaterally symmetrical evaginations from the lateral walls of the fore-brain vesicle (Figs. 459 and 460), and are at first large in proportion to the brain vesicle itself. When first formed, the optic evagination opens widely into the fore-brain vesicle (Fig. 460, right side), but as the distal part of the evagination expands more rapidly than the proximal part, there soon results a spheroidal optic vesicle attached to the fore-brain by the narrow optic stalk (Fig. 460, left side). Through the latter the cavity of the optic vesicle and the cavity of the fore-brain are in communication. With the development of the hemispheres, that part of the brain to which the optic stalks are attached becomes the inter-brain (diencephalon).

<div id="Fig457"></div>
[[File:Bailey457.jpg|600px]]

'''Fig. 457. Diagram showing location of areas shown in Fig. 456 after the formation of the neural canal.''' (Modified from Lange)

<div id="Fig458-459"></div>
[[File:Bailey458-459.jpg|600px]]

'''Fig. 458. Diagram showing, location of the (dark) optic area (see Fig. 457) after the beginning of the formation of the optic cup and optic stalk.''' (Lange)

'''Fig. 459. Dorsal view of head of chick of 58 hours' incubation.''' Mihalkovics.

:Lam. term, lamina terminalis; Fb., fore-brain; Opt. v., optic vesicle; M. b., mid-brain; H.b., hind or rhombic brain; H., heart.

===The Lens===

As each optic vesicle grows out toward the surface, its outer wall soon comes to lie just beneath the surface ectoderm. The cells of that portion of the ectoderm which overlies the optic vesicle next proliferate and cause a thickening of the ectoderm (Fig. 460, left side). This thickening of the ectoderm over the optic vesicle is apparent in the chick embryo of 36 hours incubation; in the human embryo it occurs about the third or fourth week and represents the first-step in the development of the crystalline {{lens}}. The thickened portion of ectoderm is known as the lens area (Fig. 460). The latter next becomes depressed against the outet surface of the optic vesicle forming a distinct lens invagination (Fig. 461). This becomes cup-shaped and then its edges come together and fuse, thus forming the lens vesicle (Fig. 462). At first the lens vesicle is connected with the surface ectoderm, but about the eighth week a thin layer of mesoderm grows in between the lens vesicle and the surface ectoderm, completely separating them (Fig. 463). The ingrowth of the lens vesicle against the outgrowing optic vesicle has the effect as though a small hard ball (the lens vesicle) had been pressed into a larger soft ball (the optic vesicle) (Fig. 464) . The lens vesicle pushes the outer wall of the optic vesicle in against the inner wall, the optic vesicle thus becoming transformed into the two-layered optic cup (Figs. 462, 463). Bonnet calls attention to the fact that the two processes, lens formation and the invagination of the optic vesicle to form the optic cup, are more or less independent and that it is not correct to describe the lens as actually pushing in the outer wall of the vesicle. As evidence of this is noted the fact that typical optic cup formation may occur in cases where no lens is developed. The optic cup when first formed is not a complete cup, for the invagination of the optic vesicle is carried over along the posterior surface of the optic stalk forming the choroidal fissure (Fig. 464, see also p. 545).

<div id="Fig460"></div>
[[File:Bailey460.jpg|600px]]

'''Fig. 460. Section through head of chick of two days' incubation.''' (Duval) The formation of the optic vesicle and stalk appears to be somewhat more advanced on the left than on the right.

<div id="Fig461"></div>
[[File:Bailey461.jpg|600px]]

'''Fig. 461. Section through head of chick of three days' incubation.''' (Duval)

<div id="Fig462"></div>
[[File:Bailey462.jpg|600px]]

'''Fig. 462. Showing somewhat later stage in development of optic cup and lens than is shown in Fig. 461.''' (Duval)

<div id="Fig463"></div>
[[File:Bailey463.jpg|600px]]

'''Fig. 463. Diagram of developing lens and optic cup.''' (Duval)

:The cells of the inner wall of the lens vesicle have begun lo elongate to form lens fibers. The epithelium over the lens is the anlage of the corneal epithelium. The mesodermal tissue between the latter and the anterior wall of the lens vesicle is the anlage of the substantia propria corneae.

The lens area is thicker at its center than at its periphery and when the center of the lens area becomes the bottom of the lens depression and later the posterior wall of the lens vesicle this greater thickness is maintained. In fact, the posterior wall of the vesicle becomes still thicker so that it projects into the cavity of the lens vesicle as an eminence (Fig. 465, g.). In the chick the lens vesicle is hollow. In man and in Mammals generally it is more or less filled with cells. These, however, degenerate and take no part in the formation of the permanent lens. Comparing the posterior with the anterior wall of the lens at this stage, the latter is seen to be composed of a single layer of cuboidal cells, the anlage of the anterior epithelium of the lens (Figs. 463, 465, g, h, i). This layer passes over rather abruptly into the posterior wall which consists of a single layer of greatly elongated lens cells, the anlagen of the lens fibers. The lens fibers continue to elongate until by the end of the second month they touch the anterior epithelium, thus completely obliterating the cavity of the lens vesicle (Fig. 467). A small cleft containing a few drops of fluid, the liquor Morgagni, may remain between the anterior epithelium and the lens fibers.

<div id="Fig464"></div>
[[File:Bailey464.jpg|600px]]

'''Fig. 464. Model showing lens and formation of optic cup.''' A piece has been removed from the upper part of cup to show the cavity of the optic vesicle and the position of the inner layer of the cup (nervous layer of retina). Bonnet.

When the lens fibers are first formed, the longest fibers are in the center and the fibers gradually get shorter toward the periphery of the lens where they pass over into the anterior epithelium (Fig. 465), As the lens develops, the peripheral fibers elongate more rapidly than the central, with the result that in the fully developed lens the central fibers are the shortest, forming a sort of core around which the now longer peripheral fibers extend in much the same manner as the layers of an onion (Fig. 467). The ends of the fibers meet on the anterior and posterior surfaces of the lens, along more or less definite lines which can be seen on surface examination and which are known as sutural lines. The lens fibers are at first all nucleated and as the nuclei are situated at approximately the same level in all the fibers, there results a so-called nuclear zone (Fig. 465, i). Later the nuclei disappear. The sutural lines become evident about the fifth month and mark the completion of the lens formation, although lens fibers continue to be formed throughout fcetal and in postnatal life, probably by proliferation and differentiation of the cells of the anterior epithelium, in the region where the latter pass over into the lens fibers. (The successive stages in the development of the lens are shown in Fig. 465.)

<div id="Fig465"></div>
[[File:Bailey465.jpg|600px]]

'''Fig. 465. Successive stages in the development of the lens in the rabbit embryo.''' Rabl.

:a, b, c, d, and e, are from embryos of from 11.5 to 12 days; f, at end of 12th day; g, during the 13th day; h, between the 13th and 14th days; i, from an embryo of 11 mm.

The lens capsule becomes differentiated during the third month. It is considered by some as derived from the lens epithelium and of the nature of a cuticular membrane, by others as a product of the surrounding connective tissue.

By the extension of mesodermic tissue in between the lens and the surface ectoderm, the lens becomes by the end of the sixth week completely surrounded by a layer of vascular connective tissue. This is known as the tunica lentis, and receives its blood supply mainly from the hyaloid artery (Fig. 467) which is a foetal continuation of the '''arteria centralis retina''' (p. 545). Branches from the hyaloid artery break up into a capillary network which covers both anterior and posterior surfaces of the lens. That part of the tunica vasculosa which covers the anterior surface of the lens is known as the ''membrana pupillaris''. After the earlier and more rapid formation of lens fibers ceases, the hyaloid artery begins (about the seventh month) to undergo regressive changes, and at birth is normally absent. Rarely more or less of the tunica vasculosa fails to degenerate, and if the part which persists is the membrana pupillaris there results a malformation known as congenital atresia of the pupil.

===The Optic Cup===

The way in which the optic vesicle becomes transformed into the optic cup has been partially described in considering the development of the lens (p. 536). The growing lens vesicle appears to push in the outer wall of the optic vesicle while at the same time the edges of the latter are extending around the lens vesicle, until what was originally the outer wall of the optic vesicle lies in apposition with the original inner wall, the cavity of the primary optic vesicle thus becoming completely obliterated (Fig. 466). In this way the optic vesicle is transformed into a two-layered thick-walled cup, the cleft between the two layers corresponding to the cavity of the primary vesicle. This cup is at first entirely filled with the developing lens (Fig. 466). As the cup increases in size faster than the lens, the contiguous walls of the cup and lens become separated, the cavity thus formed being the cavity of the vitreous humor (Fig. 467). There seems to be no question but that in Mammals a small amount of mesoderm at first separates the optic evagination from the lens area of the surface ectoderm. This apparently disappears, however, so that the two are in direct contact. It is still an open question w r hether a thin layer of mesoderm grows in between the edges of the cup and the lens at or just before the beginning of the formation of the vitreous. The lens now no longer fills the optic cup but lies in the mouth of the cup, while at the same time the margin of the cup is extending somewhat over its outer surface, w^here with the mesoderm it ultimately gives rise to the ciliary body and iris, and forms the boundary of the pupil. The remainder of the two-walled optic cup becomes the retina.

The Retina. Of the two layers which form the wall of the optic cup (p. 539) , the outer (away from the cavity) forms the pigmented layer, while the inner forms the remainder of the retina (Figs. 463, 467). Soon after the formation of the optic cup, it is possible to distinguish a boundary zone the future ora serrata between the larger posterior part of the retina or nervous retina and the smaller anterior non-nervous part which becomes the retinal portion of the ciliary body and iris. [ While the optic cup is forming, its two layers are both rapidly increasing in thickness by mitotic division of their cells. Especially is this true of the inner layer over that region which is to become the nervous retina, and it is the rather abrupt transition between the thicker nervous retina and the comparatively thin non-nervous anterior extension of the retina that forms the ora serrata.

<div id="Fig466"></div>
[[File:Bailey466.jpg|600px]]

'''Fig. 466. Section through optic cup and lens invagination of chick of fifty-four hours' incubation.''' Lange.
: Between the lens anlage and the pigmented layer of the retina is the broad inner layer of the optic cup, the anlage of the remainder of the retina.

The invagination which gives rise to the two-layered optic cup thus differentiates what may be called the two primary layers of the retina, the pigmented layer, and a broad layer from which are to develop all the other layers of the retina. (Figs. 463, 467) . Further development consists in a gradual differentiation, within the broad layer; of the various retinal elements and consequent demarcation of the layers which constitute the adult retina. The next layer to differentiate is the innermost layer of the retina, or layer of nerve fibers. This appears during the sixth or seventh week as a thin, clear, faintly striated zone containing a few scattered nuclei. What remains of the original inner layer of the cup has now become a comparatively thick layer with numerous chromatic and actively dividing nuclei. It may be conveniently designated the primitive nuclear layer.

<div id="Fig467"></div>
[[File:Bailey467.jpg|600px]]

'''Fig. 467. Horizontal section through eye of human embryo of 13-14 weeks.''' Modified from Lange.

The similarity in development between the retina and wall of the neural tube is to be noted. Thus the layer of nerve fibers appears to correspond quite closely to the marginal layer of the central nervous system, while the primitive nuclear layer is probably homologous with the mantle layer (pp. 449, 455). There is a similar correspondence between the retina and the central nervous system in regard to their early cellular development, the retinal cells early showing a differentiation into neuroblasts and spongiobiasts (pp.449, 455).

About the end of the eighth week the inner part of the primitive nuclear layer differentiates into the layer of eanzlion cetts (Fig. 468, h). These are large cells and with their processes constitute the third or proximal optic neurone. They can be first distinguished in the fundus of the cup and gradually extend to the ora serrata. They are the first of the cellular dements of the adult retina which can be definitely recognized as such. From each cell, two kinds of processes develop, dendrites, which ramify in this and in the more external layers of the retina, and an axone which grows toward the cavity of the eye and becomes a fiber of the layer of nerve fibers, whence it continues into the optic stalk as one of the fibers of the optic nerve. The layer of ganglion cells is thickest in an area situated somewhat lateral to the attachment of the optic stalk and known as the area centralis. It is distinguishable about the end of the fourth month. In the center of the area centralis the retinal layers become thin to form the fovea centralis which develops toward the end of foetal life. The macula lutea with its yellow pigment does not develop until after birth. The retina at this stage thus consists of four layers which from within outward are (i) the layer of nerve fibers, (2) the layer of ganglion cells, (3) the nuclear layer, (4) the pigmented layer (see Fig. 469).

<div id="Fig468"></div>
[[File:Bailey468.jpg|600px]]

'''Fig. 468. Diagram of the development of the retinal cells.''' Kallius, after CajaL a, Cone cells in unipolar stage; fe, cone cells in bipolar stage; c, rod cells in unipolar stage; d, rod cells in bipolar stage; e, bipolar cells; i, amacrine cells; g, horizontal cell; h, ganglion cells; k, Muller's cells or fibers; l, external limiting membrane.

The further development of the retina consists largely of a differentiation of the cells of the nuclear layer. This is extremely complex and our knowledge of it meager. From the cells of this layer develop (i) the rod and cone cells, (2) the bipolar cells, (3) the tangential or horizontal cells, (4) the amacrine cells, (5) Muller's cells or fibers. The differentiation of these cells and their processes /also results in the demarcation of the following layers of the adult retina; (i) the ^ layer of rods and cones, (2) the outer limiting membrane, (3) the outer nuclear layer, (4) the outer molecular layer, (5) the inner nuclear layer, (6) the inner molecular layer, (7) the inner limiting membrane (see Fig. 470).

Muller's cells or the sustentacular cells (Fig. 468, k) develop from spongioblasts which lie toward the inner limit of the nuclear layer. This accounts for the location of the nucleated portions of Muller's cells. Processes of these cells grow toward both surfaces of the retina until they reach the positions of the future outer and inner limiting membranes where they are believed to spread out horizontally and unite to form these membranes. Other spongioblasts develop into other types of glia cells, mainly spider cells, which are most numerous in the layer of ganglion cells and in the layer of nerve libers.

The rod and tone cells are first recognizable as unipolar cellsjFig. 468,0, c}. The single process of each extends outward as far as the outer limiting membrane. About as soon as these cells are recognizable, a differentiation between the rod cells and the cone cells can be made by their reactions to the Golgi silver stain, the cone cells impregnating much more completely than the rod cells. Processes next grow out from the inner ends of the cells so that they become bipolar (Fig. 468, b, d) . Both rod and cone cells are at first distributed throughout the entire nuclear layer, but later they become arranged in a distinct layer just beneath the outer limiting membrane. Each cell next gives rise to or acquires at its outer end an expansion which extends through the outer limiting membrane into the pigmented layer. As the pigmented cells give off pigmented processes which extend inward among the outer ends of the rods and cones, the layer of retina just beneath the pigmented layer consists of the outer ends of the rod cells, the tips of the cone cells, and the extensions of the pigmented cells. The nucleated portions of the rod and cone cells form the outer nuclear layer. Though the layer of rods and cones and the outer nuclear layer present the appearance in haematoxylineosin stained specimens of two distinct layers, it is evident from their development and structure that they should be regarded as a single neuro-epithelial layer. The apparent separation into two layers is due to the interposition of the outer limiting membrane, through tiny holes in which the rod and cone cells extend. The inwardly directed processes of the rod and cone cells are their axones. These cells constitute the first or distal optic neurone.

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'''Fig. 469. Vertical section through retina of a four months' human embryo.''' Modified from Lange.

The bipolar cells (Fig. 468, e), which with their processes constitute the middle or second optic neurone, also develop from cells of the nuclear layer and are probably bipolar at the time that the rod and cone cells are in the unipolar condition. Reference to the two bipolar cells shown in Fig. 468, e, e y shows that at this stage in their development their outwardly directed processes extend to the outer limiting membrane. These processes must either actually shorten or else fail to grow in length proportionately as the retina increases in thickness, for in the mature retina they end in relation with the centrally (inwardly) directed processes (axones) of the rod and cone cells. According as they are in relation with rod cells or cone cells, they are known as rod bipolars or cone bipolars. The retinal layer in which the axones of the rod and cone cells and the dendrites of the rod and cone bipolars intermingle is the outer, molecular layer of the adult retina. It is first distinctly recognizable as a molecular layer about the end of the fifth month (Fig. 470).

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'''Fig. 470. Vertical section through retina of a five and one-half months' human embryo.''' Modified from Lange.

The development of the outer molecular layer separates the originally single nuclear layer into two layers, an outer composed of the nuclei of the rod and cone cells and an inner composed of the nucleated bodies of the rod and cone bipolars, of the horizontal cells (Fig. 468, g) and of the amacrine cells (Fig. 468, / and f), all of which can be recognized in Golgi specimens by the end of the seyegth month. The rod and cone bipolars and probably most of the other cells of the inner nuclear layer send their axones centrally to lie in contact with the dendrites and bodies of the ganglion cells.

With the development of the cells of the inner nuclear layer and their processes, there differentiates the inner molecular layer which separates the inner nuclear layer and the layer of ganglion cells. It consists mainly of ramifications of the dendrites and axones of cells the bodies of which lie in the inner nuclear layer and in the layer of ganglion cells. (Fig. 470.)

===The Chorioid and Sclera===

These develop wholly from the mesoderm. The way in which the mesoderm grows in between the lens and the surface and surrounds the optic cup has been described (p. 536). That part of the mesoderm lying immediately external to the retina develops very early a closemeshed capillary network. This appears before there is any definitely limited sclera and may be considered the anlage of the chorioid, Somewhat later the mesoderm which lies just to the outside of the chorioid takes definite shape as the external fibrous tunic of the eye or sclera.

===The Vitreous===

The manner in which the vitreous humor is formed has been the subject of much controversy and remains still undetermined. As already noted in describing the development of the lens (p. 555), the latter is at first in direct contact with the inner layer of the retina (Fig. 466) . The lens and the retina separate as the vitreous forms between them. During the development of the lens the arteria centralis retinae does not stop as in the adult, with its retinal branches, but continues across the optic cup as the hyaloid artery to end in the vessels of the tunica vasculosa lentis. Some investigators consider the vitreous a transudate from these blood vessels. As the chorioidal fissure closes, some mesodermic tissue is enclosed with the artery, and some investigators consider the vitreous a derivative of this mesoderm. In Birds the formation of the vitreous humor begins before either mesoderm or blood vessels have penetrated the optic cup, and Rabl suggests that the vitreous may be a secretion of the retinal cells. Bonnet describes a double origin of the vitreous, differentiating between a retinal vitreous and a mesoderm vitreous. According to Bonnet, the primary vitreous body begins its formation before the closure of the chorioidal fissure. This primary vitreous appears at the time of formation of the optic cup, is a fibrillated secretion of the retinal cells, and fills in the vitreous space with a feltwork of fine fibrils. With the formation of the optic cup and the closure of the chorioidal fissure this type of vitreous formation ceases and a secondary vitreous body formation takes place from the cells of the pars ciliaris retinas. This is also fibrillated and there develops at this time the so-called hyaloid membrane which closely invests the vitreous. Among the fibers of the vitreous body appears the vitreous humor. Up to this point the vitreous is entirely non-cellular. There next grow into it mesodermal cells which have reached the vitreous through the chorioidal fissure along with the hyaloid artery. To what extent these cells are used up in the formation of the blood vessels of the vitreous and to what extent they remain as connective tissue cells of the mature vitreous after the blood vessels have degenerated is not known.

As already noted, the vitreous is at first crossed by the hyaloid artery which supplies the developing lens (p. 539). As lens formation becomes less active the artery becomes less important and by the end of the third month begins to atrophy. At birth nothing remains of it, but in its former course the vitreous is somewhat more fluid than elsewhere and this is known as the hyaloid canal (canal of Cloquet).

===The Optic Nerve===

Referring to the description of the optic evagination it will be recalled that the optic vesicle maintains its connection with the brain by means of the optic stalk (p. 534) . The latter is hollow and connects the cavity of the optic vesicle with the cavity of the brain. When the invagination of the optic vesicle to form the optic cup occurs (p. 536, Fig. 464), the invagination is carried along the posterior surface of the optic stalk toward the brain, and just as the invagination of the optic vesicle results in the obliteration of the cavity of the vesicle, so the invagination of the optic stalk results in an obliteration of its lumen. In Mammals the invagination of the optic stalk extends only part way to the brain, to the point where the artery enters. The chorioidal fissure closes about the seventh week.

The optic stalk consists of supportive elements only, and serves as a track along which nerve fibers extend to connect the retina and brain. Nerve fibers appear in the optic stalk about the fifth week. They appear first around the periphery and apparently crowd the neuroglia nuclei toward the center, so that the stalk at this stage may be said to consist of a mantle layer and a marginal layer, apparently analogous to these layers in the retina and brain. The nerve fibers gradually invade the entire stalk so that by the end of the third month the stalk has become^ transformed into the optic nerve among the fibers of which the original supportive elements of the stalk are still represented by neuroglia cells.

Much difference of opinion has existed in regard to the origin of the optic nerve fibers, whether they are processes of retinal cells which end in the brain or processes of brain cells which end in the retina. It is now quite generally accepted that most of the fibers of the optic nerve are the axones of nenrnneg the cell bodies of which are situated in the ganglion cell layer of the retina. These axones pass centrally into the layer of nerve fibers, which they form, and converge toward the optic nerve. Through the latter they pass to their terminations in the external geniculate bodies, optic thalami and anterior corpora quadrigemina. According to Cajal and others, some centrifugal fibers are present in the optic nerve. These are processes of cells situated in the above-mentioned nuclei, and terminate in the retina. They are fewer in number and of later development than the centripetal fibers.

As the mesodermic anlagen of the chorioid and sclera are present before the nerve fibers begin to grow into the optic stalk, the fibers must pass through these two coats in their exit from the eye. There results the fenestrated crossing of the optic nerve by these two coats, known as the lamina cribrosa.

The optic nerve fibers are medullated but have no neurilemmae. They are supported by neuroglia. The connective tissue sheaths which enclose the optic nerve are direct extensions of the meninges. These structural peculiarities accord with the peculiarities already described in the development of the nerve. Attention has been called to the fact (p. m) that just as the retina should be considered a modified and displaced portion of the central nervous system of brain cortex so the optic nerve should be considered not as a peripheral nerve, but as analogous to a central nervous system fiber tract.

==The Ciliary Body, Iris, Cornea, Anterior Chamber==

Anteriorly where they come into relation with the lens and are so arranged as to admit light to the retina, all three coats of the eye are extensively modified. Thus the retina is continued anteriorly as the pars ciliaris retinae and pars iridica retinae, the chorioid as the stroma of the ciliary body and iris, the sclera as the cornea.

===The Ciliary Body and Iris===

Both primary retinal layers (the two layers of the optic cup) are continued anteriorly as the non-nervous retinal layer of the ciliary body and iris. The outer pigmented layer consists at first of several layers of pigmented cells, but later becomes reduced to a single layer of pigmented cells which do not, however, possess pigmented processes extending inward as do the analogous cells of the nervous retina. The abrupt transition at the ora serrata where the thick pars optica retinae passes over into the pars ciliaris retinae has been mentioned (p. 540) . The inner laver of the primitive retina (optic cup) extends over the ciliary body and iris as a single layer of cells. These remain non-pigmented over the ciliary body, but over the iris acquire pigment so that the two layers form the pigmented layer of the iris.

The mesodermic tissue which forms the stroma of the ciliary body and iris is derived from the mesoderm lying between the lens and the surface ectoderm. This separates into two layers enclosing between them the anterior chamber of the eve, and it is from the posterior of these two layers that mesodermic tissue extends into the ciliary body and iris. It is continuous with the mesoderm of the tunica vasculosa lentis. During the fourth month the ciliary body undergoes foldings to form the ciliary processes. These foldings at first involve also the iris, but the iris folds soon (end of fifth month) disappear, while the ciliary processes become more prominent.

Of the smooth muscle tissue found in the ciliary body and iris, the dilator and contractor pupillse are, according to Bonnet, derived from the cells of the pigmented layer of the retina, i.e., from ectoderm. The ciliary muscle, on the other hand, develops from mesoderm. These muscles become well developed during the seventh month.

The suspensory ligament of the lens, or zonula Zinnii, first appears about the end of the fourth month. , By some the fibers of the suspensory ligament are believed to differentiate from the vitreous, by others they are considered as derived from the pars ciliaris retinae. Spaces among the fibers of the ligament enlarge and coalesce to form the canal of Petit.

===The Cornea===

The way in which the mesoderm grows in between the lens vesicle and the surface ectoderm has been described (p. 536) . This mesoderm forms a thin almost homogeneous layer containing v^rv few cells. Later that part of the layer which lies against the lens becomes more cellular and vascular, so that it is possible to distinguish between an outer homogeneous non- vascular layer and an inner cellular vascular layer. The former is the anlage of the cornea. Between the two layers vacuoles appear and coalesce to form the anterior chamber of the eye or cavity of the aqueous humor. Subsequent growth of the iris subdivides this chamber into an anterior and a ^posterior portion. The chamber separates the cornea from the pupillary membrane portion of the tunica vasculosa lentis. Bounding the chamber anteriorly and so forming the posterior layer of the cornea there develops a single layer of flat cells, the so-called " endothelium" of Descemet. Over the surface of the cornea the ectoderm remains and gives rise to a stratified squamous epithelium four to eight cells thick, the anterior corneal epithelium. Just beneath the epithelium a layer of corneal tissue retains its original homogeneous character and forms the anterior elastic membrane or membrane of Bowman. The posterior elastic membrane or membrane of Descemet is usually considered a cuticular derivative of the u endothelium." Throughout the rest of the cornea substantia propria cornea cells develop, either by proliferation of the few cells originally present or from cells which grow in from the surrounding cellular mesoderm, and become arranged parallel to the surface as the fixed connective cells of the cornea.

The Eyelids. After the lens vesicle becomes separated from the surface ectoderm, the latter folds over above and below to form the first rudiments of the upper and lower eyelids. Each fold consists of a core of mesoderm and i a covering of ectoderm. From the mesoderm develop the connective tissue elements of the lids including the tarsal cartilage. From the ectoderm develop the epithelial structures of the lids, the epidermis, the eyelashes and the glands. The edges of the lids gradually approach each other and about the beginning of the third month the epithelium of the upper licTbecomes adherent to that of the lower, thus completely shutting in the eyeball. This condition obtains until just before birth.

The eyelashes develop in the same manner as other hairs (p. 417).

The Meibomian glands, glands of Moll and the lacrymal glands develop, during the period the lids are adherent, as solid cords of ectoderm which grow into the underlying mesoderm where they ramify to form the ducts and tubules. The anlagen of the ducts and tubules of these glands al'(t LllUb at fust SUkUfToi ils of cells, their lumina being formed later by a breaking down of the central cells of the cords.

At the inner angle of the conjunctiva there develops beneath the eyelid folds a third much smaller fold. This becomes the plica scmilunaris which in man is a rudimentary structure, but in many of the lower Vertebrates, especially Birds, forms a distinct third eyelid, the so-called nictitating membrane. A few hair follicles and sebaceous glands develop in a portion of this fold forming the lacrymal caruncle..

===The Lacrymal Duct===

At a certain stage in development, a groove bounded by the maxillary process and the lateral nasal process extends from the eye to the nose (Fig. 98). This is known as the naso-optic furrow. Tin- cvlodrrm (epithelium) lying along the bottom of this groove thickens about the sixth week and forms a solid cord of cells. As development proceeds and the parts close in, this cord of ectoderm becomes enclosed within the mesoderm, excepting at its ends where it remains connected with the surface ectoderm of the eye and nose, respectively. By a breaking down of the central cells of this cord a lumen is formed and the cord becomes a tube, the lacrymal duct. The primary connection of the laojgnalduct is with the upper lid, but while the lumen is being formed an offshoot grows out to the under eyelid to form the inferior branch of the lacrymal duct.

==The Nose==

The anlage of the organ of smell is apparent in human embryos of about three weeks as two thickenings of the ectoderm, one on each side of the nasofrontal process. To these thickenings the term olfactory placodes has been applied (Kupffer) . A little later (in embryos of about four weeks) , the placodes become depressed below the surface, the depressions themselves being the nasal pits or fossa (see p 120; also Fig. 87). The placodes. which are destined to give rise to the sensory epithelium, thus come into closer relation with the olfactory lobes of the brain (rhinencephalon) which represent outgrowths of the fore-brain (telencephalon) (see p. 471).

As described in connection with the development of the face, the lateral nasal process arises on the lateral side, the medial nasal process on the medial side, of each nasal pit (p. 120 et seq.; also Fig. 96). Of these processes, the lateral is destined to give rise to the lateral nasal wall and the wing of the nose, the medial to a part of the nasal septum (see p. 120). As development proceeds, the epithelium (ectoderm) of the nasal fossae grows still deeper into the subjacent mesoderm, the fossae thus becoming converted into the nasal sacs, which lie above the oral cavity. According to Hochstetter and Peter, the nasal sacs are not at first in communication with the oral cavity, but lie above, and are separated from it by a plate of tissue which gradually becomes thinned out along the deeper part of the sacs to form the bucco-nasal membrane (Hochstetter). Later (in embryos of 15 mm.), the bucco-nasal membrane ruptures and the deep ends of the sacs thus come to open into the mouth cavity, the openings being known as the primitive choanen. In front of the primitive choanen, the nasal passages (formerly the nasal sacs) are separated from the mouth cavity by a plate of tissue, known as the primitive palate (Fig. 471). The latter is produced by the fusion of the maxillary process with the lateral and medial nasal processes (see p. 121), the outer nares thus being somewhat separated from the border of the mouth.

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'''Fig. 471. From a model of the anterior part of the head of a 15 mm human embryo.''' The lower jaws (mandibular processes) have been removed. Peter,

The further separation of the nasal passages from the o/al cavity has been described in connection with the development of the mouth (p. 286) and the development of the palatine processes of the maxillae. It may be repeated briefly, however, that from each maxillary process a horizontal extension grows across between the oral and nasal cavities until it meets and fuses with its fellow of the opposite side and with the nasal septum in the medial line, thus forming the palate which is continuous with the primitive palate mentioned above. (See Figs. 140 and 47 2.) In this way the nasal cavities or chambers become separated from the oral cavity, but remain in communication with the pharyngeal cavity through the posterior nares.

The nasal cavities increase enormously in size and the epithelial surface in extent, owing to (i) the formation of the palate alluded to above, (2) the development of the nasal concha which has been described on page 161, and (3) the development of accessory cavities maxillary, frontal and sphenoidal sinuses, which represent evaginations, so to speak, from the nasal cavities.

Probably correlated with the above-mentioned increase in extent of the nasal chambers is the fact that in lung-breathing Vertebrates the chambers have acquired a secondary function. In these forms the nose is not only an apparatus for receiving olfactory stimuli, but also serves to convey air to and from the lungs; it is in a sense a respiratory atrium. The sensory epithelium which the olfactory nerves supply is limited to relatively small areas in the superior conchae and nasal septum. Stratified columnar ciliated epithelium lines all other parts of the cavities.

Studies on the development of the olfactory nerve have led to diverse opinions, but the investigations of His and Disse go to show that the fibers are processes of cells derived from the thickened ectoderm or olfactory placodes. In human embryos of about four weeks some of the cells in the upper part of the nasal fossa become modified to form the neuro-epithelium. From the peripheral pole of each cell a short slender process grows out to the surface of the epithelium. From the opposite pole a slender process (the axone) grows centrally until it penetrates the olfactory lobe, where it ends in contact with the dendrites of the first central neurone of the olfactory tract. Most of these cells remain in the epithelial layer, but a few wander into the subjacent mesoderm and become bipolar cells which resemble the bipolar cells of the embryonic posterior root ganglia (p. 472). Other epithelial cells of the nasal fossa are converted into the sustentacular cells of the olfactory areas.

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'''Fig. 472. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

Jacobson's organ arises at the beginning of the third month as a small outpocketing of the epithelium on the lower anterior part of the nasal septum (Fig. 472). This evagination grows backward as a slender sac along the nasal septum for a distance of several millimeters and ends blindly. In the adult the sac degenerates and often disappears. In some of the lower Mammals Jacobson's organ develops to a greater degree, and some of the epithelial cells send out processes which pass to the olfactory lobes.

==The Ear==

The ear of higher Vertebrates consists of three parts the internal, middle, and external. Of these, the internal is the sensory portion proper and, so far as the epithelial elements are concerned, is of ectodermal origin, but secondarily becomes embedded in the subjacent mesoderm. It constitutes a complicated and highly specialized structure for the reception of certain stimuli that are to be conveyed to the central nervous system. From a functional standpoint it may be divided into the portion composed of the semicircular canals and their appendages, which is concerned in receiving and transmitting stimuli destined or the static and equilibration centers in the central nervous system, and the cochlear portion, which is concerned in receiving and transmitting auditory stimuli. The middle and outer ear represent modified portions of the most cranial of the branchial arches and grooves, and constitute an apparatus for conducting sound waves to the cochlear portion of the inner ear.

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'''Fig. 473. Half of a transverse section through the region of the developing ear of a sheep embryo of 13 mm.''' Bottcher.

:Aud. ves., Auditory vesicle; Co. gang., cochlear ganglion; End. ap., endolymphatic appendage; Rh.br., rhombic brain.

===The Inner Ear===

In embryos of 2 to 4 mm., the ectoderm becomes somewhat thickened over a small area lateral to the still open neural groove in the region of the future hind-brain. This thickening is often spoken of as the auditory placode (see p. 469). Owing to more rapid growth of the cells in the deeper layers of the placode, it soon becomes converted into a cup-shaped depression which is known as the auditory pit. The edges of the pit fold in and fuse and the pit thus becomes the auditory vesicle (otocyst), which finally becomes constricted from the parent ectoderm and lies free in the subjacent mesoderm (Fig. 473). At this stage (embryos of 4 to 5 mm.) the auditory vesicle is an oval or spherical sac the wall of which consists of two or three layers of undifferentiated epithelial cells. It lies against the neural tube and is connected with the latter by the acoustic ganglion (Fig. 474, a). About the same time an evagination appears on the dorsal side of the auditory vesicle, forming the anlage of the endolymphatic appendage (Fig. 474, a, b, c). The evagination continues to elongate and comes to form a club-shaped structure, the distal end of which becomes flattened to form the endolymphatic sac, the narrower proximal portion constituting the endolymphatic duct (Fig. 474 a-w). The epithelium, which at first consisted of two or three layers of cells, becomes reduced to a single layer. In the chick the endolymphatic appendage is formed out of the original union between the ectoderm and the auditory vesicle (Keibel, Krause). In Reptiles and Amphibia (Peter, Krause) and in man (Streeter), on the other hand, this appendage develops independently of the union, appearing on the dorsal side of the seam of closure in the auditory vesicle.

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'''Fig. 474. Different views (front, lateral and median) of reconstructions of the developing membranous labyrinth and acoustic nerve in human embryos of successive stages''', the view and length of the embryo being indicated under each figure. Streeter.

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'''Fig. 475. Lateral, front and median views of reconstructions of the membranous labyrinth and acoustic nerve in a human embryo of 30 mm.''' Streeter.

:In the figure on the left, the pars superior (pars sup.) of the vestibular nerve includes the three branches named above it; see also table on page 559.

In embryos of about 6 mm. the auditory vesicle (apart from the endolymphatic appendage) becomes differentiated into two portions or pouches a bulging, triangular one above, which is connected with the endolymphatic appendage, and a more flattened one below. The former is the vestibular pouch, the latter the cochlear pouch (Fig. 474, b-f). Between the two is a portion of the vesicle which is destined to give rise to the saccule and utricle, and which may be called the atrium (Streeter). Properly speaking, the atrium is a division of the vestibular pouch. The cochlear pouch is phylogenetically a secondary diverticulum which develops from the atrium, appearing first in the lowest landinhabiting Vertebrates (Amphibia).

As mentioned above, the vestibular pouch early assumes the form of a triangle, with the apex toward the endolymphatic appendage. The three borders of the triangle form the anlagen of the semicircular canals and bear the same interrelation as the latter. At the same time a vertical groove (the lateral groove) appears between the anlage of the posterior canal and the posterior end of the lateral canal (Fig. 474, b, d).

The formation of the semicircular canals is shown in Fig. 474, g-k. The edges of the triangular vestibular pouch expand and become more or less crescentic in shape. The two walls in the concavity of each crescent come together and then break away (Fig. 474, g, j, absorp. focus), thus leaving the rim of the crescent as a canal attached at its two ends to the utricle. The breaking away affects first the superior, then the posterior, and finally the lateral canal. During these gross changes the epithelium becomes reduced to a single layer of cells.

At one end of each canal an enlargement appears to form the ampulla, as shown in Fig. 474, /, m, n, and Fig. 475. a. 6. c.

The utricle and saccule represent divisions of the portion of the vestibular sac which is known as the atrium, and into which the endolymphatic appendage and cochlea open (see p. 553). In embryos of about 20 mm. a horizontal constriction begins to divide the atrium into an upper utricular portion, into which the semicircular canals open, and a lower saccular portion (Fig. 474, /, m). The constriction begins on the side opposite the endolymphatic appendage and gradually extends across the atrium until it finally divides the opening of the endolymphatic appendage into two parts (Fig. 475, a, b, c). One of these parts opens into the utricle, the other into the saccule, the two parts together constituting the utriculo saccular duct.

As stated before, the two- or three-layered epithelium of the earlier stages becomes reduced to a single layer. The cells of this layer are low cuboidal, with the exception of those over small areas in the ampullae, in the saccule, and in the utricle. Over an elongated area in each ampulla (crista ampullaris), a round area in the saccule and another in the utricle (macula acusticd), the epithelium becomes high columnar, some of the cells developing cilia on their free borders ("hair cells," neuro-epithelium) , the others becoming the sustentacular cells. These areas are the end-organs of the vestibular nerve (see p. 469) .

As already mentioned, the cochlear pouch appears as an outgrowth from the lower side of the atrium (see also Fig. 474, b-f) . The pouch becomes somewhat flattened, and, as it continues to grow in length, becomes coiled like a snailshell (Fig. 474, g-n; Fig. 475, a-c). This first formed coiled structure is the cochlear duct, or scala media. At the same time, it becomes distinctly marked off from the lower part of the atrium (now the saccule) by a constriction, the constricted portion forming the ductusr reuniens (Fig. 474, l-n; Fig 475, a-c).

All the structures thus far considered are at first closely invested by mesoderm. Later, this portion of the mesoderm gives rise to special tissues, and, in the region of the cochlear duct, to the scala vestibuli and scala tympani. The cells immediately around the vesicle proliferate and a dense fibrous layer is formed; outside of this fibrous layer the tissue becomes gelatinous; outside of this again another fibrous layer is formed, around which cartilage develops. The inner fibrous layer gives rise to the connective tissue that supports the epithelial lining of the vesicle. The gelatinous layer degenerates to form a fluid known as the perilymph, the space containing the fluid being the perilymphatic space. The outer fibrous layer becomes the perichondrium later the periosteum when the cartilage is replaced by the petrous portion of the temporal bone.

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'''Fig. 476. Section through the developing cochlea of a 90 mm cat embryo.''' Bottcher.

In the cochlear region the conditions are somewhat modified. Here the gelatinous layer does not form a complete covering for the cochlear duct, but is interrupted along two lines, (i) Laterally the fibrous layer lying next the cochlear duct is fused with the perichondrium (outer fibrous layer) (Fig. 476), (2) Medially the inner fibrous layer is fused with the perichondrium of a shelf-like process of cartilage which later ossifies to form the bony spiral lamina (Fig. 476). By these two partitions the cochlear perilymphatic space is separated into two spiral compartments which communicate only at the apex of the cochlea. The larger of these compartments, the scala vestibuli, communicates with the perilymphatic space around the utricle and saccule. The wall separating the scala vestibuli and cochlear duct becomes thinned out to form the vestibular membrane (of Reissner). The smaller compartment, the scala tympani, remains separated from the cavity of the middle ear by a thin membrane which closes the fenestra cochlea (rotunda) . In the wall between the scala tympani and the cochlear duct the organ of Corti develops (see below). A membrane, similar to that closing the fenestra cochleae, occurs between the cavity of the middle ear and the utricle, closing the fenestra vestibuli (ovalis). As alluded to above, the organ of Corti develops from the wall of the cochlear duct between the latter and the scala tympani (Fig. 476). The epithelial cells of the cochlear duct in this region become high columnar and arranged in two ridges which extend throughout the entire length of the duct. The cells of the ridge nearer the axis of the cochlea give rise to the membrana tectoria. Whether this is accomplished by cuticular secretion of the cells or by the fusion of long hair-like processes that grow from their free borders is not known. The cells of the outer ridge become differentiated into four groups. Those of the outer group (next the cells that give rise to the membrana tectoria) develop into the inner hair cells; those of the next group form the pillar cells; those of the third group differentiate into the outer hair cells; and those of the fourth (outer) group give rise to Hensen's cells. The hair cells, as the name indicates, develop delicate hair-like processes on their free borders, and, since the peripheral processes of the spiral (cochlear) ganglion cells end around them, are considered as the sensory cells of the cochlea, or auditory receptors (see p. 469) .

==The Acoustic Nerve==

The acoustic ganglionic mass is at first closely associated with the geniculate ganglion (ganglion of the facial (VII) nerve), the two together often being spoken of as the acustico-facialis ganglion (see also p. 508) . This lies in close contact with the anterior wall of the auditory vesicle when the latter is first constiicted from the ectoderm. The origin of the ganglion has not been traced in Mammals, but in cow embryos the geniculate has been seen to be connected with the ectoderm at the dorsal end of the first branchial groove (Froriep). The acoustic ganglion probably belongs to the lateral line system (Kupffer) (see also p. 430) .

Although the geniculate and acoustic ganglia are at first closely associated, each pursues an independent course of development. The description here will be confined to the acoustic. As already mentioned, this lies in close apposition to the side of the neural tube and the auditory vesicle and just anterior to the latter (Fig. 474, a). At a very early stage (embryos of 6-7 mm.), the mass shows a differentiation into two parts a dorsal one, the future vestibular ganglion, and a ventral one, the future cochlear (spiral) ganglion (Fig. 474, b, c). The ganglion cells become bipolar (see p. 469) , and, as is peculiar to the cells of the acoustic ganglia, remain in this condition. One process of each cell grows centrally to form a root fiber of the acoustic nerve, which terminates in contact with dendrites of neurones in certain nuclei in the central nervous system. The fibers from the cells of the vestibular ganglion form the vestibular root, those from the cells of the cochlear ganglion form the cochlear root. The other process grows peripherally and penetrates the wall of the auditory vesicle to enter into relation with certain cells that differentiate from the epithelial lining of the vesicle.

The peripheral processes of the vestibular ganglion cells come into relation with specialized cells (hair cells) in the ampullae of the semicircular canals

(crista ampullaris) and in the saccule and utricle (macula acustica) (see p. 556). The nerve itself becomes divided into certain branches, as indicated in the following table (Streeter). The peripheral terminations of the various branches are indicated in parentheses. Compare with Fig. 474, /, m, n, and Fig. 475, a, b, c.

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The vestibular ganglion cells, instead of remaining in a compact mass, come to form two fairly distinct masses in the course of the nerve (Fig. 475, a, b, c). One of these apparently is connected with the pars inferior, the other with the pars superior.

The cochlear ganglion cells at an early stage become closely associated with the developing cochlear duct and, as the latter forms a spiral, are carried] along with it. They thus come to form an elongated group of cells extending throughout the entire length of the cochlea (whence the name, spiral ganglion) (Fig. 474, j-n; Fig. 475, a-c). Consequently, the peripheral processes of these cells, which terminate in connection with the hair cells of the organ of Corti, are comparatively short. The central processes are naturally longer and form the cochlear nerve root which is twisted like a rope in part of its course (Fig. 475, c).

The Middle Ear. The cavity of the middle ear develops from the upper (dorsal) part of the first inner branchial groove. The epithelial lining of the cavity is thus of course derived from entoderm, and the other structures (auditory ossicles, etc.) from the adjacent mesoderm.

It has been stated elsewhere that the mesoderm in the first and second branchial arches gives rise, among other things, to certain skeletal elements. In the first arch there develops a rod of cartilage, known as Meckel's cartilage, which extends from the symphysis of the lower jaws to the region of the upper part of the first inner branchial groove (p. 164; Figs. 136, 139, 142). The proximal end of the cartilage becomes constricted to form two masses which constitute the anlagen of the malleus and incus (Figs. 135 and 136). In the second arch there develops a rod of cartilage which forms the lesser horn of the hyoid bone, the stylohyoid ligament, and the styloid process (Figs. 136, 139, .42). In close relation to the dorsal end of the styloid process, in the mesoderm destined to give rise to the periotic capsule, a mass of cartilage appears which is destined to give rise to the stapes (except the base?). It has not been fully determined whether the stapes is actually a derivative of the cartilage of the second arch or of the mesenchyme near its dorsal end. It has been suggested that the base of the stapes is of intramembranous origin and that the rest of the bone is derived from the cartilage of the second arch. Its close association with the cartilage of the second arch possibly indicates its phylogenetic origin from the latter.

At first the auditory ossicles are embedded in the mesoderm dorsal to the first inner branchial groove, that is, dorsal to the cavity of the middle ear. As development proceeds, the mesoderm is converted into a spongy tissue which finally degenerates. At the same time the ear cavity enlarges and wraps itself, as it were, around the ossicles. The latter thus come to lie within the cavity of the tympanum, but are covered by a layer of epithelium (entoderm) which is continuous with that lining the cavity.

Toward the end of foetal life, outgrowths from the cavity of the tympanum begin to invade the temporal bone. This process continues for some time after birth and results in the formation of cavities within the mastoid part of the temporal bone. These cavities are the mastoid cells, the epithelial lining of which is continuous with that of the tympanic cavity.

The Eustachian tube represents the lower (ventral) portion of the diverticulum which forms the cavity of the tympanum. In other words, as the dorsal part of the first inner branchial groove enlarges to form the cavity of the middle ear, the narrow part of the groove, just ventral to the cavity, persists as a communication between the latter and the pharynx.

The Outer Ear. The outer ear is formed from the dorsal part of the first outer branchial groove and the adjacent portions of the first and second arches (see Fig. 87). The ventral part of the groove flattens out and disappears. The dorsal part becomes deeper to form a funnel-shaped depression (during the second month ; Fig. 90) . From the deeper part of the funnel a solid mass of ectoderm grows inward until it comes into relation with the mesoderm immediately around the developing cavity of the tympanum, or, more specifically, the mesoderm surrounding the handle of the malleus. Here it spreads out into a disk-like mass. About the seventh month, the disk splits into two layers. The inner layer, which is separated from the epithelium of the middle ear by a thin sheet of mesoderm, becomes the outer layer of the tympanum. The tympanum is thus composed of an inner (entodermal) and an outer (ectodermal) layer, with a small amount of mesoderm between. From its mode of development, the tympanum may be considered in a sense as the wall which separates the first inner from the first outer branchial groove.

The split in the ectodermal disk (see above) gradually extends outward, invading the solid ectodermal in vagina tion until it finally unites with the bottom of the funnel-shaped depression on the surface, thus forming the external auditory meatus.

The external ear (or auricle) is derived from the portions of the first and second branchial arches surrounding the dorsal part of the first outer branchial groove (see Figs. 85, 87, 90, 91). About the end of the fourth week, the caudal border of the first arch exhibits three small elevations or tubercles (Fig. 477, A, 1-3), the cranial border of the second arch the same number (Fig. 477, A, 4-6). A groove, extending down the middle of the second arch, marks off a ridge (c) lying caudal to the three tubercles. The ventral tubercle (i) of the first arch gives rise to the tragus. The middle tubercle (5) of the second arch develops into the antitragus. The middle and dorsal tubercles (2 and 3) of the first arch unite with the ridge (c) on the second arch to form the helix. The dorsal tubercle (4) of the second arch gives rise to the anthelix. The ventral tubercle (6) of the second arch produces the lobule. It should be noted that in the third month the dorsal and caudal portions of the helix are bent forward and conceal the anthelix.

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'''Fig. 477. Stages in the development of the external ear (auricle).''' A, Embryo of n mm.; B, of 13.6 mm.; C, of 15 mm.; D, foetus at the beginning of the 30! month; E, foetus of 8.5 cm.: F, foetus at term. For explanation of numerals, see text. His, McMurrich.

==Anomalies==

Malformations of the nose have been alluded to in connection with hare lip, cleft palate, etc., on page 212, and are also discussed in the chapter on teratogenesis (XX). Malformations affecting the eye (cyclopia, microphthalmia, etc.) and the ear (synotia, etc.) are dealt with in the chapter on teratogenesis.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_19|Foetal Membranes]]

==References for Further Study==

===The Eye===

GALLENGA: Entwickelung des Auges. Encyklopadie der Augenheilkunde, Lief. 6 and 7, 1902.

HOLDEN: An Outline of the Embryology of the Eye, New York, 1893.

VON KOLLIKER: Die Entwicklung und Bedeutung des Glaskorpers. Zeitschr. fur wissensch. Zoolog., Bd. LXVI, 1904.

LANGE, O.: Einblicke in die embryonale Anatomie und Entwicklung des Menschenauges. 1908.

RABL, C.: Ueber den Bau und Entwickelung der Linse. Zeitschr. fur wissensch. Zool., Bd. LXII and LXV, 1898; LXVII, 1899.

RAYMON Y CAJAL.: Nouvelles contributions a 1'etude histologique de la retine. Jour, de VAnat. et de la Physiol, Vol. XXXII, 1896.

ROBINSON. A.: On the Formation and Structure of the Optic Nerve and its Relation to the Optic Stalk. Jour, of Anat. and Physiol., Vol. XXX, 1896.

VON SPEE: Recherches sur 1'origine du corps vitre. Arch, de Biol., Vol. XIX, 1902.

===The Nose===

BEARD, J.: Morphological Studies. The Nose and Jacobson's Organ. Zool. Jahrbuch, Bd. Ill, 1889.

DISSE, J.: Die erste Entwickelung der Riechnerven. Anat. Hefte, Bd. IX, 1897.

His, W.: Beobachtungen zur Geschichte der Nasen- und Gaumenbildung beim menschlichen Embryo. AbhandL d. math.-phys. Klasse Ko'nig. Sachs. Gesellsch. d. Wissensch. , 1901.

HOCHSTETTER, F.. Ueber die Bildung der primitiven Choanen beim Menschen. Verhandl. d. anat. Gesellsch., Bd. VI, 1892.

VON MIHALKOWICZ, V.: Nasenhohle und Jacobsonsches Organ. Eine morphologische Studie. Anat. Hefte, Bd. XI, 1898.

PETER, K.: Die Entwickelung des Geruchsorgans und Jacobson'schen Organs in der Reihe der Wirbeltiere. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1901.

===The Ear===

BAGINSKY, B.: Zur Entwickelung der Gehorschnecke. Arch.f. mik. Anat., Bd. XXVIII, 1886.

BOETTCHER, A.: Ueber Entwickelung und Bau des Gehorlabyrinths. Verhandl. d. Kais.Leop.-Carol. Akad., Bd. XXXV, 1869.

BROMAN, I.: Die Entwickelungsgeschichte der Gehorknochelchen beim Menschen. Anat. Hefte, Bd. XI, 1898.

FUCHS, H.: Bemerkungen iiber die Herkunft und Entwickelung der Gehorknochelchen bei Kaninchen-Embryonen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1905.

HENSEN, V.: Zur Morphologic der Schnecke. Zeitschr. f. wissensch. Zool., Bd. XIII, 1863

His, W.: Zur Entwickelung des Acusticofacialisgebiets beim Menschen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1899.

KRATJSE, R.: Entwickelungsgeschichte des Gehororgans. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1902.

{{Ref-Streeter1906a}}

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[[Category:Neural]] [[Category:Vision]] [[Category:Hearing]] [[Category:Smell]]

Book - Text-Book of Embryology 18

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=The organs of special sense =

==The Eye==

The receptive mechanisms of all the general and special sense organs are derived from the ectoderm. With the single exception of the {{eye}}, all develop as direct specializations of the ectoderm in the form of the various neuro-epithelia. The eye is peculiar among the sense organs in that its receptive cells are not derived directly from surface ectoderm, but only indirectly from the ectoderm after it has become folded in to form the neural canal. The neuro-epithelium of the eye develops as a direct outgrowth from the central nervous system. The retina is a modified part of the brain; the optic nerves correspond to central nervous system fiber tracts. Of the accessory optic structures, the lens, the epithelium of the lids and conjunctiva, the eyelashes, the Meibomian glands and the epithelium of the lacrymal apparatus arc of ectodermic origin; the coats of the eye, the sclera and chorioid, and parts of their modified anterior extensions, the cornea, ciliary body and iris, are of mesodermic origin. In the sensory divisions of the other spinal and cranial nerves, with the exception of the olfactory, the cell bodies of the neurones which serve to connect the receptive mechanisms with the brain and cord are located in parts (the sensory ganglia of the cranial and spinal nerves) which have become separated from the crests of the neural folds as the latter fuse to form the neural canal. In the eye the cell bodies of these neurones are located in the retina, but the area of ectoderm from which the retina develops first occupies a position along the neural crest analogous to that occupied by the anlagen of the spinal and cranial ganglia. In the case of the retina this area, instead of becoming split off in the closure of the neural canal, becomes folded into the canal and later pushed out toward the surface in the optic evagination (Figs. 450, 457, 458).

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'''Fig. 456. Diagram showing location of optic areas before the closure of the neural groove.''' (Modified from Lange)

The first indication of eye formation is found in the chick at the beginning of the second day of incubation ; in the human embryo, at what has been estimated as about the second or third week. At this stage the neural canal is not yet completely closed in and its anterior end shows three primary brain vesicles (p. 440, Fig. 497). The anlagen of the eyes first appear as bilaterally symmetrical evaginations from the lateral walls of the fore-brain vesicle (Figs. 459 and 460), and are at first large in proportion to the brain vesicle itself. When first formed, the optic evagination opens widely into the fore-brain vesicle (Fig. 460, right side), but as the distal part of the evagination expands more rapidly than the proximal part, there soon results a spheroidal optic vesicle attached to the fore-brain by the narrow optic stalk (Fig. 460, left side). Through the latter the cavity of the optic vesicle and the cavity of the fore-brain are in communication. With the development of the hemispheres, that part of the brain to which the optic stalks are attached becomes the inter-brain (diencephalon).

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'''Fig. 457. Diagram showing location of areas shown in Fig. 456 after the formation of the neural canal.''' (Modified from Lange)

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'''Fig. 458. Diagram showing, location of the (dark) optic area (see Fig. 457) after the beginning of the formation of the optic cup and optic stalk.''' (Lange)

'''Fig. 459. Dorsal view of head of chick of 58 hours' incubation.''' Mihalkovics.

:Lam. term, lamina terminalis; Fb., fore-brain; Opt. v., optic vesicle; M. b., mid-brain; H.b., hind or rhombic brain; H., heart.

===The Lens===

As each optic vesicle grows out toward the surface, its outer wall soon comes to lie just beneath the surface ectoderm. The cells of that portion of the ectoderm which overlies the optic vesicle next proliferate and cause a thickening of the ectoderm (Fig. 460, left side). This thickening of the ectoderm over the optic vesicle is apparent in the chick embryo of 36 hours incubation; in the human embryo it occurs about the third or fourth week and represents the first-step in the development of the crystalline {{lens}}. The thickened portion of ectoderm is known as the lens area (Fig. 460). The latter next becomes depressed against the outet surface of the optic vesicle forming a distinct lens invagination (Fig. 461). This becomes cup-shaped and then its edges come together and fuse, thus forming the lens vesicle (Fig. 462). At first the lens vesicle is connected with the surface ectoderm, but about the eighth week a thin layer of mesoderm grows in between the lens vesicle and the surface ectoderm, completely separating them (Fig. 463). The ingrowth of the lens vesicle against the outgrowing optic vesicle has the effect as though a small hard ball (the lens vesicle) had been pressed into a larger soft ball (the optic vesicle) (Fig. 464) . The lens vesicle pushes the outer wall of the optic vesicle in against the inner wall, the optic vesicle thus becoming transformed into the two-layered optic cup (Figs. 462, 463). Bonnet calls attention to the fact that the two processes, lens formation and the invagination of the optic vesicle to form the optic cup, are more or less independent and that it is not correct to describe the lens as actually pushing in the outer wall of the vesicle. As evidence of this is noted the fact that typical optic cup formation may occur in cases where no lens is developed. The optic cup when first formed is not a complete cup, for the invagination of the optic vesicle is carried over along the posterior surface of the optic stalk forming the choroidal fissure (Fig. 464, see also p. 545).

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'''Fig. 460. Section through head of chick of two days' incubation.''' (Duval) The formation of the optic vesicle and stalk appears to be somewhat more advanced on the left than on the right.

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'''Fig. 461. Section through head of chick of three days' incubation.''' (Duval)

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'''Fig. 462. Showing somewhat later stage in development of optic cup and lens than is shown in Fig. 461.''' (Duval)

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'''Fig. 463. Diagram of developing lens and optic cup.''' (Duval)

:The cells of the inner wall of the lens vesicle have begun lo elongate to form lens fibers. The epithelium over the lens is the anlage of the corneal epithelium. The mesodermal tissue between the latter and the anterior wall of the lens vesicle is the anlage of the substantia propria corneae.

The lens area is thicker at its center than at its periphery and when the center of the lens area becomes the bottom of the lens depression and later the posterior wall of the lens vesicle this greater thickness is maintained. In fact, the posterior wall of the vesicle becomes still thicker so that it projects into the cavity of the lens vesicle as an eminence (Fig. 465, g.). In the chick the lens vesicle is hollow. In man and in Mammals generally it is more or less filled with cells. These, however, degenerate and take no part in the formation of the permanent lens. Comparing the posterior with the anterior wall of the lens at this stage, the latter is seen to be composed of a single layer of cuboidal cells, the anlage of the anterior epithelium of the lens (Figs. 463, 465, g, h, i). This layer passes over rather abruptly into the posterior wall which consists of a single layer of greatly elongated lens cells, the anlagen of the lens fibers. The lens fibers continue to elongate until by the end of the second month they touch the anterior epithelium, thus completely obliterating the cavity of the lens vesicle (Fig. 467). A small cleft containing a few drops of fluid, the liquor Morgagni, may remain between the anterior epithelium and the lens fibers.

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'''Fig. 464. Model showing lens and formation of optic cup.''' A piece has been removed from the upper part of cup to show the cavity of the optic vesicle and the position of the inner layer of the cup (nervous layer of retina). Bonnet.

When the lens fibers are first formed, the longest fibers are in the center and the fibers gradually get shorter toward the periphery of the lens where they pass over into the anterior epithelium (Fig. 465), As the lens develops, the peripheral fibers elongate more rapidly than the central, with the result that in the fully developed lens the central fibers are the shortest, forming a sort of core around which the now longer peripheral fibers extend in much the same manner as the layers of an onion (Fig. 467). The ends of the fibers meet on the anterior and posterior surfaces of the lens, along more or less definite lines which can be seen on surface examination and which are known as sutural lines. The lens fibers are at first all nucleated and as the nuclei are situated at approximately the same level in all the fibers, there results a so-called nuclear zone (Fig. 465, i). Later the nuclei disappear. The sutural lines become evident about the fifth month and mark the completion of the lens formation, although lens fibers continue to be formed throughout fcetal and in postnatal life, probably by proliferation and differentiation of the cells of the anterior epithelium, in the region where the latter pass over into the lens fibers. (The successive stages in the development of the lens are shown in Fig. 465.)

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'''Fig. 465. Successive stages in the development of the lens in the rabbit embryo.''' Rabl.

:a, b, c, d, and e, are from embryos of from 11.5 to 12 days; f, at end of 12th day; g, during the 13th day; h, between the 13th and 14th days; i, from an embryo of 11 mm.

The lens capsule becomes differentiated during the third month. It is considered by some as derived from the lens epithelium and of the nature of a cuticular membrane, by others as a product of the surrounding connective tissue.

By the extension of mesodermic tissue in between the lens and the surface ectoderm, the lens becomes by the end of the sixth week completely surrounded by a layer of vascular connective tissue. This is known as the tunica lentis, and receives its blood supply mainly from the hyaloid artery (Fig. 467) which is a foetal continuation of the '''arteria centralis retina''' (p. 545). Branches from the hyaloid artery break up into a capillary network which covers both anterior and posterior surfaces of the lens. That part of the tunica vasculosa which covers the anterior surface of the lens is known as the ''membrana pupillaris''. After the earlier and more rapid formation of lens fibers ceases, the hyaloid artery begins (about the seventh month) to undergo regressive changes, and at birth is normally absent. Rarely more or less of the tunica vasculosa fails to degenerate, and if the part which persists is the membrana pupillaris there results a malformation known as congenital atresia of the pupil.

===The Optic Cup===

The way in which the optic vesicle becomes transformed into the optic cup has been partially described in considering the development of the lens (p. 536). The growing lens vesicle appears to push in the outer wall of the optic vesicle while at the same time the edges of the latter are extending around the lens vesicle, until what was originally the outer wall of the optic vesicle lies in apposition with the original inner wall, the cavity of the primary optic vesicle thus becoming completely obliterated (Fig. 466). In this way the optic vesicle is transformed into a two-layered thick-walled cup, the cleft between the two layers corresponding to the cavity of the primary vesicle. This cup is at first entirely filled with the developing lens (Fig. 466). As the cup increases in size faster than the lens, the contiguous walls of the cup and lens become separated, the cavity thus formed being the cavity of the vitreous humor (Fig. 467). There seems to be no question but that in Mammals a small amount of mesoderm at first separates the optic evagination from the lens area of the surface ectoderm. This apparently disappears, however, so that the two are in direct contact. It is still an open question w r hether a thin layer of mesoderm grows in between the edges of the cup and the lens at or just before the beginning of the formation of the vitreous. The lens now no longer fills the optic cup but lies in the mouth of the cup, while at the same time the margin of the cup is extending somewhat over its outer surface, w^here with the mesoderm it ultimately gives rise to the ciliary body and iris, and forms the boundary of the pupil. The remainder of the two-walled optic cup becomes the retina.

The Retina. Of the two layers which form the wall of the optic cup (p. 539) , the outer (away from the cavity) forms the pigmented layer, while the inner forms the remainder of the retina (Figs. 463, 467). Soon after the formation of the optic cup, it is possible to distinguish a boundary zone the future ora serrata between the larger posterior part of the retina or nervous retina and the smaller anterior non-nervous part which becomes the retinal portion of the ciliary body and iris. [ While the optic cup is forming, its two layers are both rapidly increasing in thickness by mitotic division of their cells. Especially is this true of the inner layer over that region which is to become the nervous retina, and it is the rather abrupt transition between the thicker nervous retina and the comparatively thin non-nervous anterior extension of the retina that forms the ora serrata.

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'''Fig. 466. Section through optic cup and lens invagination of chick of fifty-four hours' incubation.''' Lange.
: Between the lens anlage and the pigmented layer of the retina is the broad inner layer of the optic cup, the anlage of the remainder of the retina.

The invagination which gives rise to the two-layered optic cup thus differentiates what may be called the two primary layers of the retina, the pigmented layer, and a broad layer from which are to develop all the other layers of the retina. (Figs. 463, 467) . Further development consists in a gradual differentiation, within the broad layer; of the various retinal elements and consequent demarcation of the layers which constitute the adult retina. The next layer to differentiate is the innermost layer of the retina, or layer of nerve fibers. This appears during the sixth or seventh week as a thin, clear, faintly striated zone containing a few scattered nuclei. What remains of the original inner layer of the cup has now become a comparatively thick layer with numerous chromatic and actively dividing nuclei. It may be conveniently designated the primitive nuclear layer.

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'''Fig. 467. Horizontal section through eye of human embryo of 13-14 weeks.''' Modified from Lange.

The similarity in development between the retina and wall of the neural tube is to be noted. Thus the layer of nerve fibers appears to correspond quite closely to the marginal layer of the central nervous system, while the primitive nuclear layer is probably homologous with the mantle layer (pp. 449, 455). There is a similar correspondence between the retina and the central nervous system in regard to their early cellular development, the retinal cells early showing a differentiation into neuroblasts and spongiobiasts (pp.449, 455).

About the end of the eighth week the inner part of the primitive nuclear layer differentiates into the layer of eanzlion cetts (Fig. 468, h). These are large cells and with their processes constitute the third or proximal optic neurone. They can be first distinguished in the fundus of the cup and gradually extend to the ora serrata. They are the first of the cellular dements of the adult retina which can be definitely recognized as such. From each cell, two kinds of processes develop, dendrites, which ramify in this and in the more external layers of the retina, and an axone which grows toward the cavity of the eye and becomes a fiber of the layer of nerve fibers, whence it continues into the optic stalk as one of the fibers of the optic nerve. The layer of ganglion cells is thickest in an area situated somewhat lateral to the attachment of the optic stalk and known as the area centralis. It is distinguishable about the end of the fourth month. In the center of the area centralis the retinal layers become thin to form the fovea centralis which develops toward the end of foetal life. The macula lutea with its yellow pigment does not develop until after birth. The retina at this stage thus consists of four layers which from within outward are (i) the layer of nerve fibers, (2) the layer of ganglion cells, (3) the nuclear layer, (4) the pigmented layer (see Fig. 469).

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'''Fig. 468. Diagram of the development of the retinal cells.''' Kallius, after CajaL a, Cone cells in unipolar stage; fe, cone cells in bipolar stage; c, rod cells in unipolar stage; d, rod cells in bipolar stage; e, bipolar cells; i, amacrine cells; g, horizontal cell; h, ganglion cells; k, Muller's cells or fibers; l, external limiting membrane.

The further development of the retina consists largely of a differentiation of the cells of the nuclear layer. This is extremely complex and our knowledge of it meager. From the cells of this layer develop (i) the rod and cone cells, (2) the bipolar cells, (3) the tangential or horizontal cells, (4) the amacrine cells, (5) Muller's cells or fibers. The differentiation of these cells and their processes /also results in the demarcation of the following layers of the adult retina; (i) the ^ layer of rods and cones, (2) the outer limiting membrane, (3) the outer nuclear layer, (4) the outer molecular layer, (5) the inner nuclear layer, (6) the inner molecular layer, (7) the inner limiting membrane (see Fig. 470).

Muller's cells or the sustentacular cells (Fig. 468, k) develop from spongioblasts which lie toward the inner limit of the nuclear layer. This accounts for the location of the nucleated portions of Muller's cells. Processes of these cells grow toward both surfaces of the retina until they reach the positions of the future outer and inner limiting membranes where they are believed to spread out horizontally and unite to form these membranes. Other spongioblasts develop into other types of glia cells, mainly spider cells, which are most numerous in the layer of ganglion cells and in the layer of nerve libers.

The rod and tone cells are first recognizable as unipolar cellsjFig. 468,0, c}. The single process of each extends outward as far as the outer limiting membrane. About as soon as these cells are recognizable, a differentiation between the rod cells and the cone cells can be made by their reactions to the Golgi silver stain, the cone cells impregnating much more completely than the rod cells. Processes next grow out from the inner ends of the cells so that they become bipolar (Fig. 468, b, d) . Both rod and cone cells are at first distributed throughout the entire nuclear layer, but later they become arranged in a distinct layer just beneath the outer limiting membrane. Each cell next gives rise to or acquires at its outer end an expansion which extends through the outer limiting membrane into the pigmented layer. As the pigmented cells give off pigmented processes which extend inward among the outer ends of the rods and cones, the layer of retina just beneath the pigmented layer consists of the outer ends of the rod cells, the tips of the cone cells, and the extensions of the pigmented cells. The nucleated portions of the rod and cone cells form the outer nuclear layer. Though the layer of rods and cones and the outer nuclear layer present the appearance in haematoxylineosin stained specimens of two distinct layers, it is evident from their development and structure that they should be regarded as a single neuro-epithelial layer. The apparent separation into two layers is due to the interposition of the outer limiting membrane, through tiny holes in which the rod and cone cells extend. The inwardly directed processes of the rod and cone cells are their axones. These cells constitute the first or distal optic neurone.

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'''Fig. 469. Vertical section through retina of a four months' human embryo.''' Modified from Lange.

The bipolar cells (Fig. 468, e), which with their processes constitute the middle or second optic neurone, also develop from cells of the nuclear layer and are probably bipolar at the time that the rod and cone cells are in the unipolar condition. Reference to the two bipolar cells shown in Fig. 468, e, e y shows that at this stage in their development their outwardly directed processes extend to the outer limiting membrane. These processes must either actually shorten or else fail to grow in length proportionately as the retina increases in thickness, for in the mature retina they end in relation with the centrally (inwardly) directed processes (axones) of the rod and cone cells. According as they are in relation with rod cells or cone cells, they are known as rod bipolars or cone bipolars. The retinal layer in which the axones of the rod and cone cells and the dendrites of the rod and cone bipolars intermingle is the outer, molecular layer of the adult retina. It is first distinctly recognizable as a molecular layer about the end of the fifth month (Fig. 470).

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'''Fig. 470. Vertical section through retina of a five and one-half months' human embryo.''' Modified from Lange.

The development of the outer molecular layer separates the originally single nuclear layer into two layers, an outer composed of the nuclei of the rod and cone cells and an inner composed of the nucleated bodies of the rod and cone bipolars, of the horizontal cells (Fig. 468, g) and of the amacrine cells (Fig. 468, / and f), all of which can be recognized in Golgi specimens by the end of the seyegth month. The rod and cone bipolars and probably most of the other cells of the inner nuclear layer send their axones centrally to lie in contact with the dendrites and bodies of the ganglion cells.

With the development of the cells of the inner nuclear layer and their processes, there differentiates the inner molecular layer which separates the inner nuclear layer and the layer of ganglion cells. It consists mainly of ramifications of the dendrites and axones of cells the bodies of which lie in the inner nuclear layer and in the layer of ganglion cells. (Fig. 470.)

===The Chorioid and Sclera===

These develop wholly from the mesoderm. The way in which the mesoderm grows in between the lens and the surface and surrounds the optic cup has been described (p. 536). That part of the mesoderm lying immediately external to the retina develops very early a closemeshed capillary network. This appears before there is any definitely limited sclera and may be considered the anlage of the chorioid, Somewhat later the mesoderm which lies just to the outside of the chorioid takes definite shape as the external fibrous tunic of the eye or sclera.

===The Vitreous===

The manner in which the vitreous humor is formed has been the subject of much controversy and remains still undetermined. As already noted in describing the development of the lens (p. 555), the latter is at first in direct contact with the inner layer of the retina (Fig. 466) . The lens and the retina separate as the vitreous forms between them. During the development of the lens the arteria centralis retinae does not stop as in the adult, with its retinal branches, but continues across the optic cup as the hyaloid artery to end in the vessels of the tunica vasculosa lentis. Some investigators consider the vitreous a transudate from these blood vessels. As the chorioidal fissure closes, some mesodermic tissue is enclosed with the artery, and some investigators consider the vitreous a derivative of this mesoderm. In Birds the formation of the vitreous humor begins before either mesoderm or blood vessels have penetrated the optic cup, and Rabl suggests that the vitreous may be a secretion of the retinal cells. Bonnet describes a double origin of the vitreous, differentiating between a retinal vitreous and a mesoderm vitreous. According to Bonnet, the primary vitreous body begins its formation before the closure of the chorioidal fissure. This primary vitreous appears at the time of formation of the optic cup, is a fibrillated secretion of the retinal cells, and fills in the vitreous space with a feltwork of fine fibrils. With the formation of the optic cup and the closure of the chorioidal fissure this type of vitreous formation ceases and a secondary vitreous body formation takes place from the cells of the pars ciliaris retinas. This is also fibrillated and there develops at this time the so-called hyaloid membrane which closely invests the vitreous. Among the fibers of the vitreous body appears the vitreous humor. Up to this point the vitreous is entirely non-cellular. There next grow into it mesodermal cells which have reached the vitreous through the chorioidal fissure along with the hyaloid artery. To what extent these cells are used up in the formation of the blood vessels of the vitreous and to what extent they remain as connective tissue cells of the mature vitreous after the blood vessels have degenerated is not known.

As already noted, the vitreous is at first crossed by the hyaloid artery which supplies the developing lens (p. 539). As lens formation becomes less active the artery becomes less important and by the end of the third month begins to atrophy. At birth nothing remains of it, but in its former course the vitreous is somewhat more fluid than elsewhere and this is known as the hyaloid canal (canal of Cloquet).

===The Optic Nerve===

Referring to the description of the optic evagination it will be recalled that the optic vesicle maintains its connection with the brain by means of the optic stalk (p. 534) . The latter is hollow and connects the cavity of the optic vesicle with the cavity of the brain. When the invagination of the optic vesicle to form the optic cup occurs (p. 536, Fig. 464), the invagination is carried along the posterior surface of the optic stalk toward the brain, and just as the invagination of the optic vesicle results in the obliteration of the cavity of the vesicle, so the invagination of the optic stalk results in an obliteration of its lumen. In Mammals the invagination of the optic stalk extends only part way to the brain, to the point where the artery enters. The chorioidal fissure closes about the seventh week.

The optic stalk consists of supportive elements only, and serves as a track along which nerve fibers extend to connect the retina and brain. Nerve fibers appear in the optic stalk about the fifth week. They appear first around the periphery and apparently crowd the neuroglia nuclei toward the center, so that the stalk at this stage may be said to consist of a mantle layer and a marginal layer, apparently analogous to these layers in the retina and brain. The nerve fibers gradually invade the entire stalk so that by the end of the third month the stalk has become^ transformed into the optic nerve among the fibers of which the original supportive elements of the stalk are still represented by neuroglia cells.

Much difference of opinion has existed in regard to the origin of the optic nerve fibers, whether they are processes of retinal cells which end in the brain or processes of brain cells which end in the retina. It is now quite generally accepted that most of the fibers of the optic nerve are the axones of nenrnneg the cell bodies of which are situated in the ganglion cell layer of the retina. These axones pass centrally into the layer of nerve fibers, which they form, and converge toward the optic nerve. Through the latter they pass to their terminations in the external geniculate bodies, optic thalami and anterior corpora quadrigemina. According to Cajal and others, some centrifugal fibers are present in the optic nerve. These are processes of cells situated in the above-mentioned nuclei, and terminate in the retina. They are fewer in number and of later development than the centripetal fibers.

As the mesodermic anlagen of the chorioid and sclera are present before the nerve fibers begin to grow into the optic stalk, the fibers must pass through these two coats in their exit from the eye. There results the fenestrated crossing of the optic nerve by these two coats, known as the lamina cribrosa.

The optic nerve fibers are medullated but have no neurilemmae. They are supported by neuroglia. The connective tissue sheaths which enclose the optic nerve are direct extensions of the meninges. These structural peculiarities accord with the peculiarities already described in the development of the nerve. Attention has been called to the fact (p. m) that just as the retina should be considered a modified and displaced portion of the central nervous system of brain cortex so the optic nerve should be considered not as a peripheral nerve, but as analogous to a central nervous system fiber tract.

==The Ciliary Body, Iris, Cornea, Anterior Chamber==

Anteriorly where they come into relation with the lens and are so arranged as to admit light to the retina, all three coats of the eye are extensively modified. Thus the retina is continued anteriorly as the pars ciliaris retinae and pars iridica retinae, the chorioid as the stroma of the ciliary body and iris, the sclera as the cornea.

===The Ciliary Body and Iris===

Both primary retinal layers (the two layers of the optic cup) are continued anteriorly as the non-nervous retinal layer of the ciliary body and iris. The outer pigmented layer consists at first of several layers of pigmented cells, but later becomes reduced to a single layer of pigmented cells which do not, however, possess pigmented processes extending inward as do the analogous cells of the nervous retina. The abrupt transition at the ora serrata where the thick pars optica retinae passes over into the pars ciliaris retinae has been mentioned (p. 540) . The inner laver of the primitive retina (optic cup) extends over the ciliary body and iris as a single layer of cells. These remain non-pigmented over the ciliary body, but over the iris acquire pigment so that the two layers form the pigmented layer of the iris.

The mesodermic tissue which forms the stroma of the ciliary body and iris is derived from the mesoderm lying between the lens and the surface ectoderm. This separates into two layers enclosing between them the anterior chamber of the eve, and it is from the posterior of these two layers that mesodermic tissue extends into the ciliary body and iris. It is continuous with the mesoderm of the tunica vasculosa lentis. During the fourth month the ciliary body undergoes foldings to form the ciliary processes. These foldings at first involve also the iris, but the iris folds soon (end of fifth month) disappear, while the ciliary processes become more prominent.

Of the smooth muscle tissue found in the ciliary body and iris, the dilator and contractor pupillse are, according to Bonnet, derived from the cells of the pigmented layer of the retina, i.e., from ectoderm. The ciliary muscle, on the other hand, develops from mesoderm. These muscles become well developed during the seventh month.

The suspensory ligament of the lens, or zonula Zinnii, first appears about the end of the fourth month. , By some the fibers of the suspensory ligament are believed to differentiate from the vitreous, by others they are considered as derived from the pars ciliaris retinae. Spaces among the fibers of the ligament enlarge and coalesce to form the canal of Petit.

===The Cornea===

The way in which the mesoderm grows in between the lens vesicle and the surface ectoderm has been described (p. 536) . This mesoderm forms a thin almost homogeneous layer containing v^rv few cells. Later that part of the layer which lies against the lens becomes more cellular and vascular, so that it is possible to distinguish between an outer homogeneous non- vascular layer and an inner cellular vascular layer. The former is the anlage of the cornea. Between the two layers vacuoles appear and coalesce to form the anterior chamber of the eye or cavity of the aqueous humor. Subsequent growth of the iris subdivides this chamber into an anterior and a ^posterior portion. The chamber separates the cornea from the pupillary membrane portion of the tunica vasculosa lentis. Bounding the chamber anteriorly and so forming the posterior layer of the cornea there develops a single layer of flat cells, the so-called " endothelium" of Descemet. Over the surface of the cornea the ectoderm remains and gives rise to a stratified squamous epithelium four to eight cells thick, the anterior corneal epithelium. Just beneath the epithelium a layer of corneal tissue retains its original homogeneous character and forms the anterior elastic membrane or membrane of Bowman. The posterior elastic membrane or membrane of Descemet is usually considered a cuticular derivative of the u endothelium." Throughout the rest of the cornea substantia propria cornea cells develop, either by proliferation of the few cells originally present or from cells which grow in from the surrounding cellular mesoderm, and become arranged parallel to the surface as the fixed connective cells of the cornea.

The Eyelids. After the lens vesicle becomes separated from the surface ectoderm, the latter folds over above and below to form the first rudiments of the upper and lower eyelids. Each fold consists of a core of mesoderm and i a covering of ectoderm. From the mesoderm develop the connective tissue elements of the lids including the tarsal cartilage. From the ectoderm develop the epithelial structures of the lids, the epidermis, the eyelashes and the glands. The edges of the lids gradually approach each other and about the beginning of the third month the epithelium of the upper licTbecomes adherent to that of the lower, thus completely shutting in the eyeball. This condition obtains until just before birth.

The eyelashes develop in the same manner as other hairs (p. 417).

The Meibomian glands, glands of Moll and the lacrymal glands develop, during the period the lids are adherent, as solid cords of ectoderm which grow into the underlying mesoderm where they ramify to form the ducts and tubules. The anlagen of the ducts and tubules of these glands al'(t LllUb at fust SUkUfToi ils of cells, their lumina being formed later by a breaking down of the central cells of the cords.

At the inner angle of the conjunctiva there develops beneath the eyelid folds a third much smaller fold. This becomes the plica scmilunaris which in man is a rudimentary structure, but in many of the lower Vertebrates, especially Birds, forms a distinct third eyelid, the so-called nictitating membrane. A few hair follicles and sebaceous glands develop in a portion of this fold forming the lacrymal caruncle..

===The Lacrymal Duct===

At a certain stage in development, a groove bounded by the maxillary process and the lateral nasal process extends from the eye to the nose (Fig. 98). This is known as the naso-optic furrow. Tin- cvlodrrm (epithelium) lying along the bottom of this groove thickens about the sixth week and forms a solid cord of cells. As development proceeds and the parts close in, this cord of ectoderm becomes enclosed within the mesoderm, excepting at its ends where it remains connected with the surface ectoderm of the eye and nose, respectively. By a breaking down of the central cells of this cord a lumen is formed and the cord becomes a tube, the lacrymal duct. The primary connection of the laojgnalduct is with the upper lid, but while the lumen is being formed an offshoot grows out to the under eyelid to form the inferior branch of the lacrymal duct.

==The Nose==

The anlage of the organ of smell is apparent in human embryos of about three weeks as two thickenings of the ectoderm, one on each side of the nasofrontal process. To these thickenings the term olfactory placodes has been applied (Kupffer) . A little later (in embryos of about four weeks) , the placodes become depressed below the surface, the depressions themselves being the nasal pits or fossa (see p 120; also Fig. 87). The placodes. which are destined to give rise to the sensory epithelium, thus come into closer relation with the olfactory lobes of the brain (rhinencephalon) which represent outgrowths of the fore-brain (telencephalon) (see p. 471).

As described in connection with the development of the face, the lateral nasal process arises on the lateral side, the medial nasal process on the medial side, of each nasal pit (p. 120 et seq.; also Fig. 96). Of these processes, the lateral is destined to give rise to the lateral nasal wall and the wing of the nose, the medial to a part of the nasal septum (see p. 120). As development proceeds, the epithelium (ectoderm) of the nasal fossae grows still deeper into the subjacent mesoderm, the fossae thus becoming converted into the nasal sacs, which lie above the oral cavity. According to Hochstetter and Peter, the nasal sacs are not at first in communication with the oral cavity, but lie above, and are separated from it by a plate of tissue which gradually becomes thinned out along the deeper part of the sacs to form the bucco-nasal membrane (Hochstetter). Later (in embryos of 15 mm.), the bucco-nasal membrane ruptures and the deep ends of the sacs thus come to open into the mouth cavity, the openings being known as the primitive choanen. In front of the primitive choanen, the nasal passages (formerly the nasal sacs) are separated from the mouth cavity by a plate of tissue, known as the primitive palate (Fig. 471). The latter is produced by the fusion of the maxillary process with the lateral and medial nasal processes (see p. 121), the outer nares thus being somewhat separated from the border of the mouth.

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'''Fig. 471. From a model of the anterior part of the head of a 15 mm human embryo.''' The lower jaws (mandibular processes) have been removed. Peter,

The further separation of the nasal passages from the o/al cavity has been described in connection with the development of the mouth (p. 286) and the development of the palatine processes of the maxillae. It may be repeated briefly, however, that from each maxillary process a horizontal extension grows across between the oral and nasal cavities until it meets and fuses with its fellow of the opposite side and with the nasal septum in the medial line, thus forming the palate which is continuous with the primitive palate mentioned above. (See Figs. 140 and 47 2.) In this way the nasal cavities or chambers become separated from the oral cavity, but remain in communication with the pharyngeal cavity through the posterior nares.

The nasal cavities increase enormously in size and the epithelial surface in extent, owing to (i) the formation of the palate alluded to above, (2) the development of the nasal concha which has been described on page 161, and (3) the development of accessory cavities maxillary, frontal and sphenoidal sinuses, which represent evaginations, so to speak, from the nasal cavities.

Probably correlated with the above-mentioned increase in extent of the nasal chambers is the fact that in lung-breathing Vertebrates the chambers have acquired a secondary function. In these forms the nose is not only an apparatus for receiving olfactory stimuli, but also serves to convey air to and from the lungs; it is in a sense a respiratory atrium. The sensory epithelium which the olfactory nerves supply is limited to relatively small areas in the superior conchae and nasal septum. Stratified columnar ciliated epithelium lines all other parts of the cavities.

Studies on the development of the olfactory nerve have led to diverse opinions, but the investigations of His and Disse go to show that the fibers are processes of cells derived from the thickened ectoderm or olfactory placodes. In human embryos of about four weeks some of the cells in the upper part of the nasal fossa become modified to form the neuro-epithelium. From the peripheral pole of each cell a short slender process grows out to the surface of the epithelium. From the opposite pole a slender process (the axone) grows centrally until it penetrates the olfactory lobe, where it ends in contact with the dendrites of the first central neurone of the olfactory tract. Most of these cells remain in the epithelial layer, but a few wander into the subjacent mesoderm and become bipolar cells which resemble the bipolar cells of the embryonic posterior root ganglia (p. 472). Other epithelial cells of the nasal fossa are converted into the sustentacular cells of the olfactory areas.

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'''Fig. 472. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

Jacobson's organ arises at the beginning of the third month as a small outpocketing of the epithelium on the lower anterior part of the nasal septum (Fig. 472). This evagination grows backward as a slender sac along the nasal septum for a distance of several millimeters and ends blindly. In the adult the sac degenerates and often disappears. In some of the lower Mammals Jacobson's organ develops to a greater degree, and some of the epithelial cells send out processes which pass to the olfactory lobes.

==The Ear==

The ear of higher Vertebrates consists of three parts the internal, middle, and external. Of these, the internal is the sensory portion proper and, so far as the epithelial elements are concerned, is of ectodermal origin, but secondarily becomes embedded in the subjacent mesoderm. It constitutes a complicated and highly specialized structure for the reception of certain stimuli that are to be conveyed to the central nervous system. From a functional standpoint it may be divided into the portion composed of the semicircular canals and their appendages, which is concerned in receiving and transmitting stimuli destined or the static and equilibration centers in the central nervous system, and the cochlear portion, which is concerned in receiving and transmitting auditory stimuli. The middle and outer ear represent modified portions of the most cranial of the branchial arches and grooves, and constitute an apparatus for conducting sound waves to the cochlear portion of the inner ear.

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'''Fig. 473. Half of a transverse section through the region of the developing ear of a sheep embryo of 13 mm.''' Bottcher.

:Aud. ves., Auditory vesicle; Co. gang., cochlear ganglion; End. ap., endolymphatic appendage; Rh.br., rhombic brain.

===The Inner Ear===

In embryos of 2 to 4 mm., the ectoderm becomes somewhat thickened over a small area lateral to the still open neural groove in the region of the future hind-brain. This thickening is often spoken of as the auditory placode (see p. 469). Owing to more rapid growth of the cells in the deeper layers of the placode, it soon becomes converted into a cup-shaped depression which is known as the auditory pit. The edges of the pit fold in and fuse and the pit thus becomes the auditory vesicle (otocyst), which finally becomes constricted from the parent ectoderm and lies free in the subjacent mesoderm (Fig. 473). At this stage (embryos of 4 to 5 mm.) the auditory vesicle is an oval or spherical sac the wall of which consists of two or three layers of undifferentiated epithelial cells. It lies against the neural tube and is connected with the latter by the acoustic ganglion (Fig. 474, a). About the same time an evagination appears on the dorsal side of the auditory vesicle, forming the anlage of the endolymphatic appendage (Fig. 474, a, b, c). The evagination continues to elongate and comes to form a club-shaped structure, the distal end of which becomes flattened to form the endolymphatic sac, the narrower proximal portion constituting the endolymphatic duct (Fig. 474 a-w). The epithelium, which at first consisted of two or three layers of cells, becomes reduced to a single layer. In the chick the endolymphatic appendage is formed out of the original union between the ectoderm and the auditory vesicle (Keibel, Krause). In Reptiles and Amphibia (Peter, Krause) and in man (Streeter), on the other hand, this appendage develops independently of the union, appearing on the dorsal side of the seam of closure in the auditory vesicle.

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'''Fig. 474. Different views (front, lateral and median) of reconstructions of the developing membranous labyrinth and acoustic nerve in human embryos of successive stages''', the view and length of the embryo being indicated under each figure. Streeter.

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'''Fig. 475. Lateral, front and median views of reconstructions of the membranous labyrinth and acoustic nerve in a human embryo of 30 mm.''' Streeter.

:In the figure on the left, the pars superior (pars sup.) of the vestibular nerve includes the three branches named above it; see also table on page 559.

In embryos of about 6 mm. the auditory vesicle (apart from the endolymphatic appendage) becomes differentiated into two portions or pouches a bulging, triangular one above, which is connected with the endolymphatic appendage, and a more flattened one below. The former is the vestibular pouch, the latter the cochlear pouch (Fig. 474, b-f). Between the two is a portion of the vesicle which is destined to give rise to the saccule and utricle, and which may be called the atrium (Streeter). Properly speaking, the atrium is a division of the vestibular pouch. The cochlear pouch is phylogenetically a secondary diverticulum which develops from the atrium, appearing first in the lowest landinhabiting Vertebrates (Amphibia).

As mentioned above, the vestibular pouch early assumes the form of a triangle, with the apex toward the endolymphatic appendage. The three borders of the triangle form the anlagen of the semicircular canals and bear the same interrelation as the latter. At the same time a vertical groove (the lateral groove) appears between the anlage of the posterior canal and the posterior end of the lateral canal (Fig. 474, b, d).

The formation of the semicircular canals is shown in Fig. 474, g-k. The edges of the triangular vestibular pouch expand and become more or less crescentic in shape. The two walls in the concavity of each crescent come together and then break away (Fig. 474, g, j, absorp. focus), thus leaving the rim of the crescent as a canal attached at its two ends to the utricle. The breaking away affects first the superior, then the posterior, and finally the lateral canal. During these gross changes the epithelium becomes reduced to a single layer of cells.

At one end of each canal an enlargement appears to form the ampulla, as shown in Fig. 474, /, m, n, and Fig. 475. a. 6. c.

The utricle and saccule represent divisions of the portion of the vestibular sac which is known as the atrium, and into which the endolymphatic appendage and cochlea open (see p. 553). In embryos of about 20 mm. a horizontal constriction begins to divide the atrium into an upper utricular portion, into which the semicircular canals open, and a lower saccular portion (Fig. 474, /, m). The constriction begins on the side opposite the endolymphatic appendage and gradually extends across the atrium until it finally divides the opening of the endolymphatic appendage into two parts (Fig. 475, a, b, c). One of these parts opens into the utricle, the other into the saccule, the two parts together constituting the utriculo saccular duct.

As stated before, the two- or three-layered epithelium of the earlier stages becomes reduced to a single layer. The cells of this layer are low cuboidal, with the exception of those over small areas in the ampullae, in the saccule, and in the utricle. Over an elongated area in each ampulla (crista ampullaris), a round area in the saccule and another in the utricle (macula acusticd), the epithelium becomes high columnar, some of the cells developing cilia on their free borders ("hair cells," neuro-epithelium) , the others becoming the sustentacular cells. These areas are the end-organs of the vestibular nerve (see p. 469) .

As already mentioned, the cochlear pouch appears as an outgrowth from the lower side of the atrium (see also Fig. 474, b-f) . The pouch becomes somewhat flattened, and, as it continues to grow in length, becomes coiled like a snailshell (Fig. 474, g-n; Fig. 475, a-c). This first formed coiled structure is the cochlear duct, or scala media. At the same time, it becomes distinctly marked off from the lower part of the atrium (now the saccule) by a constriction, the constricted portion forming the ductusr reuniens (Fig. 474, l-n; Fig 475, a-c).

All the structures thus far considered are at first closely invested by mesoderm. Later, this portion of the mesoderm gives rise to special tissues, and, in the region of the cochlear duct, to the scala vestibuli and scala tympani. The cells immediately around the vesicle proliferate and a dense fibrous layer is formed; outside of this fibrous layer the tissue becomes gelatinous; outside of this again another fibrous layer is formed, around which cartilage develops. The inner fibrous layer gives rise to the connective tissue that supports the epithelial lining of the vesicle. The gelatinous layer degenerates to form a fluid known as the perilymph, the space containing the fluid being the perilymphatic space. The outer fibrous layer becomes the perichondrium later the periosteum when the cartilage is replaced by the petrous portion of the temporal bone.

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'''Fig. 476. Section through the developing cochlea of a 90 mm cat embryo.''' Bottcher.

In the cochlear region the conditions are somewhat modified. Here the gelatinous layer does not form a complete covering for the cochlear duct, but is interrupted along two lines, (i) Laterally the fibrous layer lying next the cochlear duct is fused with the perichondrium (outer fibrous layer) (Fig. 476), (2) Medially the inner fibrous layer is fused with the perichondrium of a shelf-like process of cartilage which later ossifies to form the bony spiral lamina (Fig. 476). By these two partitions the cochlear perilymphatic space is separated into two spiral compartments which communicate only at the apex of the cochlea. The larger of these compartments, the scala vestibuli, communicates with the perilymphatic space around the utricle and saccule. The wall separating the scala vestibuli and cochlear duct becomes thinned out to form the vestibular membrane (of Reissner). The smaller compartment, the scala tympani, remains separated from the cavity of the middle ear by a thin membrane which closes the fenestra cochlea (rotunda) . In the wall between the scala tympani and the cochlear duct the organ of Corti develops (see below). A membrane, similar to that closing the fenestra cochleae, occurs between the cavity of the middle ear and the utricle, closing the fenestra vestibuli (ovalis). As alluded to above, the organ of Corti develops from the wall of the cochlear duct between the latter and the scala tympani (Fig. 476). The epithelial cells of the cochlear duct in this region become high columnar and arranged in two ridges which extend throughout the entire length of the duct. The cells of the ridge nearer the axis of the cochlea give rise to the membrana tectoria. Whether this is accomplished by cuticular secretion of the cells or by the fusion of long hair-like processes that grow from their free borders is not known. The cells of the outer ridge become differentiated into four groups. Those of the outer group (next the cells that give rise to the membrana tectoria) develop into the inner hair cells; those of the next group form the pillar cells; those of the third group differentiate into the outer hair cells; and those of the fourth (outer) group give rise to Hensen's cells. The hair cells, as the name indicates, develop delicate hair-like processes on their free borders, and, since the peripheral processes of the spiral (cochlear) ganglion cells end around them, are considered as the sensory cells of the cochlea, or auditory receptors (see p. 469) .

==The Acoustic Nerve==

The acoustic ganglionic mass is at first closely associated with the geniculate ganglion (ganglion of the facial (VII) nerve), the two together often being spoken of as the acustico-facialis ganglion (see also p. 508) . This lies in close contact with the anterior wall of the auditory vesicle when the latter is first constiicted from the ectoderm. The origin of the ganglion has not been traced in Mammals, but in cow embryos the geniculate has been seen to be connected with the ectoderm at the dorsal end of the first branchial groove (Froriep). The acoustic ganglion probably belongs to the lateral line system (Kupffer) (see also p. 430) .

Although the geniculate and acoustic ganglia are at first closely associated, each pursues an independent course of development. The description here will be confined to the acoustic. As already mentioned, this lies in close apposition to the side of the neural tube and the auditory vesicle and just anterior to the latter (Fig. 474, a). At a very early stage (embryos of 6-7 mm.), the mass shows a differentiation into two parts a dorsal one, the future vestibular ganglion, and a ventral one, the future cochlear (spiral) ganglion (Fig. 474, b, c). The ganglion cells become bipolar (see p. 469) , and, as is peculiar to the cells of the acoustic ganglia, remain in this condition. One process of each cell grows centrally to form a root fiber of the acoustic nerve, which terminates in contact with dendrites of neurones in certain nuclei in the central nervous system. The fibers from the cells of the vestibular ganglion form the vestibular root, those from the cells of the cochlear ganglion form the cochlear root. The other process grows peripherally and penetrates the wall of the auditory vesicle to enter into relation with certain cells that differentiate from the epithelial lining of the vesicle.

The peripheral processes of the vestibular ganglion cells come into relation with specialized cells (hair cells) in the ampullae of the semicircular canals

(crista ampullaris) and in the saccule and utricle (macula acustica) (see p. 556). The nerve itself becomes divided into certain branches, as indicated in the following table (Streeter). The peripheral terminations of the various branches are indicated in parentheses. Compare with Fig. 474, /, m, n, and Fig. 475, a, b, c.

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The vestibular ganglion cells, instead of remaining in a compact mass, come to form two fairly distinct masses in the course of the nerve (Fig. 475, a, b, c). One of these apparently is connected with the pars inferior, the other with the pars superior.

The cochlear ganglion cells at an early stage become closely associated with the developing cochlear duct and, as the latter forms a spiral, are carried] along with it. They thus come to form an elongated group of cells extending throughout the entire length of the cochlea (whence the name, spiral ganglion) (Fig. 474, j-n; Fig. 475, a-c). Consequently, the peripheral processes of these cells, which terminate in connection with the hair cells of the organ of Corti, are comparatively short. The central processes are naturally longer and form the cochlear nerve root which is twisted like a rope in part of its course (Fig. 475, c).

The Middle Ear. The cavity of the middle ear develops from the upper (dorsal) part of the first inner branchial groove. The epithelial lining of the cavity is thus of course derived from entoderm, and the other structures (auditory ossicles, etc.) from the adjacent mesoderm.

It has been stated elsewhere that the mesoderm in the first and second branchial arches gives rise, among other things, to certain skeletal elements. In the first arch there develops a rod of cartilage, known as Meckel's cartilage, which extends from the symphysis of the lower jaws to the region of the upper part of the first inner branchial groove (p. 164; Figs. 136, 139, 142). The proximal end of the cartilage becomes constricted to form two masses which constitute the anlagen of the malleus and incus (Figs. 135 and 136). In the second arch there develops a rod of cartilage which forms the lesser horn of the hyoid bone, the stylohyoid ligament, and the styloid process (Figs. 136, 139, .42). In close relation to the dorsal end of the styloid process, in the mesoderm destined to give rise to the periotic capsule, a mass of cartilage appears which is destined to give rise to the stapes (except the base?). It has not been fully determined whether the stapes is actually a derivative of the cartilage of the second arch or of the mesenchyme near its dorsal end. It has been suggested that the base of the stapes is of intramembranous origin and that the rest of the bone is derived from the cartilage of the second arch. Its close association with the cartilage of the second arch possibly indicates its phylogenetic origin from the latter.

At first the auditory ossicles are embedded in the mesoderm dorsal to the first inner branchial groove, that is, dorsal to the cavity of the middle ear. As development proceeds, the mesoderm is converted into a spongy tissue which finally degenerates. At the same time the ear cavity enlarges and wraps itself, as it were, around the ossicles. The latter thus come to lie within the cavity of the tympanum, but are covered by a layer of epithelium (entoderm) which is continuous with that lining the cavity.

Toward the end of foetal life, outgrowths from the cavity of the tympanum begin to invade the temporal bone. This process continues for some time after birth and results in the formation of cavities within the mastoid part of the temporal bone. These cavities are the mastoid cells, the epithelial lining of which is continuous with that of the tympanic cavity.

The Eustachian tube represents the lower (ventral) portion of the diverticulum which forms the cavity of the tympanum. In other words, as the dorsal part of the first inner branchial groove enlarges to form the cavity of the middle ear, the narrow part of the groove, just ventral to the cavity, persists as a communication between the latter and the pharynx.

The Outer Ear. The outer ear is formed from the dorsal part of the first outer branchial groove and the adjacent portions of the first and second arches (see Fig. 87). The ventral part of the groove flattens out and disappears. The dorsal part becomes deeper to form a funnel-shaped depression (during the second month ; Fig. 90) . From the deeper part of the funnel a solid mass of ectoderm grows inward until it comes into relation with the mesoderm immediately around the developing cavity of the tympanum, or, more specifically, the mesoderm surrounding the handle of the malleus. Here it spreads out into a disk-like mass. About the seventh month, the disk splits into two layers. The inner layer, which is separated from the epithelium of the middle ear by a thin sheet of mesoderm, becomes the outer layer of the tympanum. The tympanum is thus composed of an inner (entodermal) and an outer (ectodermal) layer, with a small amount of mesoderm between. From its mode of development, the tympanum may be considered in a sense as the wall which separates the first inner from the first outer branchial groove.

The split in the ectodermal disk (see above) gradually extends outward, invading the solid ectodermal in vagina tion until it finally unites with the bottom of the funnel-shaped depression on the surface, thus forming the external auditory meatus.

The external ear (or auricle) is derived from the portions of the first and second branchial arches surrounding the dorsal part of the first outer branchial groove (see Figs. 85, 87, 90, 91). About the end of the fourth week, the caudal border of the first arch exhibits three small elevations or tubercles (Fig. 477, A, 1-3), the cranial border of the second arch the same number (Fig. 477, A, 4-6). A groove, extending down the middle of the second arch, marks off a ridge (c) lying caudal to the three tubercles. The ventral tubercle (i) of the first arch gives rise to the tragus. The middle tubercle (5) of the second arch develops into the antitragus. The middle and dorsal tubercles (2 and 3) of the first arch unite with the ridge (c) on the second arch to form the helix. The dorsal tubercle (4) of the second arch gives rise to the anthelix. The ventral tubercle (6) of the second arch produces the lobule. It should be noted that in the third month the dorsal and caudal portions of the helix are bent forward and conceal the anthelix.

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'''Fig. 477. Stages in the development of the external ear (auricle).''' A, Embryo of n mm.; B, of 13.6 mm.; C, of 15 mm.; D, foetus at the beginning of the 30! month; E, foetus of 8.5 cm.: F, foetus at term. For explanation of numerals, see text. His, McMurrich.

==Anomalies==

Malformations of the nose have been alluded to in connection with hare lip, cleft palate, etc., on page 212, and are also discussed in the chapter on teratogenesis (XX). Malformations affecting the eye (cyclopia, microphthalmia, etc.) and the ear (synotia, etc.) are dealt with in the chapter on teratogenesis.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_19|Foetal Membranes]]

==References for Further Study==

===The Eye===

GALLENGA: Entwickelung des Auges. Encyklopadie der Augenheilkunde, Lief. 6 and 7, 1902.

HOLDEN: An Outline of the Embryology of the Eye, New York, 1893.

VON KOLLIKER: Die Entwicklung und Bedeutung des Glaskorpers. Zeitschr. fur wissensch. Zoolog., Bd. LXVI, 1904.

LANGE, O.: Einblicke in die embryonale Anatomie und Entwicklung des Menschenauges. 1908.

RABL, C.: Ueber den Bau und Entwickelung der Linse. Zeitschr. fur wissensch. Zool., Bd. LXII and LXV, 1898; LXVII, 1899.

RAYMON Y CAJAL.: Nouvelles contributions a 1'etude histologique de la retine. Jour, de VAnat. et de la Physiol, Vol. XXXII, 1896.

ROBINSON. A.: On the Formation and Structure of the Optic Nerve and its Relation to the Optic Stalk. Jour, of Anat. and Physiol., Vol. XXX, 1896.

VON SPEE: Recherches sur 1'origine du corps vitre. Arch, de Biol., Vol. XIX, 1902.

===The Nose===

BEARD, J.: Morphological Studies. The Nose and Jacobson's Organ. Zool. Jahrbuch, Bd. Ill, 1889.

DISSE, J.: Die erste Entwickelung der Riechnerven. Anat. Hefte, Bd. IX, 1897.

His, W.: Beobachtungen zur Geschichte der Nasen- und Gaumenbildung beim menschlichen Embryo. AbhandL d. math.-phys. Klasse Ko'nig. Sachs. Gesellsch. d. Wissensch. , 1901.

HOCHSTETTER, F.. Ueber die Bildung der primitiven Choanen beim Menschen. Verhandl. d. anat. Gesellsch., Bd. VI, 1892.

VON MIHALKOWICZ, V.: Nasenhohle und Jacobsonsches Organ. Eine morphologische Studie. Anat. Hefte, Bd. XI, 1898.

PETER, K.: Die Entwickelung des Geruchsorgans und Jacobson'schen Organs in der Reihe der Wirbeltiere. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1901.

===The Ear===

BAGINSKY, B.: Zur Entwickelung der Gehorschnecke. Arch.f. mik. Anat., Bd. XXVIII, 1886.

BOETTCHER, A.: Ueber Entwickelung und Bau des Gehorlabyrinths. Verhandl. d. Kais.Leop.-Carol. Akad., Bd. XXXV, 1869.

BROMAN, I.: Die Entwickelungsgeschichte der Gehorknochelchen beim Menschen. Anat. Hefte, Bd. XI, 1898.

FUCHS, H.: Bemerkungen iiber die Herkunft und Entwickelung der Gehorknochelchen bei Kaninchen-Embryonen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1905.

HENSEN, V.: Zur Morphologic der Schnecke. Zeitschr. f. wissensch. Zool., Bd. XIII, 1863

His, W.: Zur Entwickelung des Acusticofacialisgebiets beim Menschen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1899.

KRATJSE, R.: Entwickelungsgeschichte des Gehororgans. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1902.

STREETER, G. L.: On the Development of the Membranous Labyrinth and the Acoustic and Facial Nerves in the Human Embryo. Am. Jour, of Anat., Vol. VI, No. 2, 1907.

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Book - Text-Book of Embryology 18

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=The organs of special sense =

==The Eye==

The receptive mechanisms of all the general and special sense organs are derived from the ectoderm. With the single exception of the {{eye}}, all develop as direct specializations of the ectoderm in the form of the various neuro-epithelia. The eye is peculiar among the sense organs in that its receptive cells are not derived directly from surface ectoderm, but only indirectly from the ectoderm after it has become folded in to form the neural canal. The neuro-epithelium of the eye develops as a direct outgrowth from the central nervous system. The retina is a modified part of the brain; the optic nerves correspond to central nervous system fiber tracts. Of the accessory optic structures, the lens, the epithelium of the lids and conjunctiva, the eyelashes, the Meibomian glands and the epithelium of the lacrymal apparatus arc of ectodermic origin; the coats of the eye, the sclera and chorioid, and parts of their modified anterior extensions, the cornea, ciliary body and iris, are of mesodermic origin. In the sensory divisions of the other spinal and cranial nerves, with the exception of the olfactory, the cell bodies of the neurones which serve to connect the receptive mechanisms with the brain and cord are located in parts (the sensory ganglia of the cranial and spinal nerves) which have become separated from the crests of the neural folds as the latter fuse to form the neural canal. In the eye the cell bodies of these neurones are located in the retina, but the area of ectoderm from which the retina develops first occupies a position along the neural crest analogous to that occupied by the anlagen of the spinal and cranial ganglia. In the case of the retina this area, instead of becoming split off in the closure of the neural canal, becomes folded into the canal and later pushed out toward the surface in the optic evagination (Figs. 450, 457, 458).

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'''Fig. 456. Diagram showing location of optic areas before the closure of the neural groove.''' (Modified from Lange)

The first indication of eye formation is found in the chick at the beginning of the second day of incubation ; in the human embryo, at what has been estimated as about the second or third week. At this stage the neural canal is not yet completely closed in and its anterior end shows three primary brain vesicles (p. 440, Fig. 497). The anlagen of the eyes first appear as bilaterally symmetrical evaginations from the lateral walls of the fore-brain vesicle (Figs. 459 and 460), and are at first large in proportion to the brain vesicle itself. When first formed, the optic evagination opens widely into the fore-brain vesicle (Fig. 460, right side), but as the distal part of the evagination expands more rapidly than the proximal part, there soon results a spheroidal optic vesicle attached to the fore-brain by the narrow optic stalk (Fig. 460, left side). Through the latter the cavity of the optic vesicle and the cavity of the fore-brain are in communication. With the development of the hemispheres, that part of the brain to which the optic stalks are attached becomes the inter-brain (diencephalon).

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'''Fig. 457. Diagram showing location of areas shown in Fig. 456 after the formation of the neural canal.''' (Modified from Lange)

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'''Fig. 458. Diagram showing, location of the (dark) optic area (see Fig. 457) after the beginning of the formation of the optic cup and optic stalk.''' (Lange)

'''Fig. 459. Dorsal view of head of chick of 58 hours' incubation.''' Mihalkovics.

:Lam. term, lamina terminalis; Fb., fore-brain; Opt. v., optic vesicle; M. b., mid-brain; H.b., hind or rhombic brain; H., heart.

===The Lens===

As each optic vesicle grows out toward the surface, its outer wall soon comes to lie just beneath the surface ectoderm. The cells of that portion of the ectoderm which overlies the optic vesicle next proliferate and cause a thickening of the ectoderm (Fig. 460, left side). This thickening of the ectoderm over the optic vesicle is apparent in the chick embryo of 36 hours incubation; in the human embryo it occurs about the third or fourth week and represents the first-step in the development of the crystalline lens. The thickened portion of ectoderm is known as the lens area (Fig. 460). The latter next becomes depressed against the outet surface of the optic vesicle forming a distinct lens invagination (Fig. 461). This becomes cup-shaped and then its edges come together and fuse, thus forming the lens vesicle (Fig. 462). At first the lens vesicle is connected with the surface ectoderm, but about the eighth week a thin layer of mesoderm grows in between the lens vesicle and the surface ectoderm, completely separating them (Fig. 463). The ingrowth of the lens vesicle against the outgrowing optic vesicle has the effect as though a small hard ball (the lens vesicle) had been pressed into a larger soft ball (the optic vesicle) (Fig. 464) . The lens vesicle pushes the outer wall of the optic vesicle in against the inner wall, the optic vesicle thus becoming transformed into the two-layered optic cup (Figs. 462, 463). Bonnet calls attention to the fact that the two processes, lens formation and the invagination of the optic vesicle to form the optic cup, are more or less independent and that it is not correct to describe the lens as actually pushing in the outer wall of the vesicle. As evidence of this is noted the fact that typical optic cup formation may occur in cases where no lens is developed. The optic cup when first formed is not a complete cup, for the invagination of the optic vesicle is carried over along the posterior surface of the optic stalk forming the choroidal fissure (Fig. 464, see also p. 545).

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'''Fig. 460. Section through head of chick of two days' incubation.''' (Duval) The formation of the optic vesicle and stalk appears to be somewhat more advanced on the left than on the right.

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'''Fig. 461. Section through head of chick of three days' incubation.''' (Duval)

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'''Fig. 462. Showing somewhat later stage in development of optic cup and lens than is shown in Fig. 461.''' (Duval)

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'''Fig. 463. Diagram of developing lens and optic cup.''' (Duval)

:The cells of the inner wall of the lens vesicle have begun lo elongate to form lens fibers. The epithelium over the lens is the anlage of the corneal epithelium. The mesodermal tissue between the latter and the anterior wall of the lens vesicle is the anlage of the substantia propria corneae.

The lens area is thicker at its center than at its periphery and when the center of the lens area becomes the bottom of the lens depression and later the posterior wall of the lens vesicle this greater thickness is maintained. In fact, the posterior wall of the vesicle becomes still thicker so that it projects into the cavity of the lens vesicle as an eminence (Fig. 465, g.). In the chick the lens vesicle is hollow. In man and in Mammals generally it is more or less filled with cells. These, however, degenerate and take no part in the formation of the permanent lens. Comparing the posterior with the anterior wall of the lens at this stage, the latter is seen to be composed of a single layer of cuboidal cells, the anlage of the anterior epithelium of the lens (Figs. 463, 465, g, h, i). This layer passes over rather abruptly into the posterior wall which consists of a single layer of greatly elongated lens cells, the anlagen of the lens fibers. The lens fibers continue to elongate until by the end of the second month they touch the anterior epithelium, thus completely obliterating the cavity of the lens vesicle (Fig. 467). A small cleft containing a few drops of fluid, the liquor Morgagni, may remain between the anterior epithelium and the lens fibers.

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'''Fig. 464. Model showing lens and formation of optic cup.''' A piece has been removed from the upper part of cup to show the cavity of the optic vesicle and the position of the inner layer of the cup (nervous layer of retina). Bonnet.

When the lens fibers are first formed, the longest fibers are in the center and the fibers gradually get shorter toward the periphery of the lens where they pass over into the anterior epithelium (Fig. 465), As the lens develops, the peripheral fibers elongate more rapidly than the central, with the result that in the fully developed lens the central fibers are the shortest, forming a sort of core around which the now longer peripheral fibers extend in much the same manner as the layers of an onion (Fig. 467). The ends of the fibers meet on the anterior and posterior surfaces of the lens, along more or less definite lines which can be seen on surface examination and which are known as sutural lines. The lens fibers are at first all nucleated and as the nuclei are situated at approximately the same level in all the fibers, there results a so-called nuclear zone (Fig. 465, i). Later the nuclei disappear. The sutural lines become evident about the fifth month and mark the completion of the lens formation, although lens fibers continue to be formed throughout fcetal and in postnatal life, probably by proliferation and differentiation of the cells of the anterior epithelium, in the region where the latter pass over into the lens fibers. (The successive stages in the development of the lens are shown in Fig. 465.)

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'''Fig. 465. Successive stages in the development of the lens in the rabbit embryo.''' Rabl.

:a, b, c, d, and e, are from embryos of from 11.5 to 12 days; f, at end of 12th day; g, during the 13th day; h, between the 13th and 14th days; i, from an embryo of 11 mm.

The lens capsule becomes differentiated during the third month. It is considered by some as derived from the lens epithelium and of the nature of a cuticular membrane, by others as a product of the surrounding connective tissue.

By the extension of mesodermic tissue in between the lens and the surface ectoderm, the lens becomes by the end of the sixth week completely surrounded by a layer of vascular connective tissue. This is known as the tunica lentis, and receives its blood supply mainly from the hyaloid artery (Fig. 467) which is a foetal continuation of the '''arteria centralis retina''' (p. 545). Branches from the hyaloid artery break up into a capillary network which covers both anterior and posterior surfaces of the lens. That part of the tunica vasculosa which covers the anterior surface of the lens is known as the ''membrana pupillaris''. After the earlier and more rapid formation of lens fibers ceases, the hyaloid artery begins (about the seventh month) to undergo regressive changes, and at birth is normally absent. Rarely more or less of the tunica vasculosa fails to degenerate, and if the part which persists is the membrana pupillaris there results a malformation known as congenital atresia of the pupil.

===The Optic Cup===

The way in which the optic vesicle becomes transformed into the optic cup has been partially described in considering the development of the lens (p. 536). The growing lens vesicle appears to push in the outer wall of the optic vesicle while at the same time the edges of the latter are extending around the lens vesicle, until what was originally the outer wall of the optic vesicle lies in apposition with the original inner wall, the cavity of the primary optic vesicle thus becoming completely obliterated (Fig. 466). In this way the optic vesicle is transformed into a two-layered thick-walled cup, the cleft between the two layers corresponding to the cavity of the primary vesicle. This cup is at first entirely filled with the developing lens (Fig. 466). As the cup increases in size faster than the lens, the contiguous walls of the cup and lens become separated, the cavity thus formed being the cavity of the vitreous humor (Fig. 467). There seems to be no question but that in Mammals a small amount of mesoderm at first separates the optic evagination from the lens area of the surface ectoderm. This apparently disappears, however, so that the two are in direct contact. It is still an open question w r hether a thin layer of mesoderm grows in between the edges of the cup and the lens at or just before the beginning of the formation of the vitreous. The lens now no longer fills the optic cup but lies in the mouth of the cup, while at the same time the margin of the cup is extending somewhat over its outer surface, w^here with the mesoderm it ultimately gives rise to the ciliary body and iris, and forms the boundary of the pupil. The remainder of the two-walled optic cup becomes the retina.

The Retina. Of the two layers which form the wall of the optic cup (p. 539) , the outer (away from the cavity) forms the pigmented layer, while the inner forms the remainder of the retina (Figs. 463, 467). Soon after the formation of the optic cup, it is possible to distinguish a boundary zone the future ora serrata between the larger posterior part of the retina or nervous retina and the smaller anterior non-nervous part which becomes the retinal portion of the ciliary body and iris. [ While the optic cup is forming, its two layers are both rapidly increasing in thickness by mitotic division of their cells. Especially is this true of the inner layer over that region which is to become the nervous retina, and it is the rather abrupt transition between the thicker nervous retina and the comparatively thin non-nervous anterior extension of the retina that forms the ora serrata.

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'''Fig. 466. Section through optic cup and lens invagination of chick of fifty-four hours' incubation.''' Lange.
: Between the lens anlage and the pigmented layer of the retina is the broad inner layer of the optic cup, the anlage of the remainder of the retina.

The invagination which gives rise to the two-layered optic cup thus differentiates what may be called the two primary layers of the retina, the pigmented layer, and a broad layer from which are to develop all the other layers of the retina. (Figs. 463, 467) . Further development consists in a gradual differentiation, within the broad layer; of the various retinal elements and consequent demarcation of the layers which constitute the adult retina. The next layer to differentiate is the innermost layer of the retina, or layer of nerve fibers. This appears during the sixth or seventh week as a thin, clear, faintly striated zone containing a few scattered nuclei. What remains of the original inner layer of the cup has now become a comparatively thick layer with numerous chromatic and actively dividing nuclei. It may be conveniently designated the primitive nuclear layer.

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'''Fig. 467. Horizontal section through eye of human embryo of 13-14 weeks.''' Modified from Lange.

The similarity in development between the retina and wall of the neural tube is to be noted. Thus the layer of nerve fibers appears to correspond quite closely to the marginal layer of the central nervous system, while the primitive nuclear layer is probably homologous with the mantle layer (pp. 449, 455). There is a similar correspondence between the retina and the central nervous system in regard to their early cellular development, the retinal cells early showing a differentiation into neuroblasts and spongiobiasts (pp.449, 455).

About the end of the eighth week the inner part of the primitive nuclear layer differentiates into the layer of eanzlion cetts (Fig. 468, h). These are large cells and with their processes constitute the third or proximal optic neurone. They can be first distinguished in the fundus of the cup and gradually extend to the ora serrata. They are the first of the cellular dements of the adult retina which can be definitely recognized as such. From each cell, two kinds of processes develop, dendrites, which ramify in this and in the more external layers of the retina, and an axone which grows toward the cavity of the eye and becomes a fiber of the layer of nerve fibers, whence it continues into the optic stalk as one of the fibers of the optic nerve. The layer of ganglion cells is thickest in an area situated somewhat lateral to the attachment of the optic stalk and known as the area centralis. It is distinguishable about the end of the fourth month. In the center of the area centralis the retinal layers become thin to form the fovea centralis which develops toward the end of foetal life. The macula lutea with its yellow pigment does not develop until after birth. The retina at this stage thus consists of four layers which from within outward are (i) the layer of nerve fibers, (2) the layer of ganglion cells, (3) the nuclear layer, (4) the pigmented layer (see Fig. 469).

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'''Fig. 468. Diagram of the development of the retinal cells.''' Kallius, after CajaL a, Cone cells in unipolar stage; fe, cone cells in bipolar stage; c, rod cells in unipolar stage; d, rod cells in bipolar stage; e, bipolar cells; i, amacrine cells; g, horizontal cell; h, ganglion cells; k, Muller's cells or fibers; l, external limiting membrane.

The further development of the retina consists largely of a differentiation of the cells of the nuclear layer. This is extremely complex and our knowledge of it meager. From the cells of this layer develop (i) the rod and cone cells, (2) the bipolar cells, (3) the tangential or horizontal cells, (4) the amacrine cells, (5) Muller's cells or fibers. The differentiation of these cells and their processes /also results in the demarcation of the following layers of the adult retina; (i) the ^ layer of rods and cones, (2) the outer limiting membrane, (3) the outer nuclear layer, (4) the outer molecular layer, (5) the inner nuclear layer, (6) the inner molecular layer, (7) the inner limiting membrane (see Fig. 470).

Muller's cells or the sustentacular cells (Fig. 468, k) develop from spongioblasts which lie toward the inner limit of the nuclear layer. This accounts for the location of the nucleated portions of Muller's cells. Processes of these cells grow toward both surfaces of the retina until they reach the positions of the future outer and inner limiting membranes where they are believed to spread out horizontally and unite to form these membranes. Other spongioblasts develop into other types of glia cells, mainly spider cells, which are most numerous in the layer of ganglion cells and in the layer of nerve libers.

The rod and tone cells are first recognizable as unipolar cellsjFig. 468,0, c}. The single process of each extends outward as far as the outer limiting membrane. About as soon as these cells are recognizable, a differentiation between the rod cells and the cone cells can be made by their reactions to the Golgi silver stain, the cone cells impregnating much more completely than the rod cells. Processes next grow out from the inner ends of the cells so that they become bipolar (Fig. 468, b, d) . Both rod and cone cells are at first distributed throughout the entire nuclear layer, but later they become arranged in a distinct layer just beneath the outer limiting membrane. Each cell next gives rise to or acquires at its outer end an expansion which extends through the outer limiting membrane into the pigmented layer. As the pigmented cells give off pigmented processes which extend inward among the outer ends of the rods and cones, the layer of retina just beneath the pigmented layer consists of the outer ends of the rod cells, the tips of the cone cells, and the extensions of the pigmented cells. The nucleated portions of the rod and cone cells form the outer nuclear layer. Though the layer of rods and cones and the outer nuclear layer present the appearance in haematoxylineosin stained specimens of two distinct layers, it is evident from their development and structure that they should be regarded as a single neuro-epithelial layer. The apparent separation into two layers is due to the interposition of the outer limiting membrane, through tiny holes in which the rod and cone cells extend. The inwardly directed processes of the rod and cone cells are their axones. These cells constitute the first or distal optic neurone.

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'''Fig. 469. Vertical section through retina of a four months' human embryo.''' Modified from Lange.

The bipolar cells (Fig. 468, e), which with their processes constitute the middle or second optic neurone, also develop from cells of the nuclear layer and are probably bipolar at the time that the rod and cone cells are in the unipolar condition. Reference to the two bipolar cells shown in Fig. 468, e, e y shows that at this stage in their development their outwardly directed processes extend to the outer limiting membrane. These processes must either actually shorten or else fail to grow in length proportionately as the retina increases in thickness, for in the mature retina they end in relation with the centrally (inwardly) directed processes (axones) of the rod and cone cells. According as they are in relation with rod cells or cone cells, they are known as rod bipolars or cone bipolars. The retinal layer in which the axones of the rod and cone cells and the dendrites of the rod and cone bipolars intermingle is the outer, molecular layer of the adult retina. It is first distinctly recognizable as a molecular layer about the end of the fifth month (Fig. 470).

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'''Fig. 470. Vertical section through retina of a five and one-half months' human embryo.''' Modified from Lange.

The development of the outer molecular layer separates the originally single nuclear layer into two layers, an outer composed of the nuclei of the rod and cone cells and an inner composed of the nucleated bodies of the rod and cone bipolars, of the horizontal cells (Fig. 468, g) and of the amacrine cells (Fig. 468, / and f), all of which can be recognized in Golgi specimens by the end of the seyegth month. The rod and cone bipolars and probably most of the other cells of the inner nuclear layer send their axones centrally to lie in contact with the dendrites and bodies of the ganglion cells.

With the development of the cells of the inner nuclear layer and their processes, there differentiates the inner molecular layer which separates the inner nuclear layer and the layer of ganglion cells. It consists mainly of ramifications of the dendrites and axones of cells the bodies of which lie in the inner nuclear layer and in the layer of ganglion cells. (Fig. 470.)

===The Chorioid and Sclera===

These develop wholly from the mesoderm. The way in which the mesoderm grows in between the lens and the surface and surrounds the optic cup has been described (p. 536). That part of the mesoderm lying immediately external to the retina develops very early a closemeshed capillary network. This appears before there is any definitely limited sclera and may be considered the anlage of the chorioid, Somewhat later the mesoderm which lies just to the outside of the chorioid takes definite shape as the external fibrous tunic of the eye or sclera.

===The Vitreous===

The manner in which the vitreous humor is formed has been the subject of much controversy and remains still undetermined. As already noted in describing the development of the lens (p. 555), the latter is at first in direct contact with the inner layer of the retina (Fig. 466) . The lens and the retina separate as the vitreous forms between them. During the development of the lens the arteria centralis retinae does not stop as in the adult, with its retinal branches, but continues across the optic cup as the hyaloid artery to end in the vessels of the tunica vasculosa lentis. Some investigators consider the vitreous a transudate from these blood vessels. As the chorioidal fissure closes, some mesodermic tissue is enclosed with the artery, and some investigators consider the vitreous a derivative of this mesoderm. In Birds the formation of the vitreous humor begins before either mesoderm or blood vessels have penetrated the optic cup, and Rabl suggests that the vitreous may be a secretion of the retinal cells. Bonnet describes a double origin of the vitreous, differentiating between a retinal vitreous and a mesoderm vitreous. According to Bonnet, the primary vitreous body begins its formation before the closure of the chorioidal fissure. This primary vitreous appears at the time of formation of the optic cup, is a fibrillated secretion of the retinal cells, and fills in the vitreous space with a feltwork of fine fibrils. With the formation of the optic cup and the closure of the chorioidal fissure this type of vitreous formation ceases and a secondary vitreous body formation takes place from the cells of the pars ciliaris retinas. This is also fibrillated and there develops at this time the so-called hyaloid membrane which closely invests the vitreous. Among the fibers of the vitreous body appears the vitreous humor. Up to this point the vitreous is entirely non-cellular. There next grow into it mesodermal cells which have reached the vitreous through the chorioidal fissure along with the hyaloid artery. To what extent these cells are used up in the formation of the blood vessels of the vitreous and to what extent they remain as connective tissue cells of the mature vitreous after the blood vessels have degenerated is not known.

As already noted, the vitreous is at first crossed by the hyaloid artery which supplies the developing lens (p. 539). As lens formation becomes less active the artery becomes less important and by the end of the third month begins to atrophy. At birth nothing remains of it, but in its former course the vitreous is somewhat more fluid than elsewhere and this is known as the hyaloid canal (canal of Cloquet).

===The Optic Nerve===

Referring to the description of the optic evagination it will be recalled that the optic vesicle maintains its connection with the brain by means of the optic stalk (p. 534) . The latter is hollow and connects the cavity of the optic vesicle with the cavity of the brain. When the invagination of the optic vesicle to form the optic cup occurs (p. 536, Fig. 464), the invagination is carried along the posterior surface of the optic stalk toward the brain, and just as the invagination of the optic vesicle results in the obliteration of the cavity of the vesicle, so the invagination of the optic stalk results in an obliteration of its lumen. In Mammals the invagination of the optic stalk extends only part way to the brain, to the point where the artery enters. The chorioidal fissure closes about the seventh week.

The optic stalk consists of supportive elements only, and serves as a track along which nerve fibers extend to connect the retina and brain. Nerve fibers appear in the optic stalk about the fifth week. They appear first around the periphery and apparently crowd the neuroglia nuclei toward the center, so that the stalk at this stage may be said to consist of a mantle layer and a marginal layer, apparently analogous to these layers in the retina and brain. The nerve fibers gradually invade the entire stalk so that by the end of the third month the stalk has become^ transformed into the optic nerve among the fibers of which the original supportive elements of the stalk are still represented by neuroglia cells.

Much difference of opinion has existed in regard to the origin of the optic nerve fibers, whether they are processes of retinal cells which end in the brain or processes of brain cells which end in the retina. It is now quite generally accepted that most of the fibers of the optic nerve are the axones of nenrnneg the cell bodies of which are situated in the ganglion cell layer of the retina. These axones pass centrally into the layer of nerve fibers, which they form, and converge toward the optic nerve. Through the latter they pass to their terminations in the external geniculate bodies, optic thalami and anterior corpora quadrigemina. According to Cajal and others, some centrifugal fibers are present in the optic nerve. These are processes of cells situated in the above-mentioned nuclei, and terminate in the retina. They are fewer in number and of later development than the centripetal fibers.

As the mesodermic anlagen of the chorioid and sclera are present before the nerve fibers begin to grow into the optic stalk, the fibers must pass through these two coats in their exit from the eye. There results the fenestrated crossing of the optic nerve by these two coats, known as the lamina cribrosa.

The optic nerve fibers are medullated but have no neurilemmae. They are supported by neuroglia. The connective tissue sheaths which enclose the optic nerve are direct extensions of the meninges. These structural peculiarities accord with the peculiarities already described in the development of the nerve. Attention has been called to the fact (p. m) that just as the retina should be considered a modified and displaced portion of the central nervous system of brain cortex so the optic nerve should be considered not as a peripheral nerve, but as analogous to a central nervous system fiber tract.

==The Ciliary Body, Iris, Cornea, Anterior Chamber==

Anteriorly where they come into relation with the lens and are so arranged as to admit light to the retina, all three coats of the eye are extensively modified. Thus the retina is continued anteriorly as the pars ciliaris retinae and pars iridica retinae, the chorioid as the stroma of the ciliary body and iris, the sclera as the cornea.

===The Ciliary Body and Iris===

Both primary retinal layers (the two layers of the optic cup) are continued anteriorly as the non-nervous retinal layer of the ciliary body and iris. The outer pigmented layer consists at first of several layers of pigmented cells, but later becomes reduced to a single layer of pigmented cells which do not, however, possess pigmented processes extending inward as do the analogous cells of the nervous retina. The abrupt transition at the ora serrata where the thick pars optica retinae passes over into the pars ciliaris retinae has been mentioned (p. 540) . The inner laver of the primitive retina (optic cup) extends over the ciliary body and iris as a single layer of cells. These remain non-pigmented over the ciliary body, but over the iris acquire pigment so that the two layers form the pigmented layer of the iris.

The mesodermic tissue which forms the stroma of the ciliary body and iris is derived from the mesoderm lying between the lens and the surface ectoderm. This separates into two layers enclosing between them the anterior chamber of the eve, and it is from the posterior of these two layers that mesodermic tissue extends into the ciliary body and iris. It is continuous with the mesoderm of the tunica vasculosa lentis. During the fourth month the ciliary body undergoes foldings to form the ciliary processes. These foldings at first involve also the iris, but the iris folds soon (end of fifth month) disappear, while the ciliary processes become more prominent.

Of the smooth muscle tissue found in the ciliary body and iris, the dilator and contractor pupillse are, according to Bonnet, derived from the cells of the pigmented layer of the retina, i.e., from ectoderm. The ciliary muscle, on the other hand, develops from mesoderm. These muscles become well developed during the seventh month.

The suspensory ligament of the lens, or zonula Zinnii, first appears about the end of the fourth month. , By some the fibers of the suspensory ligament are believed to differentiate from the vitreous, by others they are considered as derived from the pars ciliaris retinae. Spaces among the fibers of the ligament enlarge and coalesce to form the canal of Petit.

===The Cornea===

The way in which the mesoderm grows in between the lens vesicle and the surface ectoderm has been described (p. 536) . This mesoderm forms a thin almost homogeneous layer containing v^rv few cells. Later that part of the layer which lies against the lens becomes more cellular and vascular, so that it is possible to distinguish between an outer homogeneous non- vascular layer and an inner cellular vascular layer. The former is the anlage of the cornea. Between the two layers vacuoles appear and coalesce to form the anterior chamber of the eye or cavity of the aqueous humor. Subsequent growth of the iris subdivides this chamber into an anterior and a ^posterior portion. The chamber separates the cornea from the pupillary membrane portion of the tunica vasculosa lentis. Bounding the chamber anteriorly and so forming the posterior layer of the cornea there develops a single layer of flat cells, the so-called " endothelium" of Descemet. Over the surface of the cornea the ectoderm remains and gives rise to a stratified squamous epithelium four to eight cells thick, the anterior corneal epithelium. Just beneath the epithelium a layer of corneal tissue retains its original homogeneous character and forms the anterior elastic membrane or membrane of Bowman. The posterior elastic membrane or membrane of Descemet is usually considered a cuticular derivative of the u endothelium." Throughout the rest of the cornea substantia propria cornea cells develop, either by proliferation of the few cells originally present or from cells which grow in from the surrounding cellular mesoderm, and become arranged parallel to the surface as the fixed connective cells of the cornea.

The Eyelids. After the lens vesicle becomes separated from the surface ectoderm, the latter folds over above and below to form the first rudiments of the upper and lower eyelids. Each fold consists of a core of mesoderm and i a covering of ectoderm. From the mesoderm develop the connective tissue elements of the lids including the tarsal cartilage. From the ectoderm develop the epithelial structures of the lids, the epidermis, the eyelashes and the glands. The edges of the lids gradually approach each other and about the beginning of the third month the epithelium of the upper licTbecomes adherent to that of the lower, thus completely shutting in the eyeball. This condition obtains until just before birth.

The eyelashes develop in the same manner as other hairs (p. 417).

The Meibomian glands, glands of Moll and the lacrymal glands develop, during the period the lids are adherent, as solid cords of ectoderm which grow into the underlying mesoderm where they ramify to form the ducts and tubules. The anlagen of the ducts and tubules of these glands al'(t LllUb at fust SUkUfToi ils of cells, their lumina being formed later by a breaking down of the central cells of the cords.

At the inner angle of the conjunctiva there develops beneath the eyelid folds a third much smaller fold. This becomes the plica scmilunaris which in man is a rudimentary structure, but in many of the lower Vertebrates, especially Birds, forms a distinct third eyelid, the so-called nictitating membrane. A few hair follicles and sebaceous glands develop in a portion of this fold forming the lacrymal caruncle..

===The Lacrymal Duct===

At a certain stage in development, a groove bounded by the maxillary process and the lateral nasal process extends from the eye to the nose (Fig. 98). This is known as the naso-optic furrow. Tin- cvlodrrm (epithelium) lying along the bottom of this groove thickens about the sixth week and forms a solid cord of cells. As development proceeds and the parts close in, this cord of ectoderm becomes enclosed within the mesoderm, excepting at its ends where it remains connected with the surface ectoderm of the eye and nose, respectively. By a breaking down of the central cells of this cord a lumen is formed and the cord becomes a tube, the lacrymal duct. The primary connection of the laojgnalduct is with the upper lid, but while the lumen is being formed an offshoot grows out to the under eyelid to form the inferior branch of the lacrymal duct.

==The Nose==

The anlage of the organ of smell is apparent in human embryos of about three weeks as two thickenings of the ectoderm, one on each side of the nasofrontal process. To these thickenings the term olfactory placodes has been applied (Kupffer) . A little later (in embryos of about four weeks) , the placodes become depressed below the surface, the depressions themselves being the nasal pits or fossa (see p 120; also Fig. 87). The placodes. which are destined to give rise to the sensory epithelium, thus come into closer relation with the olfactory lobes of the brain (rhinencephalon) which represent outgrowths of the fore-brain (telencephalon) (see p. 471).

As described in connection with the development of the face, the lateral nasal process arises on the lateral side, the medial nasal process on the medial side, of each nasal pit (p. 120 et seq.; also Fig. 96). Of these processes, the lateral is destined to give rise to the lateral nasal wall and the wing of the nose, the medial to a part of the nasal septum (see p. 120). As development proceeds, the epithelium (ectoderm) of the nasal fossae grows still deeper into the subjacent mesoderm, the fossae thus becoming converted into the nasal sacs, which lie above the oral cavity. According to Hochstetter and Peter, the nasal sacs are not at first in communication with the oral cavity, but lie above, and are separated from it by a plate of tissue which gradually becomes thinned out along the deeper part of the sacs to form the bucco-nasal membrane (Hochstetter). Later (in embryos of 15 mm.), the bucco-nasal membrane ruptures and the deep ends of the sacs thus come to open into the mouth cavity, the openings being known as the primitive choanen. In front of the primitive choanen, the nasal passages (formerly the nasal sacs) are separated from the mouth cavity by a plate of tissue, known as the primitive palate (Fig. 471). The latter is produced by the fusion of the maxillary process with the lateral and medial nasal processes (see p. 121), the outer nares thus being somewhat separated from the border of the mouth.

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'''Fig. 471. From a model of the anterior part of the head of a 15 mm human embryo.''' The lower jaws (mandibular processes) have been removed. Peter,

The further separation of the nasal passages from the o/al cavity has been described in connection with the development of the mouth (p. 286) and the development of the palatine processes of the maxillae. It may be repeated briefly, however, that from each maxillary process a horizontal extension grows across between the oral and nasal cavities until it meets and fuses with its fellow of the opposite side and with the nasal septum in the medial line, thus forming the palate which is continuous with the primitive palate mentioned above. (See Figs. 140 and 47 2.) In this way the nasal cavities or chambers become separated from the oral cavity, but remain in communication with the pharyngeal cavity through the posterior nares.

The nasal cavities increase enormously in size and the epithelial surface in extent, owing to (i) the formation of the palate alluded to above, (2) the development of the nasal concha which has been described on page 161, and (3) the development of accessory cavities maxillary, frontal and sphenoidal sinuses, which represent evaginations, so to speak, from the nasal cavities.

Probably correlated with the above-mentioned increase in extent of the nasal chambers is the fact that in lung-breathing Vertebrates the chambers have acquired a secondary function. In these forms the nose is not only an apparatus for receiving olfactory stimuli, but also serves to convey air to and from the lungs; it is in a sense a respiratory atrium. The sensory epithelium which the olfactory nerves supply is limited to relatively small areas in the superior conchae and nasal septum. Stratified columnar ciliated epithelium lines all other parts of the cavities.

Studies on the development of the olfactory nerve have led to diverse opinions, but the investigations of His and Disse go to show that the fibers are processes of cells derived from the thickened ectoderm or olfactory placodes. In human embryos of about four weeks some of the cells in the upper part of the nasal fossa become modified to form the neuro-epithelium. From the peripheral pole of each cell a short slender process grows out to the surface of the epithelium. From the opposite pole a slender process (the axone) grows centrally until it penetrates the olfactory lobe, where it ends in contact with the dendrites of the first central neurone of the olfactory tract. Most of these cells remain in the epithelial layer, but a few wander into the subjacent mesoderm and become bipolar cells which resemble the bipolar cells of the embryonic posterior root ganglia (p. 472). Other epithelial cells of the nasal fossa are converted into the sustentacular cells of the olfactory areas.

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'''Fig. 472. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

Jacobson's organ arises at the beginning of the third month as a small outpocketing of the epithelium on the lower anterior part of the nasal septum (Fig. 472). This evagination grows backward as a slender sac along the nasal septum for a distance of several millimeters and ends blindly. In the adult the sac degenerates and often disappears. In some of the lower Mammals Jacobson's organ develops to a greater degree, and some of the epithelial cells send out processes which pass to the olfactory lobes.

==The Ear==

The ear of higher Vertebrates consists of three parts the internal, middle, and external. Of these, the internal is the sensory portion proper and, so far as the epithelial elements are concerned, is of ectodermal origin, but secondarily becomes embedded in the subjacent mesoderm. It constitutes a complicated and highly specialized structure for the reception of certain stimuli that are to be conveyed to the central nervous system. From a functional standpoint it may be divided into the portion composed of the semicircular canals and their appendages, which is concerned in receiving and transmitting stimuli destined or the static and equilibration centers in the central nervous system, and the cochlear portion, which is concerned in receiving and transmitting auditory stimuli. The middle and outer ear represent modified portions of the most cranial of the branchial arches and grooves, and constitute an apparatus for conducting sound waves to the cochlear portion of the inner ear.

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'''Fig. 473. Half of a transverse section through the region of the developing ear of a sheep embryo of 13 mm.''' Bottcher.

:Aud. ves., Auditory vesicle; Co. gang., cochlear ganglion; End. ap., endolymphatic appendage; Rh.br., rhombic brain.

===The Inner Ear===

In embryos of 2 to 4 mm., the ectoderm becomes somewhat thickened over a small area lateral to the still open neural groove in the region of the future hind-brain. This thickening is often spoken of as the auditory placode (see p. 469). Owing to more rapid growth of the cells in the deeper layers of the placode, it soon becomes converted into a cup-shaped depression which is known as the auditory pit. The edges of the pit fold in and fuse and the pit thus becomes the auditory vesicle (otocyst), which finally becomes constricted from the parent ectoderm and lies free in the subjacent mesoderm (Fig. 473). At this stage (embryos of 4 to 5 mm.) the auditory vesicle is an oval or spherical sac the wall of which consists of two or three layers of undifferentiated epithelial cells. It lies against the neural tube and is connected with the latter by the acoustic ganglion (Fig. 474, a). About the same time an evagination appears on the dorsal side of the auditory vesicle, forming the anlage of the endolymphatic appendage (Fig. 474, a, b, c). The evagination continues to elongate and comes to form a club-shaped structure, the distal end of which becomes flattened to form the endolymphatic sac, the narrower proximal portion constituting the endolymphatic duct (Fig. 474 a-w). The epithelium, which at first consisted of two or three layers of cells, becomes reduced to a single layer. In the chick the endolymphatic appendage is formed out of the original union between the ectoderm and the auditory vesicle (Keibel, Krause). In Reptiles and Amphibia (Peter, Krause) and in man (Streeter), on the other hand, this appendage develops independently of the union, appearing on the dorsal side of the seam of closure in the auditory vesicle.

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'''Fig. 474. Different views (front, lateral and median) of reconstructions of the developing membranous labyrinth and acoustic nerve in human embryos of successive stages''', the view and length of the embryo being indicated under each figure. Streeter.

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'''Fig. 475. Lateral, front and median views of reconstructions of the membranous labyrinth and acoustic nerve in a human embryo of 30 mm.''' Streeter.

:In the figure on the left, the pars superior (pars sup.) of the vestibular nerve includes the three branches named above it; see also table on page 559.

In embryos of about 6 mm. the auditory vesicle (apart from the endolymphatic appendage) becomes differentiated into two portions or pouches a bulging, triangular one above, which is connected with the endolymphatic appendage, and a more flattened one below. The former is the vestibular pouch, the latter the cochlear pouch (Fig. 474, b-f). Between the two is a portion of the vesicle which is destined to give rise to the saccule and utricle, and which may be called the atrium (Streeter). Properly speaking, the atrium is a division of the vestibular pouch. The cochlear pouch is phylogenetically a secondary diverticulum which develops from the atrium, appearing first in the lowest landinhabiting Vertebrates (Amphibia).

As mentioned above, the vestibular pouch early assumes the form of a triangle, with the apex toward the endolymphatic appendage. The three borders of the triangle form the anlagen of the semicircular canals and bear the same interrelation as the latter. At the same time a vertical groove (the lateral groove) appears between the anlage of the posterior canal and the posterior end of the lateral canal (Fig. 474, b, d).

The formation of the semicircular canals is shown in Fig. 474, g-k. The edges of the triangular vestibular pouch expand and become more or less crescentic in shape. The two walls in the concavity of each crescent come together and then break away (Fig. 474, g, j, absorp. focus), thus leaving the rim of the crescent as a canal attached at its two ends to the utricle. The breaking away affects first the superior, then the posterior, and finally the lateral canal. During these gross changes the epithelium becomes reduced to a single layer of cells.

At one end of each canal an enlargement appears to form the ampulla, as shown in Fig. 474, /, m, n, and Fig. 475. a. 6. c.

The utricle and saccule represent divisions of the portion of the vestibular sac which is known as the atrium, and into which the endolymphatic appendage and cochlea open (see p. 553). In embryos of about 20 mm. a horizontal constriction begins to divide the atrium into an upper utricular portion, into which the semicircular canals open, and a lower saccular portion (Fig. 474, /, m). The constriction begins on the side opposite the endolymphatic appendage and gradually extends across the atrium until it finally divides the opening of the endolymphatic appendage into two parts (Fig. 475, a, b, c). One of these parts opens into the utricle, the other into the saccule, the two parts together constituting the utriculo saccular duct.

As stated before, the two- or three-layered epithelium of the earlier stages becomes reduced to a single layer. The cells of this layer are low cuboidal, with the exception of those over small areas in the ampullae, in the saccule, and in the utricle. Over an elongated area in each ampulla (crista ampullaris), a round area in the saccule and another in the utricle (macula acusticd), the epithelium becomes high columnar, some of the cells developing cilia on their free borders ("hair cells," neuro-epithelium) , the others becoming the sustentacular cells. These areas are the end-organs of the vestibular nerve (see p. 469) .

As already mentioned, the cochlear pouch appears as an outgrowth from the lower side of the atrium (see also Fig. 474, b-f) . The pouch becomes somewhat flattened, and, as it continues to grow in length, becomes coiled like a snailshell (Fig. 474, g-n; Fig. 475, a-c). This first formed coiled structure is the cochlear duct, or scala media. At the same time, it becomes distinctly marked off from the lower part of the atrium (now the saccule) by a constriction, the constricted portion forming the ductusr reuniens (Fig. 474, l-n; Fig 475, a-c).

All the structures thus far considered are at first closely invested by mesoderm. Later, this portion of the mesoderm gives rise to special tissues, and, in the region of the cochlear duct, to the scala vestibuli and scala tympani. The cells immediately around the vesicle proliferate and a dense fibrous layer is formed; outside of this fibrous layer the tissue becomes gelatinous; outside of this again another fibrous layer is formed, around which cartilage develops. The inner fibrous layer gives rise to the connective tissue that supports the epithelial lining of the vesicle. The gelatinous layer degenerates to form a fluid known as the perilymph, the space containing the fluid being the perilymphatic space. The outer fibrous layer becomes the perichondrium later the periosteum when the cartilage is replaced by the petrous portion of the temporal bone.

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'''Fig. 476. Section through the developing cochlea of a 90 mm cat embryo.''' Bottcher.

In the cochlear region the conditions are somewhat modified. Here the gelatinous layer does not form a complete covering for the cochlear duct, but is interrupted along two lines, (i) Laterally the fibrous layer lying next the cochlear duct is fused with the perichondrium (outer fibrous layer) (Fig. 476), (2) Medially the inner fibrous layer is fused with the perichondrium of a shelf-like process of cartilage which later ossifies to form the bony spiral lamina (Fig. 476). By these two partitions the cochlear perilymphatic space is separated into two spiral compartments which communicate only at the apex of the cochlea. The larger of these compartments, the scala vestibuli, communicates with the perilymphatic space around the utricle and saccule. The wall separating the scala vestibuli and cochlear duct becomes thinned out to form the vestibular membrane (of Reissner). The smaller compartment, the scala tympani, remains separated from the cavity of the middle ear by a thin membrane which closes the fenestra cochlea (rotunda) . In the wall between the scala tympani and the cochlear duct the organ of Corti develops (see below). A membrane, similar to that closing the fenestra cochleae, occurs between the cavity of the middle ear and the utricle, closing the fenestra vestibuli (ovalis). As alluded to above, the organ of Corti develops from the wall of the cochlear duct between the latter and the scala tympani (Fig. 476). The epithelial cells of the cochlear duct in this region become high columnar and arranged in two ridges which extend throughout the entire length of the duct. The cells of the ridge nearer the axis of the cochlea give rise to the membrana tectoria. Whether this is accomplished by cuticular secretion of the cells or by the fusion of long hair-like processes that grow from their free borders is not known. The cells of the outer ridge become differentiated into four groups. Those of the outer group (next the cells that give rise to the membrana tectoria) develop into the inner hair cells; those of the next group form the pillar cells; those of the third group differentiate into the outer hair cells; and those of the fourth (outer) group give rise to Hensen's cells. The hair cells, as the name indicates, develop delicate hair-like processes on their free borders, and, since the peripheral processes of the spiral (cochlear) ganglion cells end around them, are considered as the sensory cells of the cochlea, or auditory receptors (see p. 469) .

==The Acoustic Nerve==

The acoustic ganglionic mass is at first closely associated with the geniculate ganglion (ganglion of the facial (VII) nerve), the two together often being spoken of as the acustico-facialis ganglion (see also p. 508) . This lies in close contact with the anterior wall of the auditory vesicle when the latter is first constiicted from the ectoderm. The origin of the ganglion has not been traced in Mammals, but in cow embryos the geniculate has been seen to be connected with the ectoderm at the dorsal end of the first branchial groove (Froriep). The acoustic ganglion probably belongs to the lateral line system (Kupffer) (see also p. 430) .

Although the geniculate and acoustic ganglia are at first closely associated, each pursues an independent course of development. The description here will be confined to the acoustic. As already mentioned, this lies in close apposition to the side of the neural tube and the auditory vesicle and just anterior to the latter (Fig. 474, a). At a very early stage (embryos of 6-7 mm.), the mass shows a differentiation into two parts a dorsal one, the future vestibular ganglion, and a ventral one, the future cochlear (spiral) ganglion (Fig. 474, b, c). The ganglion cells become bipolar (see p. 469) , and, as is peculiar to the cells of the acoustic ganglia, remain in this condition. One process of each cell grows centrally to form a root fiber of the acoustic nerve, which terminates in contact with dendrites of neurones in certain nuclei in the central nervous system. The fibers from the cells of the vestibular ganglion form the vestibular root, those from the cells of the cochlear ganglion form the cochlear root. The other process grows peripherally and penetrates the wall of the auditory vesicle to enter into relation with certain cells that differentiate from the epithelial lining of the vesicle.

The peripheral processes of the vestibular ganglion cells come into relation with specialized cells (hair cells) in the ampullae of the semicircular canals

(crista ampullaris) and in the saccule and utricle (macula acustica) (see p. 556). The nerve itself becomes divided into certain branches, as indicated in the following table (Streeter). The peripheral terminations of the various branches are indicated in parentheses. Compare with Fig. 474, /, m, n, and Fig. 475, a, b, c.

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The vestibular ganglion cells, instead of remaining in a compact mass, come to form two fairly distinct masses in the course of the nerve (Fig. 475, a, b, c). One of these apparently is connected with the pars inferior, the other with the pars superior.

The cochlear ganglion cells at an early stage become closely associated with the developing cochlear duct and, as the latter forms a spiral, are carried] along with it. They thus come to form an elongated group of cells extending throughout the entire length of the cochlea (whence the name, spiral ganglion) (Fig. 474, j-n; Fig. 475, a-c). Consequently, the peripheral processes of these cells, which terminate in connection with the hair cells of the organ of Corti, are comparatively short. The central processes are naturally longer and form the cochlear nerve root which is twisted like a rope in part of its course (Fig. 475, c).

The Middle Ear. The cavity of the middle ear develops from the upper (dorsal) part of the first inner branchial groove. The epithelial lining of the cavity is thus of course derived from entoderm, and the other structures (auditory ossicles, etc.) from the adjacent mesoderm.

It has been stated elsewhere that the mesoderm in the first and second branchial arches gives rise, among other things, to certain skeletal elements. In the first arch there develops a rod of cartilage, known as Meckel's cartilage, which extends from the symphysis of the lower jaws to the region of the upper part of the first inner branchial groove (p. 164; Figs. 136, 139, 142). The proximal end of the cartilage becomes constricted to form two masses which constitute the anlagen of the malleus and incus (Figs. 135 and 136). In the second arch there develops a rod of cartilage which forms the lesser horn of the hyoid bone, the stylohyoid ligament, and the styloid process (Figs. 136, 139, .42). In close relation to the dorsal end of the styloid process, in the mesoderm destined to give rise to the periotic capsule, a mass of cartilage appears which is destined to give rise to the stapes (except the base?). It has not been fully determined whether the stapes is actually a derivative of the cartilage of the second arch or of the mesenchyme near its dorsal end. It has been suggested that the base of the stapes is of intramembranous origin and that the rest of the bone is derived from the cartilage of the second arch. Its close association with the cartilage of the second arch possibly indicates its phylogenetic origin from the latter.

At first the auditory ossicles are embedded in the mesoderm dorsal to the first inner branchial groove, that is, dorsal to the cavity of the middle ear. As development proceeds, the mesoderm is converted into a spongy tissue which finally degenerates. At the same time the ear cavity enlarges and wraps itself, as it were, around the ossicles. The latter thus come to lie within the cavity of the tympanum, but are covered by a layer of epithelium (entoderm) which is continuous with that lining the cavity.

Toward the end of foetal life, outgrowths from the cavity of the tympanum begin to invade the temporal bone. This process continues for some time after birth and results in the formation of cavities within the mastoid part of the temporal bone. These cavities are the mastoid cells, the epithelial lining of which is continuous with that of the tympanic cavity.

The Eustachian tube represents the lower (ventral) portion of the diverticulum which forms the cavity of the tympanum. In other words, as the dorsal part of the first inner branchial groove enlarges to form the cavity of the middle ear, the narrow part of the groove, just ventral to the cavity, persists as a communication between the latter and the pharynx.

The Outer Ear. The outer ear is formed from the dorsal part of the first outer branchial groove and the adjacent portions of the first and second arches (see Fig. 87). The ventral part of the groove flattens out and disappears. The dorsal part becomes deeper to form a funnel-shaped depression (during the second month ; Fig. 90) . From the deeper part of the funnel a solid mass of ectoderm grows inward until it comes into relation with the mesoderm immediately around the developing cavity of the tympanum, or, more specifically, the mesoderm surrounding the handle of the malleus. Here it spreads out into a disk-like mass. About the seventh month, the disk splits into two layers. The inner layer, which is separated from the epithelium of the middle ear by a thin sheet of mesoderm, becomes the outer layer of the tympanum. The tympanum is thus composed of an inner (entodermal) and an outer (ectodermal) layer, with a small amount of mesoderm between. From its mode of development, the tympanum may be considered in a sense as the wall which separates the first inner from the first outer branchial groove.

The split in the ectodermal disk (see above) gradually extends outward, invading the solid ectodermal in vagina tion until it finally unites with the bottom of the funnel-shaped depression on the surface, thus forming the external auditory meatus.

The external ear (or auricle) is derived from the portions of the first and second branchial arches surrounding the dorsal part of the first outer branchial groove (see Figs. 85, 87, 90, 91). About the end of the fourth week, the caudal border of the first arch exhibits three small elevations or tubercles (Fig. 477, A, 1-3), the cranial border of the second arch the same number (Fig. 477, A, 4-6). A groove, extending down the middle of the second arch, marks off a ridge (c) lying caudal to the three tubercles. The ventral tubercle (i) of the first arch gives rise to the tragus. The middle tubercle (5) of the second arch develops into the antitragus. The middle and dorsal tubercles (2 and 3) of the first arch unite with the ridge (c) on the second arch to form the helix. The dorsal tubercle (4) of the second arch gives rise to the anthelix. The ventral tubercle (6) of the second arch produces the lobule. It should be noted that in the third month the dorsal and caudal portions of the helix are bent forward and conceal the anthelix.

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'''Fig. 477. Stages in the development of the external ear (auricle).''' A, Embryo of n mm.; B, of 13.6 mm.; C, of 15 mm.; D, foetus at the beginning of the 30! month; E, foetus of 8.5 cm.: F, foetus at term. For explanation of numerals, see text. His, McMurrich.

==Anomalies==

Malformations of the nose have been alluded to in connection with hare lip, cleft palate, etc., on page 212, and are also discussed in the chapter on teratogenesis (XX). Malformations affecting the eye (cyclopia, microphthalmia, etc.) and the ear (synotia, etc.) are dealt with in the chapter on teratogenesis.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_19|Foetal Membranes]]

==References for Further Study==

===The Eye===

GALLENGA: Entwickelung des Auges. Encyklopadie der Augenheilkunde, Lief. 6 and 7, 1902.

HOLDEN: An Outline of the Embryology of the Eye, New York, 1893.

VON KOLLIKER: Die Entwicklung und Bedeutung des Glaskorpers. Zeitschr. fur wissensch. Zoolog., Bd. LXVI, 1904.

LANGE, O.: Einblicke in die embryonale Anatomie und Entwicklung des Menschenauges. 1908.

RABL, C.: Ueber den Bau und Entwickelung der Linse. Zeitschr. fur wissensch. Zool., Bd. LXII and LXV, 1898; LXVII, 1899.

RAYMON Y CAJAL.: Nouvelles contributions a 1'etude histologique de la retine. Jour, de VAnat. et de la Physiol, Vol. XXXII, 1896.

ROBINSON. A.: On the Formation and Structure of the Optic Nerve and its Relation to the Optic Stalk. Jour, of Anat. and Physiol., Vol. XXX, 1896.

VON SPEE: Recherches sur 1'origine du corps vitre. Arch, de Biol., Vol. XIX, 1902.

===The Nose===

BEARD, J.: Morphological Studies. The Nose and Jacobson's Organ. Zool. Jahrbuch, Bd. Ill, 1889.

DISSE, J.: Die erste Entwickelung der Riechnerven. Anat. Hefte, Bd. IX, 1897.

His, W.: Beobachtungen zur Geschichte der Nasen- und Gaumenbildung beim menschlichen Embryo. AbhandL d. math.-phys. Klasse Ko'nig. Sachs. Gesellsch. d. Wissensch. , 1901.

HOCHSTETTER, F.. Ueber die Bildung der primitiven Choanen beim Menschen. Verhandl. d. anat. Gesellsch., Bd. VI, 1892.

VON MIHALKOWICZ, V.: Nasenhohle und Jacobsonsches Organ. Eine morphologische Studie. Anat. Hefte, Bd. XI, 1898.

PETER, K.: Die Entwickelung des Geruchsorgans und Jacobson'schen Organs in der Reihe der Wirbeltiere. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1901.

===The Ear===

BAGINSKY, B.: Zur Entwickelung der Gehorschnecke. Arch.f. mik. Anat., Bd. XXVIII, 1886.

BOETTCHER, A.: Ueber Entwickelung und Bau des Gehorlabyrinths. Verhandl. d. Kais.Leop.-Carol. Akad., Bd. XXXV, 1869.

BROMAN, I.: Die Entwickelungsgeschichte der Gehorknochelchen beim Menschen. Anat. Hefte, Bd. XI, 1898.

FUCHS, H.: Bemerkungen iiber die Herkunft und Entwickelung der Gehorknochelchen bei Kaninchen-Embryonen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1905.

HENSEN, V.: Zur Morphologic der Schnecke. Zeitschr. f. wissensch. Zool., Bd. XIII, 1863

His, W.: Zur Entwickelung des Acusticofacialisgebiets beim Menschen. Arch.f. Anat. u. Phys., Anat. Abth., Suppl., 1899.

KRATJSE, R.: Entwickelungsgeschichte des Gehororgans. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre d. Wirbeltiere, Bd. II, Teil II, 1902.

STREETER, G. L.: On the Development of the Membranous Labyrinth and the Acoustic and Facial Nerves in the Human Embryo. Am. Jour, of Anat., Vol. VI, No. 2, 1907.

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[[Category:Neural]] [[Category:Vision]] [[Category:Hearing]] [[Category:Smell]]

Book - Text-Book of Embryology 17

2024-01-25T01:10:23Z

Z8600021:

{{Bailey 1921}}
{{Online Editor Neural}}

=The Nervous System=

==General Considerations==

There are certain features of the nervous system in general and particularly of the vertebrate nervous system, the comprehension of which makes the processes of development of the nervous system in man more intelligible. First, the nervous systems of the lower Vertebrates are in many respectssimpler than those of higher forms and their variations throw light upon thecauses which determine neural structures. Second, as the nervous systems of all Vertebrates develop from the same germ plasm, there are resemblances between certain features of both the embryonic and adult systems of lower vertebrates and certain developmental stages in the higher. Certain structures met with in lower adult forms may be regarded as representing stages of arrested development although specialized and aberrant in many respects of structures found in higher forms. Vestigial structures in the developing nervous systems of higher forms may be regarded as recurring developmental necessities in the attainment of the adult form.

Stated in the most general terms, coordination of bodily activities in response to both external and internal conditions is the biological significance of the nervous system. This implies a transmission of some form of change from one part to another or, in other words, conduction. This functional necessity is shown structurally in the elongated form of the histological elements of the nervous system. That such changes habitually pass along each element or neurone in some one direction seems to find a natural structural expression in the receptive body and dendrites of the neurone, and in its long transmitting axone.

It is also evident that coordination can only be performed by a transmission of a change from some given structure either back to that structure or to some other structure to cause a responsive change. We thus have not only in the vertebrate, but at a very early stage in the invertebrate nervous system, a differentiation into afferent and efferent components, the two together usually being termed the peripheral nervous system. The histological elements of these components are the afferent and efferent peripheral neurones. All structures which are so affected as to transmit the change to the afferent peripheral neurones may be conveniently termed receptors, those structures affected by the efferent peripheral neurones may be termed effectors (Sherrington). Receptors include various "sensory" structures whose principal function appears to be to limit to some particular kind of stimulus the changes affecting the afferent nervous elements connected with. them. Effectors include various structures (muscles, glandular epithelia) whose activities are influenced by the nervous system (Fig. 358). A primitive nervous mechanism, thus composed of (i) afferent peripheral neurones which transmit the stimulus from a receptor to (2) efferent peripheral neurones which in turn transmit the stimulus to an effector, is a simple, two-neurone reflex arc (Fig. 358).

At the same time these neurones, as they increase in number, are obviously brought into relation with each other with more economy of space by having common meeting places. This, together with the factor noted below, leads to the concentration of an originally diffuse nervous system, spread out principally in connection with the outer (ectodermal) surface, into a more centralized (ganglionic) type of nervous system, which at the same time has in part retreated from the surface layer (ectoderm) from which it was originally derived

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'''Fig. 358. A two-neurone reflex arc in a Vertebrate.''' gg.. Ganglion, van Gehuchten.

Furthermore, when we consider the great number of receptors and effectors in even simple forms, it is apparent that for effective coordination there must be a considerable degree of complexity of association between the afferent and efferent neurones. These associations may be to some extent accomplished by various branches of the afferent and efferent neurones coming directly into various relations with each other, but it is also evident that when a certain degree of complexity is reached, such an arrangement would necessitate an extraordinary number of afferent and efferent neurones or an extraordinary development of branches of each where they connect. Accordingly we find a second category of neurones, the intermediate or central neurones which mediate between the afferent and efferent peripheral neurones. These central neurones, together with portions of peripheral neurones in immediate relation with them, form, in all fairly well differentiated nervous systems, including those of all Vertebrates, the central as distinguished from the peripheral nervous system.

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'''Fig. 359. Illustrating the withdrawal from the surface of the bodies of the afferent peripheral neurones.''' After Retzius.

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'''Fig. 360. A three-neurone reflex arc.''' van Gehuchten. Afferent peripheral neurone; 2, intermediate or central neurone; 3, efferent peripheral neurones.

The change or stimulus would now pass from receptor through (i) afferent peripheral neurones, (2) intermediate neurones, (3) efferent peripheral neurones to effector. This arrangement constitutes a three-neurone reflex arc (Fig. 360), and is evidently capable of complicated combinations which may be further increased in complexity by the intercalation in the arc of other intermediate neurones. Finally, in the central nervous system certain structures consisting of intermediate neurones are developed which represent the mechanisms for certain coordinations of the highest order. Such are the higher coordinating centers (suprasegmental structures of Adolf Meyer).

As a result of the preceding, it follows that in seeking the explanation for various nervous structures there must always be kept in mind, first, their correlation with peripheral structures and, second, the degree of development of the central coordinating mechanism represented by the intermediate or central neurones. The most important features common to the nervous systems of all Vertebrates owe their uniformity either to a corresponding uniformity in the peripheral receptors and effectors, or to a uniformity in the coordinations of the stimuli received and given put by the central nervous system. Variations in structure are due to variations of either the peripheral or central factor above mentioned. In the lower Vertebrates the former factor plays a relatively more important part than in the higher Vertebrates, the central apparatus being simpler; while in the development of the higher vertebrate nervous systems the dominating factor is the increasing complexity of the central mechanism. The superiority of the nervous system of man does not consist, in the main, of superiority in sense organs or motor apparatus, but in the enormous development of the intermediate neurone system.

==General Plan of the Vertebrate Nervous System==

The Vertebrate is an elongated bilaterally symmetrical animal progressing in a definite direction, primitively perhaps by alternating lateral contractions performed by a segmented lateral musculature. Associated with these characteristics are the bilateral character of the nervous system and its transverse segmentation, shown by its series of nerves, a pair to each muscle segment. The definite direction of progression involves a differentiation of the forward extremity of the animal, such as the location there of. the mouth and respiratory apparatus and the development there of specialized sense organs, the nose, eye, ear, lateral line organs, and taste buds, which increase the range of stimuli received by the animal and thereby render possible a greater range of responsive activities in obtaining food and in reproduction. As a natural outgrowth of these specializations, the highest development of the central coordinating mechanism also takes place at the forward end or head. This concentration and development of various mechanisms in the anterior end is usually termed cephalizatian, and is a tendency exhibited also by various groups of Invertebrates in which the same general conditions are present.

The typical vertebrate nervous system, then, consists of a bilateral central nervous system connected by means of a series of segmental nerves with peripheral structures (receptors and effectors) and exhibiting at its anterior extremity a higher development and specialization in both its peripheral and central parts.

The general features of the typical vertebrate nervous system are best revealed by a brief examination of certain stages in its development.

The entire nervous system, except the olfactory epithelium and parts of certain ganglia (see p. 422), is derived ontogenetically from an elongated plate of thickened ectoderm, the neural plate. This plate extends longitudinally in the axis of the developing embryo, its position being usually first indicated externally by a median groove, the neural groove ([[Book_-_Text-Book_of_Embryology_17#Fig372|Fig. 372]]), the edges of the plate being elevated into the neural folds ([[Book_-_Text-Book_of_Embryology_17#Fig373|Fig. 373]]). The neural folds are continuous around the cephalic end of the plate, but diverge at the caudal end, enclosing between them in this region the blastopore. Even at this stage, the neural plate is usually broader at its cephalic end, thereby indicating already the future differentiation into brain and spinal cord ([[Book_-_Text-Book_of_Embryology_17#Fig375|Fig. 375]]). The neural folds now become more and more elevated ([[Book_-_Text-Book_of_Embryology_17#Fig374|Fig. 374]]), presumably due in part to the growth of the whole neural plate, and finally meet dorsally and fuse, thus forming the neural tube (Figs. 52 and [[Book_-_Text-Book_of_Embryology_17#Fig391|391]]). The fusion of the lips of the neural plate to form the neural tube usually begins somewhere in the middle region of the plate and thence proceeds both forward and backward (Fig. 83). The last point to close anteriorly is usually considered as marking the cephalic extremity of the neural tube, and is called the anterior neuropore.

Even before the neural plate closes to form the tube, there is often a differentiation of cells along each edge, forming an intermediate zone between the neural plate and the non-neural ectoderm ([[Book_-_Text-Book_of_Embryology_17#Fig391|Fig. 391]]). As the neural plate becomes folded dorsally into the neural tube these two zones are naturally brought together at the point of fusion of the dorsal lips of the neural plate. The two zones thus brought together are not included in the wall of the neural tube, but form a paired or unpaired ridge of cells lying along its dorsal surface. This ridge of cells is called the neural crest ([[Book_-_Text-Book_of_Embryology_17#Fig391|Fig. 391]]). Later, each half of the neural crest separates from the other half and from the neural tube and passes ventrally down along the sides of the tube, at the same time becoming transversely divided into blocks of cells ([[Book_-_Text-Book_of_Embryology_17#Fig396|Fig. 396]]). These masses of cells are the rudiments of the cerebrospinal ganglia and differentiate into the afferent peripheral neurones, and into some at least of the efferent peripheral visceral neurones (sympathetic) as well as some other accessory structures (see pp 459 to 464). The peripheral processes of these ganglion cells (afferent peripheral nerve fibers) pass to the receptors, the central processes (afferent root fibers) enter the dorsal part of the nerve tube ([[Book_-_Text-Book_of_Embryology_17#Fig392|Fig. 392]]). In the case of the special sense organs there is an interesting tendency on the part of portions of the neural tube, either evaginations (optic vesicles, olfactory bulbs), or ganglia, to fuse with ectodermal thickenings (placodes) at the site of the future sense organs. There appear to be often two series of ganglionic placodes in the head, a dorsal (suprabranchial) series and a ventral (epibranchial) series, the latter being often known as gill cleft organs. The former appear to be especially connected with the development of the acustico-lateral system, the latter probably with the gustatory (see p. 432 )- ([[Book_-_Text-Book_of_Embryology_17#Fig361|Fig. 361]]). The bodies of the efferent neurones (except the sympathetic) remain in the neural tube, lying in its ventral half, and send their axones out as the efferent peripheral nerve fibers to the effectors.

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'''Fig. 361. Transverse section through the head of a 7 day Ammocoetes in the region of the trigeminal ganglion.''' von Kupffer.

The formation of the neural plate and its closure into a tube are the embryological expression of the above noted tendency of highly specialized neural structures to concentrate and withdraw from the surface (p. 418). The same is true of the less highly specialized placodes, in which this process is not carried so far. The neural plate may thus be regarded as the oldest placode. The afferent peripheral neurones would naturally originate from the borders of this plate, such portions being the last to separate from the non-neural ectoderm or outer surface. They may be regarded as the youngest portions, phylc genetically, of the plate, and there seems to be some variation among Chordates as to the degree of inclusion of the afferent peripheral neurones in the plate.

In the neural tube thus formed, there can be distinguished four longitudinal plates or zones : A ventral median plate (floor plate}, a dorsal median plate (roof plate), where the fusion occurred, and two lateral plates (e.g., [[Book_-_Text-Book_of_Embryology_17#Fig404|Fig. 404]]).

Two points are to be noted : First, that the neural plate is a bilateral structure and the future development of the tube will naturally take place principally in the side walls or lateral plates of the formed tube; second, that the primary connection between the two side walls is the ventral median plate, the dorsal median plate having been produced by a secondary fusion. This being the case, the ventral connection between the two lateral plates will naturally be more extensive and possibly more primitive than the dorsal. The ventral and dorsal median plates do not usually develop nervous tissue, but bands of vertical elongated ependyma cells. In places the roof plate expands into thin membranes which are covered with vascular mesodermal tissue forming chorioid plexuses, such as the chorioid plexuses of the lateral, third and fourth ventricles ([[Book_-_Text-Book_of_Embryology_17#Fig370|Fig. 370]]).

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'''Fig. 362. Scheme of a median sagittal section through a vertebrate brain before the closure of the neuropore.''' von Kupffer.

:A., Archencephalon; D., deuterencephalon; Ms., medulla spinalis (spinal cord); cd., notochord; en., neuronteric canal; ek., ectoderm; en., entoderm; J., infundibulum; np., neuropore; pv., ventral cephalic fold; tp., tuberculum posterius

It has already been seen that even at its first appearance the neural plate exhibits a differentiation into an anterior expanded part, the brain, and a posterior narrower part, the spinal cord. After closure, in many Vertebrates at least, a three-fold division can be made out: (1) A caudal part of the neural tube, the spinal cord, which gradually expands cranially into (2) the caudal part of the brain (deuterencephalon, v. Kupffer) ([[Book_-_Text-Book_of_Embryology_17#Fig362|Fig. 362]]). These two parts lie above the notochord and all the typical cerebrospinal nerves are connected with them. (3) Cranially, at the anterior end of the notochord, the brain wall expands ventrally forming the third portion (archencephalon) . At the forward extremity is seen the anterior neuropore. The deuterencephalon is thus an epichordal part of the brain, while the archencephalon is prechordal. At the boundary between the two is a ventral infolding of the brain wall the ventral cephalic fold (plica encephali ventralis). At this stage the brain resembles that of Amphioxus in many respects. From each side wall of the archencephalon an evagination appears, the optic vesicle ([[Book_-_Text-Book_of_Embryology_17#Fig376|Fig. 376]]) which develops into the retina and optic nerve.

In the next stage ([[Book_-_Text-Book_of_Embryology_17#Fig363|Fig. 363]]), there is a tendency for the neural tube to bend ventrally around the anterior end of the notochord. This bending is the cephalic flexure. At the same time the dorsal wall above the cephalic fold becomes expanded and is marked off from that part of the dorsal wall lying caudally by a transverse constriction, the rhombo-mesencephalic fold, and from the part of the dorsal wall lying cranially by another transverse fold at the site of the future posterior commissure. The middle part of the brain, the roof of which is thus marked off, is the mid-brain or mesencephalon. Its floor is the middle projecting part of the ventral cephalic fold. The cephalic expansion of the brain, practically the former archencephalon, is now the of the three primary brain expansions, fore-brain or prosencephalon and the caudal expansion, is the rhombic brain or rhombencephalon.

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'''Fig. 363. Scheme of a median sagittal section through a vertebrate brain after the formation of the three primary brain expansions.''' von Kupffer. P.. prosencephalon; M., mesencephalon; R., rhombencephalon ; Ms., spinal cord; cw., chiasma eminence; J., infundibulum; It., lamina terminalis; pv., ventral cephalic fold; pn., processus neuroporicus; pr., rhombo-mesencephalic fold; r. 1 , unpairecTolfactory placode; ro., recessus (prae-?) opticus; tp., tuberculum posterius.

These three primary brain expansions ("vesicles"), the fore-brain, midbrain and rhombic brain, are constant throughout the Vertebrates. Beginning at the location of the former neuropore (processus neuroporicus) and passing caudally along the floor of the fore-brain we have the lamina terminalis or endwall of the brain, containing a thickening which indicates the site of the future anterior (cerebral) commissure, next the recessus praopticus, then another thickening, the chiasma eminence, and finally a diverticulum, the recessus postopticus and infundibulum ([[Book_-_Text-Book_of_Embryology_17#Fig363|Fig. 363]]).

At a later stage (Fig. 364), there appear two evaginations in the roof of the fore-brain, the anterior epiphysis or paraphysis and the posterior epiphysis or epiphysis proper (pineal body). Immediately caudal to the paraphysis is a transverse infolding of the brain roof, the velum transversum. The line aa ([[Book_-_Text-Book_of_Embryology_17#Fig364|Fig. 364]]) extending from this fold to the optic recess indicates the location of a fold in the side walls in some forms and is taken by some as the boundary between two subdivisions of the fore-brain, the end-brain or telenccphalon and the inter-brain or diencephalon. Cranial to the epiphysis proper, is a commissure in 'the dorsal wall (commissura habenularis) connecting two structures which develop in the crests of the side walls, the ganglia habenula.

From the dorsal part of the telencephalon is developed the pallium. The ventral anterior part evaginates toward the olfactory pit, its end receiving the olfactory fibers. This region is often termed the rhinencephalon. Thickenings of the basal lateral walls of the telencephalon form the corpora striata.

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'''Fig. 364. Scheme of a median sagittal section through a vertebrate brain showing the five-fold division of the brain.''' von Kupffer.

:T., Telencephalon; D., diencephalon; M., mesencephalon; Mt., metencephalon; Ml., myelencephalon; c., cerebellum; cc., cerebellar commissure; ch., habenular commissure; cp., posterior commissure; cw., chiasma eminence; e., epiphysis; e*., paraphysis; J., infundibulum; lt. t lamina terminalis; pn., processus neuroporicus; pr., rhombo-mesencephalic fold; pv., ventral cephalic fold; ro., recessus (prae-) opticus; si., sulcus intraencephalicus posterior; tp., tuberculum posterius. The lines aa., dd and ff indicate the boundaries between four divisions.

The roof of the mesencephalon finally develops the "optic lobes." The dckened part of the roof lying immediately caudal to the rhombo-mesencephalic fold develops into the cerebellum. The part of the tube of which this forms the roof is often called the hind-brain or metencephalon, while the rest of the lombencephalon is then termed the after-brain or myelencephalon. The roof of i is portion, which has become very thin in the course of its development, forms epithelial part of the tela chorioidea of the fourth ventricle. The conicted portion of the tube between the rhombic brairv and mid-brain is the \thmus.

The above subdivisions of the three primary expansions into five parts (end-, inter-, mid-, hind- and after-brains), especially the subdivisions of the rhombic brain, do not have the morphological value of the three primary divisions but have a certain value for descriptive purposes. The cavities of the brain are the ventricles and their connecting passages, namely, the third ventricle of the diencephalon and the fourth ventricle of the rhombencephalon, the two being connected by the mid-brain cavity (aquceductus Sylvii). The telencephalon usually develops a more or less paired character, its cavities being then paired diverticula of the unpaired fore-brain cavity and known as the lateral ventricles.

Before the closure of the brain part of the neural tube, transverse constrictions appear across the neural plate. The transverse rings into which the tube, when completed, is thus divided are known as neuromeres. They are held to represent a primitive segmentation of the head, similar, perhaps, to that exhibited by the spinal nerves and segmental somatic musculature (primitive segments) of the trunk. The neuromeres may appear before the head somites. To what extent they correspond to the somites or to the visceral segmentation (p. 430) and also to the cranial nerves is a matter of dispute. Concerning their number there have been various views, the evidence inclining to three in the fore-brain, two in the mid-brain and six in the rhombic brain ([[Book_-_Text-Book_of_Embryology_17#Fig365|Fig. 365]]). Their presence and number are most in doubt in the cephalic end of the tube, the highly modified prosencephalon.

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'''Fig. 365. Chick embryos; 1, of 22 hours' incubation; 2, of 24 hours; 3, of 25.5 hours; 4, of 26 hours. Showing respectively 2, 5, 6, and 7 primitive segments.''' Hill.
: cp., Caudal limit of fore-brain ; fr., caudal limit of mid -brain; u., first primitive segment; ps., primitive streak; I-II, neuromeres.

The general features of the vertebrate nervous system which especially illuminate conditions met with in the human nervous system are the following: (1) The correlation between the peripheral structures (receptors and effectors) and the nervous system. (2) The distinction between the epichordal and prechordal portions of the brain. The latter (fore-brain) is, in accordance with its anterior position (comp. p. 420), the most highly modified part of the neural tube. (3) The distinction between the segmented and suprasegmental parts of the brain (Adolf Meyer).* The segmental part of the brain is that portion in more immediate connection with peripheral segmental structures. Its epichordal part is spinal-like and most clearly segmental. Its prechordal part, both as to its peripheral and central portions, is so highly modified that its segmental character is more obscure. It and the rest of the prechordal brain are most conveniently treated together as fore-brain. The suprasegmentai parts of the brain, or higher coordinating centers, are the cerebellum, midbrain roof and the pallium (cerebral hemispheres). Their general functional significance has been mentioned (p. 420). Some of their general structural characteristics are : First, that they are each expansions of the dorso-lateral walls of the neural tube; second, that in them the neurone bodies are placed externally and in layers (cortex), the nerve fibers (white matter) lying within; third, that each appears to have originally had an especially close relation with some one of the three great sense organs of the head, the olfactory, visual or acustico-lateral system; fourth, that each is connected with the rest of the brain by bundles of centripetal and centrifugal fibers, and often there are specialized groups of neurone bodies in other parts of the brain for the origin or reception of such bundles. Each higher center has also its own system of association neurones.

It will accordingly be most convenient to consider : (1) the spinal cord, (2) the segmental part of the epichordal brain, (3) the cerebellum, (4) the midbrain roof, (5) the prosencephalon.

==Spinal Cord and Nerves==

As already brought out, there are two principal morphological differences between the afferent and efferent peripheral neurones. First, the neurone bodies of the former are located outside the neural tube, while the neurone bodies of the latter lie within the walls of the neural tube. Second, the afferent nerves enter the dorsal part of the lateral walls of the tube, while the efferent nerves leave the ventral part of the lateral walls, their neurone bodies lying in this ventral part. The effect of this upon the structural arrangements within the tube is the production in the tube of two columns of neurone bodies, a dorsal gray column for the reception of the dorsal or afferent roots and a ventral, gray column containing the efferent neurone bodies.

<nowiki>*</nowiki> This distinction apparently ignores the fact that the primitive neuromeric segmentation of the neural tube involves its dorsal as well as its ventral walls and thus "suprasegmental" as well as "segmental " structures were originally segmental. This may be granted, but while the demonstration of the primitive segmentation of the neural tube may be valuable as showing the primitive mechanism which has undergone later modifications, the importance of such later modifications renders the above distinction necessary. The main significance of the nervous system is its associative character and its progressive development is not as a segmental, but as a more and more highly developed associating mechanism.

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'''Fig. 366. Transverse section through the body of a typical Vertebrate.''' Showing the peripheral (segmental) nervous apparatus. Froriep.
:Small dots, afferent visceral neurones; coarse dots, afferent somatic neurones; dashes, efferent visceral (ventral root and sympathetic) neurones; lines, efferent somatic neurones. Darm, gut; Ggl. spin., spinal ganglion; Ggl. vert., vertebral sympathetic ganglion; Ggl. mesent., mesenteric sympathetic ganglion. The peripheral sympathetic ganglionic plexuses (Auerbach and Meissner) are not shown. Muse., muscle; Rad. dors., dorsal root; Rad. vent., ventral root; R. comm., white ramus communicans. Two sympathetic neurones are represented as intercalated in the visceral efferent pathway. It doubtful if there should be more than one.

Another important differentiation arises apparently from the important physiological difference in general character between the activities of what may be termed the internal (visceral or splanchnic) and the external (somatic) structures. Internal activities are to a certain extent independent of activities which have to do more with the reactions of the organism to the external world, and consequently their nervous mechanisms have a more or less independent character, forming what is often called the autonomic (sympathetic) system. This independence is exhibited structurally by the intercalation in the peripheral pathway of additional neurones, whose bodies form visceral ganglia connected in various ways among themselves and probably having their own reflex arcs or plexuses. These ganglia are nevertheless to some extent under the control of the efferent neurones of the central nervous system, some of which send their axones to such ganglia ([[Book_-_Text-Book_of_Embryology_17#Fig366|Fig. 366]]). There are thus in the central nervous system two categories of efferent peripheral neurones, those innervating visceral structures "via sympathetic ganglia and those innervating somatic structures. The bodies of the somatic efferent neurones are located in the ventral gray matter of the nerve tube, while the bodies of the splanchnic efferent neurones are believed to occupy more central and lateral positions in the lower half of the gray matter of the neural tube (Fig. 366). It is uncertain whether there are similar afferent splanchnic neurones in the sympathetic ganglia, and thus distinct from those in the spinal ganglia, or whether these all lie in the spinal ganglia and are consequently not fully differentiated from the somatic afferent neurones.

The muscular segmentation of the trunk has already been mentioned and also the corresponding segmental arrangement of the spinal nerves. Local extensions of this musculature and of its overlying cutaneous surface in the form of fins and limbs cause corresponding increase in the size of those segments of the cord innervating them. This is due to the increased number of afferent fibers and consequent increase in the dorsal white columns and in the receptive dorsal gray columns, also to the increase in the number of efferent peripheral neurones whose bodies occupy the ventral gray column (e.g., cervical and lumbar enlargements). (Compare also the differentiation in the cervical cord and lower medulla of the columns and nuclei of Goll for the lower extremities and those of Burdach for the upper extremities).

In general, the intermediate neurones of the cord fall into two categories; intersegmental (ground bundles), connecting cord segments, and those sending long ascending bundles to suprasegmental structures (see pp. 442 and 443.)

==The Epichordal Segmental Brain and Nerves==

The principal peripheral structures which exert a determining influence on the structure of the epichordal brain are: The mouth, the respiratory apparatus (gills and later lungs), and two specialized sensory somatic structures, the acustico-lateral system and the optic apparatus.

In the gills we have essentially a series of vertical clefts forming communications between the pharynx and the exterior, the intervals between the clefts being the gill arches. The musculature of the gill arches is morphologically splanchnic (pp. 272 and 280). The gill or branchial musculature is in closer relations with stimuli from the external world than is the visceral musculature of the body. As a result of this the former is not of the smooth involuntary type, like the visceral musculature of the body, but is of the striated voluntary type, like the somatic musculature. The branchial receptors are naturally visceral in character and there is also in this region a series of specialized visceral receptors, the end buds of the gustatory system. The development of this whole specialized visceral apparatus in this region of the head has apparently caused a corresponding reduction of the somatic musculature.

The musculature of the mouth is also splanchnic, the mouth itself beingregarded by many morphologists as a modified pair of gill clefts which has replaced an older mouth lying further forward in the region of the hypophysis. The existence of this series of gill clefts has naturally caused a branchiomeric pir splanchnic segmentation of the musculature of this region as opposed to the somatic muscular segmentation seen in the trunk. Whether these two kinds of segmentation correspond in this region is uncertain. (In this connection see Fig. 390 and p. 466.)

In the acustico-lateral system three parts may be distinguished : (1) a remarkable series of cutaneous sense organs, extending in lines over the head and body and known as the lateral line organs; (2) the vestibule, including the semicircular canals; (3) the cochlea (organ of hearing proper Cor ti's organ) . In the higher Vertebrates, the lateral line organs have disappeared, owing to a change from a water to a land habitat; the labyrinth has remained unchanged, and the cochlea has undergone a much higher development and specialization.

Regarding the optic apparatus, it is sufficient to point out here that its motor part, the eye muscles, is usually taken to represent the sole remaining somatic musculature belonging to the head proper.

The peripheral nerves of the epichordal part of the brain have fundamentally the same arrangements as the spinal nerves, namely, the peripheral afferent neurone bodies are separate from the nerve tube, forming ganglia, while the bodies of the efferent neurones are located centrally in the morphologically ventral portions of the lateral walls of the nerve tube. There are, however, important differences, clearly correlated with the peripheral differentiations and specializations outlined above, and affecting the afferent and efferent nerves.

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'''Fig. 367. Diagram showing the principal branches of the cranial nerves in a fish.''' (Modified from Wiedersheim.)
:mk. c., Meckel's cartilage; ol. o., olfactory organ; p.q., palato-quadrate; s., spiracle; I-V, brachial clefts; I, II, III, IV, VI, the first, second, third, fourth and sixth cranial nerves. The remaining nerves are differently shaded.

:Black - The afferent general somatic system (trigeminal, Vth nerve); g.g., Gasserian ganglion; md., mandibularis; mx., maxillaris; op. p., opthalmicus profundus.

:Oblique Shading - The lateral line system from its center (t.a.), the tuber acusticum. Bucc. VII, buccalis branch of VII; md. ex., external mandibular branch of VII; l.n. X, lateralis nerve, with its supra-temporal branch (s.t.) and its commissural connection (c) with op. s.

:Light dots - The afferent brachio-visceral (splanchnic) system (dark gray for the IX) and heavier dots the efferent brachio-visceral system.

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'''Fig. 368. Diagram showing the distribution of the cranial nerves in the Amniota.''' (Modified from Wiedersheim.)

First to be considered is the afferent- part of the trigeminus ([[Book_-_Text-Book_of_Embryology_17#Fig367|Figs. 367]] and [[Book_-_Text-Book_of_Embryology_17#Fig368|368]]). The peripheral branches of the ganglion (semilunar or Gasserian ganglion) of this nerve innervate that part of the external (somatic) surfaces of the head (skin and stomodaeal epithelium) which have not been encroached upon by the spinal afferent nerves. This nerve is accordingly more strictly comparable with the afferent spinal nerves. The central processes of the semilunar ganglion cells, after entering the brain, form a separate descending bundle, the spinal V. It is interesting to note that the terminal nucleus of this bundle of fibers is the morphological continuation in the brain of the dorsal gray column of the cord. The extensiveness of the area innervated by the trigeminus may be partly due to disappearance or specialization of anterior somatic nerves and also to the growth of the head.

The organs of the lateral line are innervated by a quite distinct system of ganglionated afferent nerves whose central connections are nearly identical with those of the acoustic ([[Book_-_Text-Book_of_Embryology_17#Fig367|Fig. 367]]). With the disappearance of the lateral line organs and the specialization of the cochlear part of the ear vesicle, there is a disappearance of the lateral line nerves (comp. [[Book_-_Text-Book_of_Embryology_17#Fig367|Figs. 367]] and [[Book_-_Text-Book_of_Embryology_17#Fig368|368]]) and a wellmarked division of the acoustic nerve into vestibular and cochlear portions, the former innervating the older vestibule-semicircular canal portion, the latter, the more recent cochlea. Centrally, the vestibular nerve forms also a descending bundle of fibers and has its own more or less specialized terminal nuclei. The latter is also true of the cochlear nerve.

The afferent portions of the facial, glossopharyhgeal and vagus nerves innervate the splanchnic receptors of the pharyngeal and branchial surfaces as well as of a large part of the viscera. The facial, glossopharyngeal and vagus also innervate the specialized splanchnic receptors, the gustatory system mentioned above. This system of taste buds has a very extensive development in certain lower Vertebrates, especially the Bony Fishes. In the latter the system of nerves innervating these structures is naturally much more extensive and its central terminations and nuclei cause important modifications of the medulla. In Mammals the remnants of this system are represented by the taste buds in the mouth, the nerves innervating them being the chorda tympani branch of the facial and the lingual branch of the glossopharyngeal ([[Book_-_Text-Book_of_Embryology_17#Fig368|Fig. 368]]). The central branches of the ganglia of these three nerves, after entering the brain, form a descending bundle of fibers, the tractus solitarius (or communis).

The somatic musculature of the head, as above mentioned, is usually taken to be represented by the eye muscles and, later, the tongue muscles. The tongue is one of the newer structures, rising in importance with the change to a land habitat, and its muscles are probably an invasion from the neck region caudal to the branchial arches (p. 290). The eye muscles are innervated by the III, IV and VI cranial nerves, the tongue muscles by the XII which is a more recent addition to the cranial nerves. All of these nerves are characterized by having their neurone bodies located in the most medial (morphologically most ventral) portions of the lateral brain walls, and they all, except the IV, emerge near the mid-ventral line. In these respects they resemble the major or somatic part of the ventral spinal roots. (For illustration see Figs. 389, 367 and 368).

The splanchnic musculature of the jaws and the branchial arches is innervated by the efferent portions of the V, VII, IX, X (and XI). The neurone bodies or nuclei of origin of these nerves lie more laterally than those of the III, IV, VI and XII, and their axones also leave the nerve tube more laterally along with the incoming afferent fibres. These nerves all exhibit a characteristic segmental arrangement corresponding to that of the gill clefts. The VII, IX, and the various nerves making up the X, divide dorsal to the corresponding gill clefts into prebranchial and postbranchial branches, also giving off suprabranchial branches. The efferent element, or component, forms a part of each postbranchial branch. These relations are shown clearly in the accompanying diagrams ([[Book_-_Text-Book_of_Embryology_17#Fig367|Figs. 367]] and [[Book_-_Text-Book_of_Embryology_17#Fig368|368]]). Part of the vagus also innervates the viscera and this nerve is thus divisible into branchial and visceral portions.

Two peculiarities may be noted in regard to these splanchnic nerves : First, that the afferent portions have ganglia resembling those of the spinal nerves; second, that the branchial efferent portions consist simply of one neurone proceeding all the way from the nerve tube to the muscle innervated, thus resembling the somatic rather than the visceral nerves of the trunk. As already noted (p. 429), these nerves regulate activities somatic in character but involving splanchnic structures. It is thus seen that the dominating factor is functional rather than morphological present functional necessities modify those of the past.

With the change from a water to a land habitat and the accompanying disappearance of gills and appearance of lungs, we have various suppressions and modifications of the branchial musculature ([[Book_-_Text-Book_of_Embryology_17#Fig368|Fig. 368]]). There are two striking specializations of the branchial musculature. One is the origin of the facial (mimetic) musculature in the highest Vertebrates. This is derived from the muscles of the hyoid arch, innervated naturally by extensions of the facial nerve. The other is a specialization of muscles, probably of the caudal branchial arches, into cervico-cranial muscles (head-movement), innervated by what may be considered a caudal extension of the vagus nerve, namely, the spinal accessory (p. 466). The splanchnic laryngeal musculature and its nerves show a certain degree of specialization (sound-production) in higher forms. The efferent V is naturally a large constant nerve, in correlation with the uniformly developed jaw musculature in all jaw-bearing (gnathostome) Vertebrates (Figs. 367 and 368). These various changes in peripheral structures are thus due either to environmental influences or to developments within the central nervous system (p. 420). One of the most important environmental influences is the change from a water to a land habitat. The influence of the central nervous system is shown in the further development and specialization of a number of peripheral structures as motor "instruments" of suprasegmental mechanisms.

The effects, then, of the peripheral arrangements upon the arrangements within the neural tube are:
# The formation of separate tracts and terminal nuclei for (a) the unspecialized somatic afferent V nerve (spinal V and posterior horn) ; (b) the specialized somatic vestibular nerve (descending or spinal VIII and various terminal nuclei) and also the cochlear nerve and its various terminal nuclei; (c) the splanchnic afferent nerves (tractus solitarius and its terminal nuclei).
# The separation of the efferent neurone bodies lying in the neural tube into two main longitudinal series of nuclei (a) the somatic efferent nuclei, occupying a more medial position, their axones emerging from the neural tube as medial ventral nerve roots; (b) the splanchnic efferent nuclei occupying a more lateral position, their axones emerging laterally and forming mixed roots with the incoming afferent fibers ([[Book_-_Text-Book_of_Embryology_17#Fig369|Fig 369]]).

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'''Fig. 369 Diagram of a transverse section through the lower human medulla showing the origin of the X and XII cranial nerves.''' Schafer.

:Ganglion cell of afferent vagus sending central arm (root fiber) to solitary tract (f. s.) and collateral to the nucleus of the solitary tract (f. s. n.). It is not certain that the axones of the cells of this terminal nucleus take the course indicated in the figure, n. amb., nucleus ambiguus and d. n, X, dorsal efferent nucleus of the vagus, both of which send out axones as the efferent root fibers of the vagus. These two represent the lateral or splanchnic efferent nuclei of this region, n. XII, nucleus of the hypoglossus the axones of which pass out medially as efferent root fibers of the XII. This nucleus represents the medial or somatic efferent nuclei of this region. f. s.. tractus solitarius or descending roots of vagus, glossopharyngeus and facial; d. V., descending spinal root of the trigeminus; r., restiform body; o., inferior olivary nucleus (''olive"); pyr.. pyramid.

The intermediate neurones of the epichordal segmental brain, as well as of the cord, fall into two general systems. One of these is the system of inter segmental neurones, connecting various segments of the segmental brain and cord. This system may be collectively termed the ground bundles (of the cord) and reticular formation (of the brain). These neurones may be regarded as not only furnishing the various reflex communications between the afferent and efferent cerebrospinal peripheral neurones, but as also forming a system upon which the descending neurones from the higher coordinating centers (suprasegmental structures) act, before the efferent peripheral neurones are reached. This system may thus be regarded in general as more closely associated with the efferent than with the afferent peripheral neurones. Certain tracts in this system and their nuclei of origin have reached a considerable degree of differentiation, due principally to association with higher centers. Among these differentiated reticulo-spinal tracts may be mentioned the medial longitudinal fasciculus, the rubro-spinal tract, and the various tracts from Deiters' nucleus. The other system consists of nuclei which are associated with the afferent axones as their terminal nuclei, the axones of which form long afferent tracts to suprasegmental structures. Especially well-marked differentiations of nuclei and tracts of this system are usually due both to its connections with peripheral structures and with the higher centers. The principal afferent suprasegmental tracts to the cerebellum are mentioned below (p. 436). Those to mid-brain roof and (via added neurones) to pallium are the medial fillet or lemniscus from the nuclei of the columns of Goll and Burdach, the lateral lemniscus from the cochlear terminal nuclei and other ascending tracts from terminal nuclei of peripheral afferent neurones.

==The Cerebellum==

The other great factor (see p. 420) affecting the structure of the epichordal brain is the development in it of two higher coordinating centers or suprasegmental structures, the cerebellum and optic lobes. The cerebellum is a development of the dorsal part of the lateral walls of the tube just caudal to the isthmus and was probably primarily developed in correlation with the acustico-lateral system, especially with the lateral line and vestibulo-semicircular canal portions (p. 430). Due probably to the fact that it is thus an important "equilibrating" mechanism, the cerebellum has acquired other important connections besides its original ones with the acustico-lateral system. In the vertebrate series it is especially developed in all active balancing forms (Fig. 370). In Mammals it has acquired important connections with the greatly enlarged pallium (cerebral hemispheres), in accordance with its general regulative influence (static and tonic) upon motor reactions. The great development of the cerebellum has profoundly modified the anatomical arrangements of the rest of the brain and cord, owing to its numerous and massive connections. The following important masses of gray matter and fiber bundles may be mentioned as cerebellar afferent connections: Clarke's column cells, and other cells in the cord, and the spino-cerebellar tracts; the lateral nuclei, inferior olives and the restiform body in the medulla; part of the pes pedunculi, the pontile nuclei and middle peduncle of the cerebellum. The superior cerebellar peduncle to the red nucleus, together with tracts to Deiter's nucleus, belong to the cerebellar efferent connections. The cortico-pontile portion of the pes, the pontile nuclei and the middle peduncle represent the most recently developed cerebral connections (comp. pp. 440-442 and Fig. 371).

==The Mid-brain Roof==

This expansion of the dorsal part of the neural tube constitutes a higher coordinating center for impulses received by various somatic nerves spinal, cochlear and optic. Owing to its being, in all forms below mammals, the principal visual center, the optic part (optic lobes) varies in proportion to the development of the eye, animals with poorly developed eyes having small optic lobes. In mammals, the optic part (anterior corpora quadrigemina or colliculi) is relatively less important, owing to a taking over of a portion of its coordinating functions by the neopallium (pp. 440, 442) , but the cochlear part (posterior corpora quadrigemina or colliculi) has increased in importance, owing to the rise of the cochlear organ (organ of Corti). The centripetal and centrifugal connections of the mid-brain roof are not so massive or extensive and consequently do not modify the other parts of the brain and cord as profoundly as do those of the cerebellum. It sends descending tracts to afterbrain and cord segments.

==The Prosencephalon==

The division of this part of the brain into the telencephalon and diencephalon has already been indicated (p. 425). In the diencephalon may be noted (i) the absence of the notochord ventral to the brain, thereby permitting a ventral expansion of the brain walls, the hypothalamus, associated with an organ not well understood, the hypophysis; (2) certain more or less vestigial structures, such as the pineal eyes (epiphyses), and other primitive structures, such as the ganglia habenulae, in the dorsal part, this dorsal portion being collectively termed the epithalamus; (3) nuclei in (i) and (2) connected with olfactory and gustatory tracts; (4) receptive nuclei for the optic tract and the cochlear path from the posterior colliculus; (5) receptive nuclei for secondary tracts from the end stations of more caudal somatic ganglia (nuclei of Go 11 and Burdach and medial lemniscus). The last two (4 and 5) constitute the thalamus and increase in importance in the higher vertebrates (see p. 440, Fig. 371).

In the telencephalon there may be roughly distinguished an anterior and basal part, the rhinencephalon, in especially intimate relations with the olfactory nerve; a thickening of the basal wall, the corpus striatum ; and a thinner- walled dorsal part, the pallium. The latter may be regarded in a sense as a dorsal development of the corpus striatum and first appears as a distinct structure in the Amphibia.

The peripheral or segmental apparatus which are connected with the prosencephalon are the highly modified optic and olfactory organs. While the optic apparatus primarily originates from the prechordal brain, in the lower Vertebrates its highest coordinating center, as mentioned above, lies partly in the epichordal portion (optic lobes). It is possible that this connection is secondary and contingent upon two functional necessities, the importance of correlation with stimuli coming via more caudal nerves (cochlear and spinal nerves) , and the innervation of its motor apparatus by epichordal nerves, the III, IV and VI. With the development of the neopallium in Mammals (see p. 447) and the consequent projection of visual stimuli upon it, the lower prechordal (thalamic) centers form part of the newer pathway to the neopallium and thus increase in importance, while the optic lobes recede, assuming the position of a reflex center, especially for the visual motor apparatus.

The olfactory nerves enter the anterior extremity of the brain and are connected by secondary and tertiary tracts with regions lying more caudally, where in some cases the olfactory stimuli are associated with gustatory and probably with visual stimuli. One of these regions is the hypothalamus which receives both olfactory and gustatory tracts (Herrick) . More dorsal olfactory pathways pass to the epithalamus. Both epithalamus and hypothalamus give rise to descending systems which doubtless ultimately reach efferent nuclei. In fact, this part of the brain presents, apparently, a complicated primitive mechanism for the correlation especially of olfactory and gustatory stimuli, also to some extent of visual stimuli and stimuli via the trigeminal nerve, the whole forming a sort of oral sense, probably controlling the feeding activities (Edinger).

The next factor in the further development of this part of the brain is the rise in importance of the pallium upon which at first are projected mainly olfactory stimuli (Fig. 370).

A further and still more extensive development of the pallium arises when other kinds of stimuli are projected to a considerable extent upon it, thus giving rise to a distinction between the older olfactory pallium (archipallium) and the newer non-olfactory pallium (neopallium} . The latter appears first in the lateral dorsal portion of the pallial wall and by its subsequent development the archipallial wall is rolled inward upon the mesial surface of the hemispheres. Further changes consist in the extension caudally of this portion pari passu with the extension caudally of the neopallium and then the practical obliteration of its middle portion by the great neopallial commissure, the corpus callosum (Fig. 370, G and H).

In addition to the increasing projection of stimuli from all parts of the body upon the neopallium and the consequent increase in centripetal fiber terminations and in centrifugal neurone bodies lying in its walls, a second factor in the development of the neopallium is the enormous increase of its association neurones. It is the latter feature which especially distinguishes the human from other mammalian brains.

The biological significance of these changes lies in the fact that there is thus produced a mechanism not only for the association of all kinds of stimuli, but also for very complex coordinations between these stimuli. In this way an extensive symbolization and formulation of individual experience (memory, language, etc.) can take place. The formulated experience of one generation can be immediately transmitted (by education in the broad sense of the term) to the plastic late-developing neopallia of the next generation. In this way a racial experience may be rapidly built up without the direct intervention of the slow processes of heredity and natural selection and each generation profit by the accumulated experience of past generations to a much greater extent. The nervous mechanism, the pallium, is provided by inheritance; experience is not inherited but " learned." The pallial associative mechanisms are continuously modified by their activities, thus affecting the character of subsequent pallial reactions (associative memory). Such reactions are usually termed psychical or conscious, as distinguished from the reflex reactions of other parts of the nervous system.

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'''Fig. 370. A-F are sagittal sections showing structures lying in the median line and also paired structures (e.g., pallium) lying to one side of the median line.''' (Edinger) The cerebellum is black. It is doubtful whether the membranous roof in A indicated as pallium is strictly homologous with that structure in other forms, In B, Pallium indicates prepallial structures.

:Aq. SyL, Aquseductus Sylvii; Basis mesen., basis mesencephali; Bulb, olf., bulbus olfactorius; Corp. striat., corpus striatum; Epiph., epiphysis; G. h., ganglion habenulae; Hyp., hypophysis; Infund., infundibulum; Lam. t., lamina terminalis; Lob. elect., lobus electricus; L. vagi, lobus vagi; L. opt., mid-brain roof; Med. obi., medulla oblongata; Opt., optic nerve; Pl.chor., plexus chorioideus; Rec. inf., recessus infundibuli; Rec. mam., recessus mammillaris; Saccus vase., saccus vasculosus; Sp. c., spinal cord; ventr., ventricle; v. m. a., velum medullare anterius; v.m. p., velum medullare posterius.

:G and H show the mesial surface of the cerebral hemispheres in a low (G) and high (H) Mammal. G. Elliot Smith, Edinger, slightly modified.

The exposed gray matter of the olfactory regions is shaded, the darker shade indicating the archipallium (preterminal area and hippocampal formation), the lighter shade indicating the rhinencephalon, which consists of the anterior and the posterior (principally pyriform) olfactory lobes. In Amphibia and Reptiles the hippocampal formation includes all or nearly all of the mesial surface. As the early neopallium appears in the lateral hemisphere walls, the neopallial commissural fibers first pass across the median line in the ventral or anterior commissure. With the increase of the neopallium and its extension on the mesial hemisphere walls, its commissural fibers pass across more dorsally via the archipallial or fornix commissure (psalterium) forming the neopallial commissure or corpus callosum, the great development of which nearly obliterates the anterior hippocampal formation.

Com. ant., Anterior commissure; corp. callosum, corpus callosum; Fimbr., fimbria; Fiss. hippocampi, hippocampal fissure; Lam. t., lamina terminalis; Lob. olf. ant., anterior olfactory lobe; Lob. pyrfformis pyriform lobe; Psalt., psalterium (fornix commissure); Sept. pell., septum pellucidum; Tuo. olf., tuberculum olfactorium. Only a part of the gray (cortex) of the hippocampal formation appears, as the gyrus dentatus, on the mesial surface; the remainder forms an eminence, the cornu Ammonis, on the ventricular surface. This invagination is indicated extenu'lyby the hippocampal fissure. The exposed fiber bundle forming the edge of this formation (fimbria) passes forward (fornix and its commissure) and thence descends, as the anterior pillar of the fornix, behind the anterior commissure. The anterior pillar is partly indicated by a few lines in this region in the figure.

In the course of these developments the pallium or cerebral hemispheres have enormously increased in size until in man they overlap all the other parts of the brain. Naturally the extensive connections of the neopallium with the rest of the brain have profoundly modified the latter. Among the new structures which have on this account been added to the older structures of the rest of the brain, the following may be mentioned: (i) The centripetal connections of the neopallium, consisting mainly of what are usually termed the thalamic radiations. These consist essentially of a system of neurones passing from the above mentioned termini in the thalamus of general somatic, acoustic and optic ascending systems to certain areas in the cerebral hemispheres. In this system we can distinguish (a) the continuation of the fillet (general somatic) to the central region (somaesthetic area) of each hemisphere; (b) the optic radiation from the lower thalamic optic center (lateral geniculate body) to the calcarine (visual) area of the hemisphere; (c) the acoustic radiation from the medial geniculate body of the thalamus to the upper temporal region (auditory area) of the hemisphere. Associated with these last two connections are the increase of the geniculate bodies and the diminution of the mid-brain in importance already alluded to (p. 437). (2) The centrifugal connections consisting of (a) the pyramids passing from the precentral area of each hemisphere to various lower efferent neurones, or neurones affecting the latter, and forming part of the internal capsule and pes pedunculi ; (b) fibers from various parts of the hemisphere, forming the greater part of the rest of the internal capsule and pes, and terminating principally in the pontile nuclei whence a continuation of this system (the fibers of the middle peduncle), passes to the cerebellar hemisphere. The great increase in size of the cerebellar hemispheres, of the contained nuclei dentati, and probably of the superior cerebellar peduncles are further effects of this new connection, which has already been alluded to (see Cerebellum, p. 436 ), ( Fig. 371)

Another important effect of the development of the pallium is the assumption by man of the upright position, due both to the specialization of the hand to execute pallial coordinations and its consequent release from locomotion, and also to the overhanging of the eyes by the enlarged cranium. The great increase of cerebellar connections may be partly due to the new problems of equilibrium connected with the upright position.

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'''Fig. 371. Principal afferent and efferent suprasegmental pathways (excepting the archipallial connections, the efferent connections of the mid- brain roof and the olivo-cerebellar connections)''' Neopallial connections are indicated by broken lines. Intersegmental connections are omitted Some peripheral elements are indicated. Each neurone group (nucleus and fasciculus) is in dicated by one or several individual neurones. Decussations of tracts are indicated by an X

:ac., Acoustic radiation, from medial gemculate body to temporal lobe; br. conj., brachium conjunctivum (superior cerebellar peduncle); brack, pon., brachium ponds (middle cerebellar peduncle); b.q. i., brachium quadrigeminum inferias (a link in the cochlear pathway) ; c. g. I., lateral or external geniculate body; c. g. m., medial or internal geniculate body; c. quad., corpora quadrigemina; f.cort.-sp., cortico-spinal fasciculus (pyramidal tract); f.c. p.-f. frontal cortico-pontile fasciculus (from frontal lobe); f.c.-p.t., temporal cortico-pontile fasciculus (from temporal lobe); f.c.-p.o., occipital cortico-pontile fasciculus (from occipital lobe); f.ctm.f fasciculus cuneatus (column of Burdach); f.grac., fasciculus gracilis (column of Goll) ; f. s.-t., tract from cord to mid-brain roof and thalamus (sometimes included in Gowers' tract); f.sp.-c.d., dorsal spino-cerebellar fasciculus (tract of Flechsig); f.sp.-c.v., ventral spino-cerebellar fasciculus (tract of Gowers, location of cells in cord uncertain) ; lem. lot., lateral lemniscus or lateral fillet; lemniscus -med., medial lemniscus or fillet (the part to the thalamus is mainly a neopallial acquisition); n.coch., cochlear nerve; n. cun., (terminal) nucleus of the column of Burdach; n.grac., nucleus of the column of Goll; n.dent., nucleus dentatus; n. opt., optic nerve; n.r., nucleus ruber (red nucleus); pes ped., pes pedunculi (crusta); pulv. thai., pulvinar thalami; pyr., pyramid; rod. ant., ventral spinal root; rod. post,. dorsal spinal root; rod. opt., optic radiation (from lateral geniculate body, and pulvinar (?), to calcarine region); somaes., bundles from thalamus to postcentral region of neopallium; s p. gang., spinal ganglion; ihal., thalamus.

==General Development of the Human Nervous System during the First Month==

One of the earliest stages in the development of the human nervous system is shown in the 2 mm. embryo of about two weeks (Fig. 372). This shows the stage of the open neural groove. The appearance of a transverse section of the neural plate, groove and folds, in other forms, is shown in Figs. 373 and 374.

The neural folds now become more and more elevated and finally meet, thus forming the neural tube as previously described (p. 421). The fusion of the neural folds begins in the middle region and thence extends cranially and caudally. The stage of partial closure of the neural tube is shown in Eternod's figure of a human embryo of 2.1 mm. (Fig. 375, b). This order of closure indicates, to some extent, the order of subsequent histological development; the extreme caudal and cephalic extremities are more backward than the parts which close first. The last point to close anteriorly marks, as stated previously (p. 42 1), the cephalic extremity of the neural tube and is the anterior neuropore. As indicated in Eternod's embryo, the anterior end of the neural plate is broader even before its closure; thus when the tube is completed its anterior end is more expanded. This expansion is the future brain, the narrower caudal portion being the future spinal cord. Before the closure of the brain part of the tube the beginnings of the three primary brain vesicles are also indicated (Fig. 84). At this stage the neural plate shows no differentiation into nervous and supporting elements. The neural tube is composed of the two lateral walls and the median roof and floor plates (comp. p. 423) (Figs. 307 and 404).

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'''Fig. 372. Dorsal view of human embryo, two millimeters in length, with yolk.''' von Spee, Kollmann. The amnion is opened dorsally.

The appearance of the anterior end of the neural tube with the closure completed, except the anterior and posterior neuropores, is shown in the model of one half of the tube. The external appearance and also the inner surfaces are shown in Figs. 376 and 377. At this stage the cephalic flexure (see p. 424) is already quite pronounced, the cephalic end of the brain tube being bent ventrally at about a right angle to the longitudinal axis of the remaining portion of the tube. This bending begins before the closure of the cephalic part of the neural tube (Fig. 84). From each side of the brain near the cephalic extremity is an evagination of the brain wall, the beginning of the optic vesicles.

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'''Fig. 373. Transverse section through dorsal part of embryo of frog (Rana fusca).''' x, Groove indicating evagination to form mesoderm. Ziegler.

The process of evagination and consequently the location of the vesicle begins before the closure of the tube. Dorsal and anterior to the optic vesicles can be seen a slight unpaired protrusion of the dorsal wall, the beginning of the pallium. The area basal to it and extending a short distance into the anterior wall of the optic vesicle is the site of the future corpus striatum (Figs. 376 and 377).

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'''Fig. 374. Transverse section of dog embryo with ten pairs of primitive segments.''' Bonnet.

Caudal to the pallium and separated from it by a slight constriction (indicated best by the ridge on the inner wall) is another protrusion of the dorsal wall, the roof of the diencephalon. Still further caudally and separated from the roof of the diencephalon by another slight constriction is another expansion of the dorsal wall, the roof of the mid-brain or of the mesencephalon which arches over the cephalic flexure. It is separated by another constriction (plica rhombo-mesencephalicd) from the rhombic brain or rhombencephalon, which latter tapers into the cord. A ventral bulging of the rhombencephalon indicates the future pans region (Figs. 376 and 377).

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'''Fig. 375. (a) Ventral view; (&) dorsal view of human embryo with 8 pairs of primitive segments (2.11 mm).''' Eternod. From models by Ziegler. In b the amnion has been removed, merely the cut edge showing; in a the yolk sac has been removed.

Even at this early stage the cavity of the caudal part of the rhombencephalon is expanded dorsally due to an expansion of the roof plate, which forms only the narrow dorsal median part of the rest of the tube. This expansion reaches its maximum about opposite the auditory vesicle.

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'''Fig. 376. Lateral view of the outside of a model of the brain of a human embryo two weeks old.''' His.

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'''Fig. 377. Lateral view of inner side of the same model shown in Fig. 414.''' His. P.f. is the ridge corresponding to the peduncular furrow on the outer side.

The principal changes in form during the next two weeks are the following (Figs. 378 and 434): The cephalic flexure becomes still more pronounced so that the anterior end of the neural tube is folded back upon the ventral side of the rest 01 the brain, an effect probably enhanced by the expansion of the ventral wall of the anterior portion (Figi 378 and 434). In the space thus enclosed the dorsum sellae is subsequently formed. Associated with this increase of the cephalic flexure is an increased prominence of the mid-brain roof. The pontine flexure has begun, there being now a bending of the whole tube in the pons region, the concavity of the bend being dorsal. At the same time there is a corresponding tendency for the roof of the rhombencephalon to become shorter and wider. There is also a further thinning of the above mentioned expanded portion of the roof plate in this region, and associated with this a thrusting of the thick lateral walls outward at the top so that they come to lie almost flat instead of vertically as in the cord. From the cord to the place of greatest width above mentioned, this dorsal thrusting apart of the lateral rhombic walls obviously becomes more and more pronounced. In front of this region of greatest width, the roof plate becomes narrower and the dorsal parts of the walls (alar plates) form the rudiment of the cerebellum, the rest of the rhombic brain forming the medulla oblongata. Each lateral wall of the rhombic brain is now divided into a dorsal longitudinal zone or plate (alar plate) and a ventral zone or plate (basal plate) by a longitudinal furrow along its inner surface, the sulcus limitans. A study of the external appearances and transverse sections of this part of the brain tube will make these relations clear (Figs. 418, 398 to 401 and 489). Neuromeres are also present at this stage (see p. 459). In the meantime the neural tube has also become bent ventrally at the junction of the brain and cord, forming the cervical flexure. The pallium has increased in size and now forms a considerable prominence on the brain tube. Its boundaries are also much more clearly marked off (see Fig. 433). On the inner side of the tube, the area below the bulging of the pallium is the corpus striatum. Externally, just below the bulging, we have the region where the olfactory lobes are differentiated. The proximal part of the optic evagination has become longer and narrower. The ventral expansion of the diencephalon is the hypothalamus, the portion of the diencephalon dorsal to the latter being the thalamus. Two slight protrusions of the ventral wall of the hypothalamus have appeared; the caudal one is the mammillary region, the anterior one the infundibulum. The cavity of the diencephalon (third ventricle) is connected by the mid-brain cavity (iter or aqu&ductus Svlvii) with the rhombic brain cavity or iourth ventricle.

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'''Fig. 378. Profile view of a model of the brain of a human embryo during the third week.''' His. A, Optic vesicle; A.v., auditory vesicle; Br, pons region; H, pallium; Hh. cerebellum; J, isthmus; M, mid-brain; AT and Rf, medulla; NK, cervical flexure; Pm, mammillary region; Tr, infundibulum; Z, inter-brain or diencephalon.

==Histogenesis of the Nervous System==

The neural plate is at first a simple columnar epithelium. The various processes by which this is converted into the fully formed nervous system are : (i) cell proliferation; (2) cell migration; (3) cell differentiation. These processes are not entirely successive in point of time, but overlap each other. Cell division is present from the first, increases to a certain period in development and then practically ceases; cell migration is partly a necessary concomitant and resultant of cell division, and cell differentiation is in part due to the growth of the cytoplasm and is in part a result of environmental differences produced by these processes. In development the following stages may be distinguished :

(1) Stage of indifferent epithelium; (2) appearance of nerve elements (neurones) and resulting differentiation into supporting and nerve elements; (3) growth of neurones and resulting differentiation and development of (a) peripheral neurones, (b) lower intermediate or intersegmental neurones, (c) neurones of higher centers and neurone groups in connection with them (suprasegmental neurones). These stages do not occur simultaneously throughout the whole neural tube, some parts being more backward in development than others (p. 443) . In general the spinal cord and epichordal segmental brain are most advanced in development. Furthermore, the ventral part of the brain tube precedes the dorsal. The most backward part of the whole neural tube is the pallium.

The various phases of differentiation of the neurone are (1) the development of the axone and, later, of its branches; (2) the growth of the dendrites; (3) the formation of accessory coverings or sheaths, the neurilemma and the myelin (medullary) sheath. The principal internal differentiations are (i) the appearance of the neurofibrils; (2) the chromophilic bodies of Nissl; (3) pigment. These latter may all be regarded as products of the nucleus and undifferentiated cytoplasm of the nerve-cell.

===Epithelial Stage===

Development of Neuroglia.

From the very first, the neural plate exhibits dividing cells similar to those seen in the non-neural ectoderm. The cell divisions are indirect and the mitoses are confined to the outer part of the ectoderm, occurring between the outer ends of the resting epithelial cells (Fig. 370). These dividing cells have been termed by His germinal cells. When the neural tube is formed, the mitoses are still confined to the outer, now the luminal, surface, this being a general phenomenon in developing epithelial tubular structures. As a result the daughter nuclei migrate away from the lumen.

In the most advanced parts of the neural tube (see p. 438), the mitoses increase in number up to about the fourth to sixth week of development, and then diminish anc 1 finally nearly disappear about at the end of two months. At about the time the blood vessels penetrate the tube, the mitoses are no longer entirely confined to the proximity of the lumen.

As a result of proliferation, the epithelial wall very early assumes the ap. pearance of a stratified epithelium at least there are several strata of nuclei. There are at this stage in many forms two layers, an outer or marginal layer, free of nuclei, and an inner or nuclear layer (Figs. 380 and 381). In a human embryo, however, of about two weeks this division into layers is yet hardly evident, though there are several strata of nuclei. Apparently these layers are not well-marked until the radial arrangement of the myelospongium, as described below, has become more pronounced.

Accompanying the above changes, changes also manifest themselves in the character of the cells. At about the time of the closure of the neural tube, the cell boundaries become indistinct and finally practically obliterated, thus forming a syncytium, the myelospongium. At the same time, the syncytium becomes very alveolar in structure and a general spongioplasmic reticulum is formed (Figs. 380 and 381) by the anastomosing denser strands (trabeculae) of protoplasm. At a very early stage (two weeks), these trabeculae unite along the inner and outer walls of the neural tube forming internal and external limiting membranes. The nuclei of the neural tube have at first an irregular arrangement in the reticulum, at least in the human embryo. This is followed by a more radial arrangement of both nuclei and protoplasmic filaments (Fig 382), forming nucleated radial masses of protoplasm the sponglioblasts (Figs. 381 to 384). There is some dispute as to the loss, complete or incomplete, of identity of the epithelial cells in the formation of the spongioblasts. According to Hardesty, they are formed by a collapse of the epithelial cells and a rearrangement of their denser parts into axial filaments. The radial arrangement does not extend into the outer part of the neural tube which, retaining its irregular reticular character, is now non-nucleated in the human embryo and forms the marginal layer. The increase in the thickness and circumference of the walls of the tube and the resulting tensions may be a factor in this arrangement of the protoplasmic filaments. At the boundary between the marginal and nuclear layers the reticulum appears to be especially dense.

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'''Fig. 379. From the neural tube of an embryo rabbit shortly before the closure of the tube''', g, Germinal or dividing cell; w, peripheral zone, position of the later marginal layer. His.

'''Fig. 380. Pig of 5 mm, unflexed. Just after closure of the neural tube.''' Segment of a vertical section of the lateral wall of the tube, g, Germinal cells; m, beginning of marginal layer; mli, internal limiting membrane; r, radial columns of protoplasm. The resting nuclei lie in the inner or nuclear layer. Hardesty.

'''Fig. 381. Pig of 7 mm, unflexed. Segment from the ventro-lateral wall of the neural tube'''; g y Germinal cells; mli, internal limiting membrane; mle, external limiting membrane r radial, axial filaments of the syncytial protoplasm; p, beginning of pia mater. Hardesty.

'''Fig. 382. Pig of 10 mm "crown-rump" measurement. Segment from lateral wall of neural tube.''' b, boundary between nuclear layer and marginal layer (m). Other references same as in 381. Hardesty. a indicates the zone in which the dividing cells are located. Later, it is composed of the inner ends of the ependyma cells (column layer of His}.

With the further increase and development of the nervous elements (see p. 455) the radial arrangement of the spongioblasts noted above becomes more and more obliterated. As shown by Golgi preparations, in their migration from the lumen (Fig. 384) the spongioblasts lose their connection with the lumen, their peripheral processes become abbreviated and disappear, and they finally differentiate into the irregular branching neuroglia cells (Fig. 385). According to Hardesty, there is simply a general nucleated mass which changes form pari passu with changes in the enclosed . differentiating nervous elements, finally assuming shapes dependent upon the character of the spaces between the formed nervous elements. An exception to this is a layer of nucleated elements which remain next the lumen and form the ependyma cells which still send radial extensions into the wall of the neural tube (Figs. 383 and 384). These cells develop cilia projecting into the lumen.

A still later differentiation in the supporting elements of the tube is the appearance of neuroglia fibers a product of the spongioblastic protoplasm, but differing from it chemically (Fig. 385). The exact relation of these neuroglia fibers to the nucleated neuroglia cells in the adult is a matter of dispute.

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'''Fig. 383, Hardesty. Combination drawing from sections of pig of 15 mm.''' The upper part is from a section of the same stage as the lower but stained by the Golgi method. By migration and differentiation the mantle layer has been formed. The cells remaining near the lumen form the ependyma layer (ep.). b, Boundary between mantle and marginal layers; ep, ependyma; mli and mle, internal and external limiting membranes; mv, differently arranged mid-ventral portion of the marginal layer; r, radial filaments; cs, connective tissue syncytium.

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'''Fig. 385. Hardesty Combination drawing from transverse sections of the spinal cord of 20 cm. pig.''' Showing the first appearance of neuroglia fibers, a, Neuroglia cell as shown by the Benda method of staining; a', similar cell by the Golgi method; b and b r , non-nucleated masses; d, free nuclei; e and f, differentiating neuroglia fibers; s, "seal-ring" cells, enveloping myelinating nerve-fibers.

With the penetration of blood vessels into the neural tube a certain amount of mesodermal tissue is brought in. How much of the supporting tissue of the nervous system is derived from the mesoderm is uncertain, but it is most probable that it is relatively small in amount and is confined principally to the connective tissue of the walls of the blood vessels.

==Early Differentiation of the Nerve Elements==

It has been seen that some of the actively dividing cells (germinal cells) at first simply increase the ordinary epithelial elements of the tube which in turn form the myelospongium, the spongioblasts and finally the ependyma and the neuroglia. Other daughter cells produced by the division of the germinal cells differentiate into nerve cells as described below. Still others probably migrate outward as indifferent cells, which later proliferate and form cells which differentiate into neuroglia and nerve cells.

According to recent researches (Cajal), by means of the silver stain of Cajal the first indication of the differentiation of cells into nerve cells is the appearance of neurofibrils in the cytoplasm of cells near the lumen. The part of the cell in which the neurofibrils first appear is called the fibrillogenous zone (Held) and is usually in the side furthest from the lumen. The cells in which these appear are apparently without processes, and are accordingly termed apolar cells (Cajal). (Fig. 386.)

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'''Fig. 386. Section through the wall of the fore-brain vesicle of a chick embryo of 3.5 days.''' Cajal.

:A, b arid c, Differentiating nerve cells in apolar stage, the neurofibrils are black; a, cell in a stage transitional to the bipolar stage; B, bipolar cells; c (at lower right corner), cone of "growth" of developing axone; e, tangential axone. The cells in the bipolar stage have migrated out ward, but the neuroblast or mantle layer has not yet been differentiated.

The next step in the development of many, but probably not all, of these cells is their transformation into bipolar cells by the outgrowth of two neurofibrillar processes, one directed toward the lumen, the other, usually thicker, toward the periphery, the cell body at the same time beginning to migrate outward (Fig. 386). This bipolar stage may be regarded as conditioned to some extent by the radial arrangement of the other elements, due in turn partly to the original epithelial structure and partly, possibly, to tensions produced by the growth of the tube. It is also interesting as recalling conditions in sensory epithelia and in the cerebrospinal ganglia. The bipolar stage is most common probably in those parts where the elements show a radial arrangement in the adult. Such are the layered cortices of the mid-brain and pallium. Nerve cells maintaining a connection, by central processes, with the luminal wall have been described in lower Vertebrates. This connection may be explained as due to a persistence of the central processes of cells in the bipolar stage.

The next stage is a monopolar stage produced by the atrophy of the luminal process. Cells in this stage are the neuroblasts of His, the peripheral processes being the developing axones (Fig. 387). As seen in ordinary stains, the above differentiation of the neuroblasts is marked by a corresponding differentiation of the nuclear layer into an inner layer retaining its previous characteristic radial arrangement, and an outer layer characterized by fewer nuclei more irregularly arranged. The latter layer is the mantle, or neurone layer (Fig. 404) . There are now three layers: (i) inner (nuclear), (2) mantle (neurone) and (3) marginal. The mantle layer is thus produced by the migration and differentiation of cells into neuroblasts. While this process may begin near the lumen (apolar nerve cell of Cajal) and progress as the cell has moved somewhat further away (bipolar stage), the monopolar stage is probably reached only when such cells form a part of the mantle layer. In other words, the mantle layer is created by the migration to a certain location and differentiation to a certain stage of the primitive nerve cells. The mantle layer, as previously stated, probably also contains indifferent cells which may by further proliferation and subsequent differentiation become either glia or nerve cells. * The looser arrangement of the cells of the mantle layer is probably in some measure due to the growth of the dendrites which appear soon after the axones. It may be also due to the beginning vascularization of the tissues with resulting transudates (His) which usually, however, begins somewhat later. The association in time of vascularization and further growth of neurocytoplasm (dendrites) is significant. When the cell-proliferation near the lumen has ceased, the supply of new cells ceases, and as the cells of the inner layer continue to differentiate into cells of the mantle layer, the inner layer, being no longer replenished from within, is reduced to the single layer of cells which remain behind as ependyma cells (p. 451).

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'''Fig. 387. Dorsal portion of the lumbar cord of a chick embryo of three days.''' Cafal. A, B, Cells in the apolar stage with fibrillogenous zones; B shows transition to the bipolar stage; E, further advanced bipolar cell; G, cells in monopolar stage or neuroblasts of His; a, giant cone of growth. These cells have migrated to the outer part of the nuclear layer, thereby forming the beginning of the mantle layer.

* It is an open question as to how late in development these " extraventricular " cell-divisions, involving " indifferent " cells, may occur. The neuroglia cells, however, like other supporting elements, preserve this capacity of division indefinitely, as shown by the increase in neuroglia cells in pathological conditions.

==Differentiation of the Peripheral Neurones of Cord and Epichordal Segmental Brain==

Efferent Peripheral Neurones. The differentiation of a mantle or neurone layer from the outer part of the original nuclear layer is practically universal throughout the whole neural tube. It appears first and is consequently most advanced, however, in the ventral part of the lateral walls of the cord and epichordal brain. The axones of neuroblasts occupying the basal plate of this region of the neural tube grow out through the external limiting membrane and emerge as the efferent ventral root fibers. The appearance of these early root fibers in the duck is shown in Fig. 388. The process is similar in the human embryo and begins about the third week. The neurones thus differentiated are the efferent peripheral neurones.

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'''Fig. 388. Ventral part of wall of lumbar cord of 70-hour duck embryo, showing efferent root fibers first emerging from cord (combined from two sections).''' Cajal. A, Spinal cord; B, perimedullary space; C, meningeal membrane; a, b, cones of radially directed axones; c, d, cones of transversely directed axones; Z>, bifurcated cone; E,F, cones crossing perimedullary space; G, aberrant cones.

In some forms, at least, cells appear to migrate out from the tube along with the efferent root fibers. Their fate is not certain, but they probably either metamorphose into the neurilemma cells or possibly form part of the sympathetic ganglia (see p. 492). In general the questions affecting the differentiation of the efferent fibers are the same as for the afferent and are further dealt with later (pp. 462-465).

The majority of the efferent root fibers pass to the differentiating somatic muscles which they innervate, forming specialized terminal arborizations (the motor end plates). The fibers to the dorsal musculature form, together with the afferent fibers (p. 460), the dorsal branch of the peripheral spinal nerve; others form part of the ventral branch which sends a branch mesially toward the aorta. Some of the fibers of the mesial branch take a longitudinal course. This mesial branch is the white ramus communicans and terminates in the various sympathetic ganglia which are later formed along its course (p. 461).

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'''Fig. 389. Diagram (lateral view) of the brain of a 10.2 mm human embryo (during the fifth week).''' Showing the roots of the cranial nerves. His. Ill, Oculomotor; IV, Trochlear; V, Trigeminus (m, efferent root, s, afferent root) ; VI, Abducens; VII, Facial; VIII, Acoustic (c, cochlear part, v t vestibular part); IX, Glossopharyiigeus; X, Vagus; XI, Spinal accessory; XII, Hypoglossus. ot., Auditory vesicle; Rh.l., rhombic lip. The two series of efferent roots (medial and lateral) are clearly shown.

(Comp. Figs. 225, 227, 394 and 36^.) The fibers to the sympathetic ganglia ire the visceral (splanchnic) fibers of the ventral root. There are a few other fibers which grow dorsally from neuroblasts in the ventro-lateral walls of the cord and thence out via the dorsal root (Fig. 392). They also are probably visceral.

In the cord the splanchnic fibers, with the exception above noted, issue with the somatic fibers in a common ventral root. In the epichordal segmental brain, however, there is a differentiation of the efferent neuroblasts of the basal plate into two series of nuclei, a medial and a lateral. The medial series consists of the nuclei of the XII, VI, IV and III cranial nerves, and their axones grow out as medial ventral root fibers (except the IV) (Fig. 389) to the differentiating muscles of the tongue and eyeball which they respectively innervate. These muscles are probably somatic and their nerves are the somatic efferent cranial nerves corresponding with the greater part of the fibers of the ventral roots of the cord (compare p. 432). The lateral series consists of the nuclei of the efferent portions of the roots of the XI, X, IX, VII and V cranial nerves and their axones grow out as lateral roots (Fig. 389) to the differentiating striated branchial (splanchnic) muscles (sternocleidomastoideus, trapezius, pharynx, larynx, face and jaw) and also to muscles of the viscera (via sympathetic?). The lateral nuclei and their roots are thus splanchnic. (Cf. pp. 302-3, 462, 464.) Their root fibers, with the incoming afferent fibers, form the mixed roots of these nerves. The positions of these various nuclei and their roots are clearly indicated in Figs. 389, 398-401, 409 and 413 and require no further description. Additional details are mentioned in connection with the afferent cranial nerves. In the region of the vagus nerve, there are differentiated two series of lateral nuclei, a ventro-lateral (nucleus ambiguus X) and a dorso-lateral (dorsal efferent nucleus X) (comp. Fig. 369). Fig. 414 apparently indicates the beginning of this differentiation. The significance of the dorso-lateral nucleus is uncertain. It possibly sends fibers to the sympathetic system.

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'''Fig. 390. Diagram of the floor of the 4th ventricle of a 10 mm human embryo.''' Illustrating the rhombic grooves and their relations to the cranial nerves. The point of attachment of the acoustic and the sensory root of the trigeminal nerve is shown by dotted circles; the motor nuclei are represented by heavy dots. Streeter.

At about this period six transverse rhombic grooves are plainly marked in the floor of the fourth ventricle, standing in relation with the nerves of this region (Fig. 390). They are ordinarily regarded as neuromeric, but the above relation would indicate that they have primarily a branchiomeric character (Streeter). It will be noticed that each of the three main ganglionic masses of this region (p. 465) corresponds to two of the grooves. (Comp. p. 435).

The further development of the efferent neurones exhibits phases common to many other nerve-cells with a large amount of cytoplasm (somatochrome cells). The further development of the neurofibrils of cell body and dendrites is, according to some observations, at first confined to the peripheral portions, leaving a clear zone in the vicinity of the nucleus. The chromophilic substance first appears as distinct granules about the end of the second month, there being apparently a diffuse chromophilic substance present before this period. The chromophilic granules also are first differentiated in the peripheral portions of the cell. A still later differentiation is the pigment, which probably does not appear till after birth. This increases greatly in amount in later years and is then an indication of senility of the nerve-cell.

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'''Fig. 391. Three stages in the closure of the neural tube and formatiqn of the neural crest (spinal ganglion rudiment).''' From transverse sections of a human embryo of 2.5 mm. (13 pairs of primitive segments, 14-16 days), -von Lenhossek.

Afferent Peripheral and Sympathetic Neurones. It has already been mentioned (p. 421) that in the closure of the neural tube certain cells forming an intermediate band between the borders of the neural plate and the nonneural ectoderm are brought together by the fusion of the lips of the plate and form a ridge on the dorsal surface of the neural tube, this ridge being known as the neural crest (Fig. 391).

In the SPINAL CORD, at three weeks, the neural crest has separated from the cord and split into two longitudinal bands. The ventral border of each band shows a transverse segmentation into rounded clumps of cells, forming the rudiments of the spinal ganglia which later become completely separated. The efferent roots have begun to develop but the afferent roots appear later (fourth week, Fig. 396). The cells composing these rudiments are polyhedral or oval rather than columnar and proliferation still proceeds among them A differentiation of these cells soon begins. Some, usually larger cells begin to assume a bipolar shape. Their central processes grow toward the dorsal part of the lateral walls (alar plate) of the neural tube which they enter (Fig. 392), becoming afferent (dorsal) root fibers. These fibers enter the marginal layer and there divide (Figs. 392 and 403) into ascending and descending longitudinal arms which constitute the beginning of the dorsal (posterior) juniculus of the cord. The peripheral processes of the developing ganglion cells grow toward the periphery, uniting with the ventral root and forming with it the various branches of the peripheral spinal nerve (compare Figs. 22 5> 227,394 and 366). Other peripheral branches pass as a part of the white ramus communicans to the sympathetic ganglia through which they proceed to the visceral receptors. These latter fibers are thus visceral afferent fibers.

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'''Fig. 392. Part of a transverse section through the cord and spinal ganglion of a 56-hour chick embryo''' (combined from two sections). Cajal. A, Efferent cell of dorsal root; B, cone of growth of central process (afferent dorsal root fiber) of spinal ganglion cell; C, bifurcation of afferent root fibers in cord, forming beginning of dorsal funiculus or dorsal white column of cord.

It is now known that the spinal ganglion is a much more complicated structure and has more forms of nerve cells than was formerly realized. The differentiation into these various types has not yet been fully observed. The bipolar cells, however, become unipolar in the manner shown in Fig. 393. The cell body first becomes eccentrically placed with reference to the two processes and then, as it were, retracts from them, remaining connected with them by a single process. This change may economize space.

According to most authorities, many of the cells of the neural crest do not cease their migration by forming spinal ganglia, but undifferentiated cells wander still further ventralward and form, probably also undergoing still further proliferation, the rudiments of the various sympathetic ganglia, becoming subsequently differentiated into the sympathetic cells. By this migration there is first formed a longitudinal column of cells ventral to the spinal ganglia (Fig. 395) and, later, in relation with the white communicating rami (Fig. 394). This column becomes segmented (seventh week), forming ultimately the ganglia of the vertebral sympathetic chain. In the meanwhile, the cells of the column proliferate in places, forming rudiments which, by migration and further differentiation, form the ganglia of the various prevertebral sympathetic plexuses (cardiac, cceliac, pelvic, etc.). Further migrations lead to the formation of the ganglia of the peripheral plexuses (Auerbach, Meissner, etc.). All these ganglia, probably, are innervated by fibers from the white ramus, along whose course they apparently migrated. The axones of their cells pass to visceral structures either in the same segment or, via the longitudinal chain, to those of other segments. Some also join the branches of the peripheral spinal nerves (gray ramus}. Fibers of the white ramus also pass longitudinally in the chain to vertebral ganglia of other segments. The possibility previously mentioned (p. 456) of a contribution to the sympathetic ganglia by cells migrating out along with the ventral roots must be kept in mind. It would seem a priori more probable that these latter would furnish the efferent sympathetic cells, but the efferent cells predominate in the sympathetic and must thus be regarded as derived partly or wholly from the neural crest which furnishes at least the major part of all the sympathetic cells.

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'''Fig. 393. Section of spinal ganglion of 12-day chick embryo.''' Cajal. Showing various stages of the change from the bipolar to the unipolar condition. A,B, Unipolar cells; C, D, F, G, cells in transitional stage; E, bipolar cell; H, immature cell. The neurofibrils are well shown.

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'''Fig. 394. From a transverse section of a chick embryo of 4.5 days.''' Neumayer.

It seems probable that not all the cells of the neural crest form nerve cells, but some, usually smaller cells, become closely applied to the spinal ganglion cells, forming amphicytes, while others (lemmocytes) wander out along the nerve fibers and become the neurilemma cells, forming the neurilemma. These cells in this case would be quite strictly comparable to the glia cells of the neural tube. According to another view, the neurilemma cells are of mesodermal origin. While this point cannot be considered entirely determined, it seems fairly certain that in some types at least the former view is correct, removal of the neural crest having resulted in the formation of efferent nerves without neurilemma cells (Harrison). The modification into neurilemma cells seems to be accomplished by their enveloping the axones and becoming closely applied to them.

The peripheral nerve grows toward the periphery as a bundle of fibers which forms, as seen in many stains, a common fibrillated mass, dividing at its extremity into the developing branches of the nerve. The lemmocytes closely envelop each of these growing tips, but proximally only envelop the main nerve trunk (Bardeen). The final clear separation of the fibrillated mass into the individual nerve fibers is accomplished, according to Gurwitsch, by these accompanying cells forming septa within the mass and finally enveloping each axone as its neurilejnma sheath. Growth in bundles appears to be characteristic also of the axones (tracts and fasciculi) of many neurone groups in the central nervous system.

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'''Fig. 395. From a transverse section through a shark (Scyllium) embryo of 15 mm.''' Showing the origin of the sympathetic ganglion. Onodi. In mammals the cells are more scattered and their origin from the spinal ganglion rudiment not so clear.

Owing to the presence of these migrating cells as well as of mesodermal cells, the peripheral nerves in their earlier stages appear cellular in character; later the fibrous elements predominate, the nuclei becoming more scattered and changing into the flatter nuclei characteristic of the neurilemma (Fig. 394). According to one view (Balfour;, the nerve fibers themselves are differentiated from the cytoplasm of these cell-strings and are thus multicellular structures. Still another view is that of Hensen, according to which the fibers are a differentiation in situ from preexisting syncytial bridges uniting the parts connected subsequently by the formed nerve fibers. This differentiation may not be primarily connected with the neuroblasts (Apathy, Paton) . An intermediate view between this and the outgrowth view of His is that of Held, according to which the neurofibrillar substance is an outgrowth from the neuroblast body, or at least a differentiation proceeding from that body, but always within the preexisting cellular bridges of Hensen. The differentiating fiber is thus always intracellular instead of intercellular as according to the His-Cajal view. The experiments of Harrison above alluded to, in which the accompanying migrating cells were eliminated and naked axones (axis-cylinders) nevertheless developed, apparently disposes of the cell-string theory of Balfour. The growth of the fibers in the marginal layer of the central nervous system is also unfavorable to this theory. The apparently proven capacity of growing axones to find their way through foreign tissues (aberrant regenerating nerve fibers, Cajal), through ventricular fluid (Cajal), and even through serum (Harrison) seems to throw the weight of evidence in favor of the view of His. The latter is the view adopted in this description, though many of the most important facts of development are not perhaps entirely irreconcilable with any of these views. The general conception of the neurone is affected by these questions and the related question of anastomoses between the nervous elements, whether present at all, and if present, whether primary or secondarily acquired.

From the above it would seem that the cells of the neural crest have the capacity of differentiating into afferent neurones, efferent (sympathetic) neurones and supporting cells. Other cells of the neural crest differentiate into the chromafnne cells of the suprarenal glands and similar structures (p. 396).

There are several views as to the development of the myelin sheath. According to one view (Vignal), it is a product of the neurilemma cells, being formed in a manner analogous to the formation of fat by fat cells. According to Wlassak, the various substances composing the myelin (fat, lecithin and protagon) are first found in the central nervous system in the protoplasm of the spongioblasts, their probable original source being the blood of the meningeal blood vessels. Later, the myelin is laid down around the axones, appearing first as drops or granules. The same process takes place in the peripheral nervous system. The supporting elements of the nervous system thus would have a chemical as well as a mechanical function. Another view (Gurwitsch) is that the myelin is a product of the axone and is, at its first appearance, quite distinct from the neurilemma cells.

As the appearance of the myelin sheath is a final stage in the development of the neurone, the various neurone systems would naturally becorr Trwelinated in about the same sequence in which their axones develop. This is probably true in a general way, but the development of both axones and sheaths requires further study before any law can be exactly formulated. Coarse fibers apparently become medullated early, the sheaths of such fibers being usually thicker.

Although the myelin sheath is apparently an accessory structure, its formation is of great importance, not only from the above reason, but also because its appearance possibly indicates the assumption by the neurone of its capacity for the precise performance of its final functions. The functional significance of the myelin sheath is not, however, entirely clear. Its importance is enhanced by the fact that its integrity depends upon the integrity of its neurone and that we possess precise stains for demonstrating both its normal and abnormal conditions.

In the region of the RHOMBENCEPHALON, the neural crest very early exhibits a division into three masses: a glossopharyngeo-vago-accessorius, an acusticofacialis, and a trigeminus. These masses soon become separated from each other and from the neural tube, the glossopharyngeus also showing a partial separation from the vago-accessorius mass (Fig. 396).

The vago-accessorius group, at about three weeks, is a mass of cells much larger at the cranial end and continuous by a narrow band of irregular cells with the spinal neural crest. The cranial end of the mass shows a partial division into a dorsal and ventral part. The former becomes the ganglion of the vagus root, the latter the ganglion of the trunk (nodosum). The glossopharyngeus mass likewise shows a division into a dorsal group of cells, the future ganglion of the root and a ventral group, the future ganglion of the trunk (petrosum). The two ventral groups are associated with epidermal thickenings (placodes), but it is doubtful whether any ganglion cells are derived from the thickenings. These thickenings probably represent the thickenings associated in water-inhabiting Vertebrates with the development of certain sense organs, either lateral line or epibranchial (see p. 422). At this stage there are no afferent fibers, the cells not yet being differentiated into neurones. Some fibers found among the cells are efferent (see p. 458). The glossopharyngeus cells lie in the region of the third branchial arch, the vagus in the region of the fourth.

During the fourth and fifth weeks the processes of the cells begin to develop (Fig. 396), and the cell masses finally become definite ganglia with afferent root fibers passing into the neural tube and peripheral processes passing outward, forming, with the associated efferent fibers, the peripheral branches of the nerves in question (Fig. 397). The root and trunk ganglia of the vagus and glossopharyngeus, respectively, are also now connected by fiber bundles instead of cellular strands. At the same time there is a diminution of cells in the caudal part of the vago-accessorius group, this part finally being composed almost exclusively of efferent fibers emerging from the lateral surface of the medulla and cord. A few groups of cells (accessory root ganglia) persist, however, and develop into ganglion cells, some being found there at birth (Streeter) . This would indicate the presence of a small and hitherto undetected afferent element in the spinal accessory nerve, which is usually regarded as purely efferent. The spinal accessory nerves are thus identical with the vagus in their early development and consist at first of a homologous series of efferent roots and ganglia. This indicates that the spinal accessory might be regarded as a specialized part of the vagus extending caudally into the cord (Streeter) (see p. 434) *

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'''Fig. 396. From a reconstruction of the peripheral nerves in a human embryo of 4 weeks (6.9 mm).''' Streeter.
:UI-XII, III to XII cranial nerves; C.I, D. /,, L.I., 5. /., ist cervical, ist dorsal, ist lumbar, and ist sacral nerves, respectively; i, 2, 3, branchial arches; Ot. v., auditory vesicle; IX-X-XI gang, crest, ganglionic or neural crest of IX, X and XI cranial nerves. Fiber masses are represented by fine lines, ganglion cell masses by dots.

From this point on, the further development of the efferent fibers of the X and XI nerves and of the peripheral processes of their ganglia is the further growth of the various branches of these nerves and their connection with the differentiating structures innervated by them. At the same time there is an increasing concentration of the cells, thereby forming more definite ganglionic masses. The changes taking place are similar to those exhibited in the differentiation of the spinal nerves (p. 460), The central relations of the nerves of this region of the medulla are shown in Fig. 398. (Comp. Fig 369). The glossopharyngeus at the same time develops its branches, most of the peripheral fibers running in the third arch (lingual branch). Somewhat later (i 2 to 14 mm. embryo) another bundle (tympanic branch) (Fig. 397) passes forward to the second arch. This forms the typical branchiomeric arrangement in which there is a forking of the nerve into prebranchial and postbranchial branches, the latter being larger and containing the efferent element (see p. 434 and Fig. 367).

* According to another view (Bremer) , the spinal accessory nuclei and roots are to be regarded as representing a specialization of lateral nuclei of the ventral gray column of the cord whose root fibers pass in the dorsal branches of the spinal nerves to the dorsal trunk musculature (p. 45 7 > comp. Fig. 366). According to this view, the muscles innervated by the XI would be somatic. The possible pomology of the lateral efferent nuclei and roots of the medulla with those dorsal root fibers of the cord which arise from cells in the ventral gray column (p. 457 and Fig. 392) may be mentioned in this connection.

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'''Fig. 397. Lateral view of a reconstruction of a 10 mm. human embryo.''' Showing the origin and distribution of the peripheral nerves. The ganglionic masses are represented by darker and the fiber bundles by lighter shading. For purposes of orientation the diaphragm and some of the viscera are shown. The arm and leg are represented by transparent masses into the substance of which the nerve branches mav be followed. Streeter.

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'''Fig. 398. Transverse section through the rhombic brain of a 10.2 mm human embryo (during the fifth week).''' X, Vagus; XII, Hypoglossus. His.

While the ganglia of the facialis and acusticus are derived from the same mass of cells (p. 465, Fig. 396) and are later still in very close apposition, it must be remembered that they are totally different in character. At four weeks they are differentiated from each other (Fig. 399). The relations of the two ganglia are shown in Figs. 397 and 399. It is probable that the ganglion of the facial (geniculate ganglion) shows an early differentiation into dorsal and ventral parts similar to the ganglia of the IX, and X, and also has associated placodes. The peripheral branches of the cells of the geniculate ganglion develop into the great superficial petrosal and chorda tympani. Both of these nerves enter into secondary relations with the V. There is some doubt as to whether the chorda is a prebranchial or postbranchial nerve (Fig. 397; also compare p. 432 and Figs. 367 and 368^

The VII, XX and X are, as already mentioned, branchial (splanchnic) nerves and the central processes of their ganglia ail have a common destination; they grow into the lateral surface of the medulla oblongata, enter the marginal layer of the alar plate, and there bend caudally, forming a comrion descending bundle of fibers in the marginal layer, the tractm solita.ius (Figs. 398 and 432; see also pp. 432, 435).

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'''Fig. 399. Transverse section through the acoustic region of the rhombic brain of a 10.2 mm human embryo.''' VI, Abducens and its nucleus; VII G.g., geniculate ganglion; VIII G. c., cochlear ganglion of acoustic nerve; VIIIG.v., vestibular ganglion of VIII nerve. His.

The acoustic ganglionic mass is elongated at an early stage, and is in < onr.ection with an ectodermal thickening (placode) which gives rise to the acoustic receptors (p. 558). From the upper part of the mass a bundle of peripheral processes forms a branch which subsequently innervates the ampullae of the superior and lateral semicircular canals and the utricle, while from the lower part a branch develops to the ampulla of the posterior canal and to the saccule. The nerve and ganglion (ganglion of Scarpa] is thus at first vestibular and at this stage the cochlear part of the ear vesicle is not indicated as a separate outgrowth. As the lower border of the vesicle grows out into the cochlea, the lower border of the ganglion becomes thickened and develops into the cochlear ganglion (the ganglion spirale). It will be recalled that the vestibular part of the ear is the older part phylogenetically, the cochlea being a more recent specialized diverticulum of the older structure. (See p. 552 and Figs 464 and 465.)

The central processes of the acoustic ganglionic mass first develop from the upper part, forming the vestibular nerve root which enters the marginal layer of the medulla. A portion at least of its fibers bends caudally, forming a descending tract. The central processes of the cells of the cochlear ganglion, forming the cochlear nerve root, pass dorsally, cross the vestibular ganglion and enter the medulla dorsal and lateral to the vestibular root fibers (Fig. 399).

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'''Fig. 400. Transverse section through the rhombic brain in the region of the trigeminus (V) nerve of a 10.2 mm human embryo.''' a.W., Spinal V; G.G., Gasserian ganglion; V.m., efferent root of V nerve. His.

The trigeminus is the most anterior of the ganglionic masses (Fig. 396). Embryological evidence has been brought to show that it consists of two or more nerves which subsequently fuse. Placodes have also been described. It is possible that such placodes represent those belonging to the most anterior division of the lateral line system in lower forms, and probably in this case would not properly belong to the V (comp. Fig. 367). From the ganglionic mass (Gasserian or semilunar ganglion) the three principal branches ophthalmic, maxillary and mandibular are formed, the two latter passing into the maxillary process and mandibular arch, respectively (Fig 397). The central processes, forming the afferent root (portio major} of the V, enter the marginal layer of the alar plate of the rhombencephalon and form a descending bundle, the spinal V (Figs. 400, 401, 402 and 432).

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'''Fig. 401. Transverse section through the trigeminal region of the rhombic brain of a 10.2 mm human embryo.''' a. W., Spinal V; V. s., Gasserian ganglion; V. m., part of efferent root of V nerve. His.

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'''Fig. 402. Part of a transverse section through the rhombic brain of a chick embryo toward the fourth day, showing the trigeminal roots.''' Cajal. Aj part of the efferent (masticator) nucleus of the V; B, efferent root of the V; C, bipolar cells of the Gasserian ganglion; D, beginning of descending tract (spinal V) formed by the central processes of C.

The trigeminus exhibits its spinal-like character in the behavior of its visceral portion (comp. p. 461). Cells of the ganglionic mass migrate further peripherally and form sympathetic ganglia (ciliary, otic, sphenopalatine (?) submaxillary(?) ). As in the cord, the question has arisen whether efferent roots may not also contribute a portion. Cells have been described as migrating with the oculomotor root fibers and forming part of the ciliary ganglion (Carpenter).

Besides those already described (cerebrospinal, sympathetic), the only other peripheral neurones of the nervous system are connected with the PROSENCEPHALON and are a part of the eye and nose. The visual receptors (rods and cones) and peripheral afferent neurones (bipolar cells) appear to be represented by portions of the retina and are described elsewhere (Chap. XVIII).

In the nose there is first a placode (p. 422) from which neuroblasts develop. Some of these migrate toward the neural tube and probably differentiate into lemmocytes, a few becoming ganglion cells.* The majority of the neuroblasts remain in the olfactory epithelium, sending their axones (fila olfactoria) into the olfactory bulb, the peripheral afferent olfactory neurones thus apparently displaying the primitive ectodermal location of afferent peripheral neurones (p. 418 and Fig. 359). (Comp. p. 551.)

==Development of the Lower (Intersegmental) Intermediate Neurones==

It has already been seen how, by migration and by differentiation of the cells during migration, the nucleated layer comprising the greater part of the thickness of the wall of the neural tube is differentiated into two layers an inner nucleated layer retaining its earlier characteristics, and an outer nucleated (mantle) layer, composed largely of the differentiating neuroblasts and characterized in ordinary staining by more widely separated nuclei. It has also been seen that this differentiation takes place earlier and more rapidly at first in the ventral part of the lateral walls (basal plate) , and that the first cells to migrate and differentiate are those whose axones grow out through the neural wall and pass out as the ventral root fibers.

Not much later than the above differentiation of the efferent peripheral neurones, axones of other neuroblasts also grow toward the periphery of the tube but do not pass beyond its wall. Such neuroblasts become intermediate neurones (p. 419). The migrating bodies of these neuroblasts are checked at the inner boundary of the marginal layer, but their growing axones enter the marginal layer and there, apparently on account of their inability to penetrate the external limiting membrane, turn cranially or caudally, or bifurcate, and form longitudinal ascending and descending fibers. These longitudinal fibers constitute a part of the future white columns (see p. 477), and their cells are therefore often called column cells. Many axones from such cells in all parts of the lateral walls (heteromeric or commissural column cells) pursue a ventral course through the mantle layer, arising around near the periphery and crossing the floor plate, ventral to the lumen, to become longitudinal ascending and descending fibers in the marginal zone of the opposite side. These early decussating axones form, in the cord, the beginning of the anterior commissure (Fig. 403). Other neuroblasts, the axones of which do not cross the median line, become tautomeric column cells.

* The latter are probably transient, but possibly in some forms persist as the ganglion cells of the nervus terminalis of Pinkus.

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'''Fig. 403. Part of a section through the lumbar spinal cord of a 76-hour chick embryo.''' Cajal. A, Ventral root; B, spinal ganglion; C, bifurcation of dorsal root fibers forming beginning of dorsal funiculus; a, b, c, neuroblasts showing various stages of differentiation into intermediate neurones, some, at least, (c) becoming heteromeric column cells; d, efferent neurone.

It is about this time that the afferent root fibers enter the marginal layer of the dorsal part (alar plate) of the lateral wall and form in the marginal layer various bundles of longitudinal fibers above described (dorsal funiculus, actus solitarius, descending vestibular, and spinal V) (Figs 403, 404, 398, 399, 401, 402 and 432). In the cord the ascending arms grow to a greater length than the descending. In the rhombic brain the reverse is usually the case.

The longitudinal fibers of the afferent roots and of the intermediate neurones thus form an external layer occupying the marginal layer of the neural tube. This is the beginning of the differentiation into white and gray matter, i.e., into that part of the neural tube containing only the axones of the neurones and into that part containing the cell bodies and the beginnings and terminations of the axones. The terminations of axones are formed by a turning of the longitudinal fibers into the mantle layer or gray matter to form there terminal arborizations. Later, the longitudinal fibers develop branches (collaterals) which also pass into the gray matter. The differentiation of the white matter is completed several months later by the myelination of the nerve fibers.

The longitudinal axones of intermediate neurones which are formed at this period in the cord and epichordal brain are located ventrally near the median line. These medial tracts occupy the position of the future medial longitudinal fasciculi, the reticulo-spinal and ventral ground bundles, and may be regarded on both comparative anatomical and embryological grounds as a primitive system of long and short ascending and descending tracts mediating between cerebrospinal afferent and efferent peripheral neurones, and not having at this period connections with the higher centers. Other more lateral tracts of this character are formed somewhat later, the whole forming the beginning of the reticular formation + ventro-lateral ground bundle system (compare Figs. 404, 411, 414 and 416).

While merging more or less imperceptibly into the following stages, it may in a general way be said that at this stage of development there is differentiated what might be termed the primary and probably the oldest coordinating mechanism of the nervous system, most clearly segmental in character and having general features common not only to all Vertebrates, but to many Invertebrates. It is characterized by afferent and efferent peripheral neurones arranged segmentally and connected longitudinally in the central nervous system by crossed and uncrossed intersegmental intermediate neurones. (Compare pp. 435 and 436) . At the anterior end of this part of the nervous system (epichordal segmental brain) there are also exhibited differentiations due to fundamental vertebrate differentiations in the peripheral receptive and effective apparatus. Some of these are: (i) The differentiation of the splanchnic (visceral) receptive and motor apparatus, giving rise in the nervous system to (a) a separate system of afferent root fibers (tractus solitarius) including the more specialized gustatory apparatus; (b) a distinct series of lateral efferent nuclei. (2) The concentration of the non-specialized somat'c afferent innervation into one nerve (trigeminus and its central continuation, the spinal V). (3) The specialized somatic sense organ, the ear, with its older vestibular and newer cochlear divisions with central continuations of its nerves, including a vestibular descending tract.

These differentiations of the peripheral afferent apparatus lead to the later formation of special terminal nuclei for their central continuations and secondary tracts from these nuclei to suprasegmental structures (p. 436, Fig. 371).

The peripheral and intermediate neurones of the more highly modified cranial end of the tube, or FORE-BRAIN, appear to lag behind in development, but in its basal part the neuroblasts are beginning to be differentiated (fifth week) . In the development of the eye, the brain wall is evaginated, carrying with it the future retina comprising, apparently, the sensory epithelial cells or receptors (rods and cones), the afferent peripheral neurones (bipolar cells of retina) and the receptive or primary intermediate neurones (ganglion cells of retina and optic nerve). The histogenesis of these elements is dealt with elsewhere, but it may be pointed out here that the axones of the ganglion cells of the retina grow toward the inner side of the optic cup (away from the original luminal surface), pass thence in the marginal layer of the optic stalk, undergo a partial ventral decussation (optic chiasma) in the floor plate, and terminate in certain thalamic nuclei (lateral geniculate bodies) and in the roof of the mid-brain. The so-called optic nerve is thus obviously a central, secondary tract. The development of this tract does not apparently take place until a later period than the differentiation of the earlier secondary tracts of the cord and rhombic brain (after the sixth week) .

In the case of the olfactory organ, it has already been seen that the peripheral neurones develop at first apart from the neural tube and send their axones into the olfactory bulb. The latter is an evagination of the neural tube which receives the olfactory fibers, thereby constituting a complicated terminal nucleus for the latter. The axones of bulb cells (the mitral cells) which pass along the stalk of the bulb are thus the secondary tract of this system. Many of them decussate in the anterior commissure. Secondary (and tertiary) olfactory tracts find their way to caudal parts of the rhinencephalon and to hypothalamus, thalamus and epithalamus, forming, with other tracts, a highly modified prechordal intersegmental mechanism (p. 537). Other olfactory tracts proceed to the suprasegmental archipallium which develops efferent bundles to the segmental brain.

The embryological development of the peripheral apparatus, especially of its receptive portions, as shown by the various separate ganglionic rudiments (Fig. 396) and placodes, exhibits a segmental character which, though not in all respects primitive, is of practical value. These segments are (Adolf Meyer) : (1) The olfactory apparatus, nose, without efferent elements. (2) The visual apparatus, eye, with the eye-moving III and IV mid-brain nerves as its efferent portion. (3) The general sensory apparatus of the surfaces of the head and mouth, the afferent trigeminus, with the jaw-moving efferent trigeminus. (4) The auditory (and vestibular) apparatus, the ear (VIII nerve), with the VI (turning the eye to the source of sound) and VII (ear and face muscles) efferent nerves. In the latter, the original ear-moving apparatus has been replaced largely, in man, by the muscles of expression. (5) The visceral segment (IX, X, and XII nerves), not indicated externally in forms without gills. The afferent portion is concerned with taste and visceral stimuli, the efferent with tasting, swallowing, sound-production and other visceral functions. Overlapping with other segments is due to its visceral as opposed their somatic character. The apparent dislocation shown by the abducens is due to its common use by more than one segment.

Caudal to this is the mechanism for head movement (N. XI) , its afferent portion being the upper spinal nerves. Following this, there is the segmental series of spinal nerves which in places shows a tendency to fuse (plexuses) into larger segments (phrenic segment, limb segments) . All such modifications are expressions of more recent functional adjustments modifying preexisting ones.

These segments may be regarded as a series of reflex arcs, each one of which may have a certain amount of physiological independence but which are associated by intersegmental neurones. The latter class of intermediate neurones probably effects certain groupings of various efferent neurones, furnishing mechanisms which secure harmonious responses of groups of effectors involved in certain definite reactions (e.g., limb-movements, associated eye movements). These effector-associating mechanisms may be acted on directly (reflex) by afferent neurones or by the efferent arms of suprasegmental mechanisms.

Superadded to this segmental apparatus are the suprasegmental mechanisms which develop later, the pallium being the last to be completed. These receive bundles from the segmental nervous system and send descending bundles to the intersegmental neurones (pp.427, 435 and 436 and Fig. 371).

==Further Differentiation of the Neural Tube==

===The Spinal Cord===

From this time on, differences of structure between cord and epichordal segmental brain become more marked and make it more convenient to treat their later development separately. The ventral half of the cord for a considerable period maintains its lead in development. At four weeks (Fig. 404) this lead is not so pronounced as in the immediately following period. At this stage it will be noticed that the lumen is narrower in the ventral part, as if due to the greater thickening of the ventral walls (basal plates). The increase of the mantle layer (gray) of the basal plate marks the beginning of the ventral (anterior) gray column or horn. The increase in the basal plate may be partly due to neuroblasts migrating from the alar plate. These would be intermediate neurones. The development of the mantle layer at the expense of the inner layer, due to differentiation and migration of the cells of the latter, is well shown, but is more marked in the following stages.

As already mentioned, the axones of the heteromeric cells, many of which lie in the dorsal half of the lateral walls, after decussating (anterior commitsure), form longitudinal fibers in the marginal layer along the ventral surface of the opposite side, mostly mesial to the emerging ventral roots (Fig. 44) These longitudinal fibers are the beginning of the ventral (anterior) white columns or funiculi of the cord. The sides of the tube between the dorsal and ventral roots contain at first only a few longitudinal fibers the beginning of the ventrolateral juniculi. Their number soon rapidly increases, the fibers apparently coming from ventrally located tautomeric cells. The dorsal root fibers, as stated before (p. 460), form small round bundles in the marginal layer of the dorsal halves (Fig. 404). This is the beginning of the dorsal (posterior) white columns or funiculi,.

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'''Fig. 404. Half of a transverse section of the spinal cord of a 4 weeks, (6.9 mm) human embryo.''' Dp, Roof plate; Bp, floor plate. His.

At four weeks there are blood vessels in the mesodermal tissue surrounding the neural tube. Branches of these soon penetrate the tube itself.

From its first appearance in the cord as an oval bundle, during the fourth week, the dorsal funiculus steadily increases in size, forming a "root zone" in the marginal layer of the dorsal half, but not reaching the roof plate (Fig. 405). This increase in size is probably produced in part by the addition on its inner side of overlapping ascending arms of dorsal root fibers from lower cord segments. The mantle layer of this part contains an increasing number of cells forming curved or arcuate fibers. (Fig. 405.) The increase in the mantle cells of the dorsal part marks the beginning of the dorsal (posterior) gray column or horn (terminal nucleus of the dorsal root fibers) . Later, other cells become differentiated from the inner layer which do not apparently form arcuate fibers (Fig 405) and which subsequently become part of the posterior horn. It is possible that the axones of some of these cells form the comparalively small ground bundles of the dorsal funiculus. During this period of development of the dorsal portions of the lateral walls the latter have approached each other, reducing the dorsal part of the lumen to a slit. The roof plate has undergone a slight infolding (Fig. 406). Ventral to the dorsal roots there is a groove running along each side of the cord (marginal furrow of His). At four and one-half weeks the number of fibers of the ventro-lateral funiculus has greatly increased and another groove has appeared parallel and ventral to the marginal furrow and forming the dorsal boundary of the ventrolateral funiculus (cylinder furrow of His) (Figs. 405 and 406). The portion of the lateral wall lying between these two grooves or furrows forms an intermediate plate which contains few fibers in its marginal layer at this period, and is thus backward in development. Grooves appear on the luminal wall, apparently corresponding approximately to the outer grooves.

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'''Fig. 405. Half of a transverse section of the spinal cord of a 4.5 weeks (10.9 mm) human embryo.''' His. A.s., Artery in ventral longitudinal sulcus; A.sp.a., ventral (anterior) spinal artery; Bp, floor plate; Dp, roof plate; 7. 1., inner layer. The faint inner outline is the outline of the cord proper.

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'''Fig. 406. Half of a transverse section of the spinal cord of a human embryo of 18.5 mm.''' (7.5 weeks). His.

The further growth of the dorsal funiculi and the concomitant growth of the associated gray matter, i.e., of the cells of the adjoining mantle layer, proceed until we have the conditions shown in Figs. 406 and 407. At the same time there is a further approximation of the dorsal portions of the lateral walls so that the widest part of the lumen is further ventral. At about eight weeks the portion of the wall near the median line, which has formed a ridge by the apposition of the two inner layers and the roof plate (Fig. 406 Y), and is uncovered as yet with fibers, differentiates a marginal layer (eight and one-half weeks, Fig. 407) into which fibers grow forming, on each side, in the upper part of the cord, the column of Goll or fasciculus gracilis (Fig. 408). Many of these fibers, at least, are the ascending arms of caudal dorsal root fibers, which are thus added mesially to the continuations of upper cord roots. It will be noted that there is now a massive dorsal gray column and that the original oval bundle has extended around on the mesial side of this gray column.

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'''Fig. 407. Half of a transverse section of the spinal cord of a human embryo of 24 mm. (8.5 weeks).''' His.

While these changes are taking place, the dorsal portions of the lateral walls have fused, probably beginning at the most dorsal part, thus forming the dorsal septum. This may be accompanied by a certain amount of rolling in from the dorsal part indicated by the direction of the ependyma cells (Fig. 408). The growth of the ventral funiculi and gray columns results in the appearance and subsequent increasing depth of the. ventral longitudinal fissure. The cord now resembles the adult cord in many features, having well-marked white* and gray columns, but contains a disproportionately small amount of fibers. A further and later change consists in a rolling inward, as it were, of the dorsal gray column so that it becomes separated from the ventral gray column, and that portion of it formerly facing dorsally comes to face more mesially, the roots entering more dorsally. This change may be due partly to the development of the intermediate plate which has in the meantime taken place. In this plate axones of tautomeric cells have begun to form the limiting layer of the lateral funiculus. From the cells of the intermediate plate are formed the neck of the dorsal gray column, also the cells of Clarke's column and the their fibers become myelinated during the sixth month.

*The term "white" column is used for convenience, The funiculi do not become "white" until processus reticularis. In the course of these developments, the ventro-lateral ground bundles, formed primarily by heteromeric and tautomeric cord cells, receives various accessions. These are first the long descending intersegmental tracts from epichordal brain nuclei in the formatio reticularis which as they proceed down the cord naturally overlap externally the ground bundles already formed there. They include the medial longitudinal fasciculi; tracts from Deiters 1 nuclei and the rubro-spinal tracts which occupy the ventrolateral funiculi external to the ground bundles. In the lateral funiculi there are also added the ascending tracts from cord nuclei to suprasegmental structures.

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'''Fig. 408. Half of a transverse section of the spinal cord of a human foetus of about 3 months.''' His.

These are the dorsal spino-cerebellar tracts from Clarke's columns, ventral spinocerebellar tracts, and tracts to mid-brain roof and thalamus (spino-tectal and thalamic). Finally (fifth month) the descending tracts from the pallium are added, the direct and crossed cor tico- spinal (pallio- spinal or pyramidal] tracts, the latter being thrust, as it were, into the lateral funiculus.

The development of the cord, then, is produced by (1) the proliferation of the epithelial cells and the formation of the nuclear and marginal layers; (2) the multiplication, differentiation and growth of the neuroblasts (mantle layer) ; (3) the development of the ventral roots; (4) formation of the funiculi (white columns when myelinated) by the growth into the marginal layer of (a) dorsal root fibers of the cord, the ascending arms of which overlap those root fibres entering higher cord segments, (b) cord neuroblasts forming intersegmental (ground bundle) tracts next to the gray matter, (c) descending intersegmental tracts from the segmental brain, representing continuations principally of cerebellar efferent tracts, (d) afferent suprasegmental tracts from cord nuclei, (e) descending pallio-spinal tracts. In addition to this, there are general factors of growth, such as increasing vascularization, increasing amount of neurone cytoplasm (especially dendrites) , increased size of axones and, finally, the acquisition by the latter of myelin sheaths.

The vertebral column grows faster in length than the inclosed spinal cord. The result of this is that the caudal spinal nerves making their exit through the intervertebral foramina are, so to speak, dragged caudalward and instead of proceeding outward at right angle to the cord, pass caudally to reach their foramina. The leash of nerve roots thus formed, lying within the caudal part of the vertebral column, constitutes the cauda equina. The coverings of the cord retain their original connections at the caudal end of the vertebral canal and form a prolongation of the cord membranes enclosing the thin, terminal part of the cord, the filum terminate.

==The Epichordal Segmental Brain==

In the fifth week, the walls of the rhombencephalon are comparatively thin. In the caudal region of the medulla oblongata (p. 447) , the dorsal part of each lateral wall is upright and is bent at a considerable angle with the ventral part (basal plate), the groove on the inner surface between the two being the sulcus limitans. The roof of this region is formed by the thin expanded roof plate (Figs. 398-401).

Anterior to this, the roof plate is not expanded, the alar plates almost meeting in the mid-dorsal line. This thicker part of the roof is the rudiment of the cerebellum. Its caudal edges are attached to the expanded roof plate.

In front of the cerebellum the tube is narrower and is compressed laterally. This part is the isthmus (Fig. 409) . Anterior to this, the roof plate and alar plates expand into the mid-brain roof, the basal and floor plates forming the basal part of the mid-brain.

Certain gross changes which from now on take place in the medulla may conveniently be noted here. At about this time (fifth week) the outer borders of the alar plate become folded outward and then downward, being thus turned back on the plate itself ([[#Fig414|Figs. 414]] and 378). This fold is called the primary rhombic lip, and is most marked along the caudal border of ' the cerebellum. The folds of the lip then fuse, forming a rounded eminence composing the border of the alar plate to which the roof plate is attached laterally. Subsequently, the attachment to the roof plate is shifted dorsally in the medulla, caudally in the cerebellum. The portion of this lip which thins off into the roof plate is the tania of the medulla and the posterior velum and taenia of the cerebellum. The thin roof plate itself becomes tbe epithelial part of the tela chorioidea of the fourth ventricle. At the caudal apex of the fourth ventricle a fusion of the lips of the opposite sides forms the obex.

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'''Fig. 409. Transverse section through the isthmus of a 10.2 mm human embryo.''' D.IV, Decussation of trochlear nerve; M. L, marginal layer; Nu. IV, nucleus trochlear nerve.

A further complication is due to the increasing pontine flexure by which the dorsal walls of the tube are brought close together ([[#Fig410|Fig. 410]]). The transverse fold of the tela thus produced is the chorioid fold. At about the same time lateral pocketings outward of the dorsal walls occur just caudal to the cerebellum which contain portions of the chorioid fold. These are the lateral recesses. By further growth and vascularization, the mesodermal part of the chorioid fold forms the chorioid plexus of the fourth ventricle (metaplexus). Finally, in the human brain an aperture appears in the caudal portion of the roof of the ventricle the foramen of Magendie (metapore) ; and, according to many authorities, one also occurs in the roof of each of the lateral recesses the foramina of Luschka. The roof of the fourth ventricle, where present, is thus composed of an inner ependymal epithelium the expanded roof plate of the neural tube and an outer mesodermal covering containing blood vessels. Other gross changes chiefly involve the basal plate. At the beginning of the fifth week this does not much exceed the alar plate in thickness and is separated from the opposite basal plate by an inner median sulcus (Fig. 414). The basal plate now increases in thickness and thereby both deepens the sulcus and contributes to a flattening out of the lateral walls, so that all portions by the sixth week lie approximately in the same horizontal plane ([[#Fig416|Fig. 416]]). Later, the floor plate increases in thickness more rapidly and the sulcus becomes shallower (eight weeks) ([[#Fig417|Fig. 417]]). The band of vertical ependyma fibers passing through it is the septum medulla. It is bounded on each side by a vertical extension of the marginal layer which for convenience will be referred to as the septal marginal layer ([[#Fig415|Figs. 415]], [[#Fig416|416]] and [[#Fig417|417]]).

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'''Fig. 410. Lateral view of a model of the brain of a 7.5 weeks (18.5 mm) human embryo.''' His.

The histological condition of this part of the tube at the beginning of five weeks has already been described. The lateral walls consist of an inner layer of closely packed cells, of a mantle layer consisting of efferent neurones and a simple system of intermediate neurones, and an outer marginal layer containing the longitudinal bundles of incoming afferent roots and longitudinal axones of intermediate neurones (see p. 474). It has been seen that this condition has been brought about by the proliferation of cells near the tube cavity, which migrate outward, at the same time many of them differentiating into neuroblasts and nerve cells and thereby forming the mantle layer. As in the cord, the basal plate takes the lead and thus at first outstrips the alar plate, as shown in its greater thickness above mentioned. This process likewise terminates sooner in the basal plate, few cell divisions being present there at seven weeks. At about the end of the fifth week (see p. 489) the alar plate begins to develop very rapidly. Its period of proliferation is about terminated at the end of the second month. When the cell proliferation near the ventricle has ceased, the inner layer is reduced by outward migration to a single layer of epend] ma cells (compare pp. 455 and 456).

While the efferent nuclei continue to develop and the central continuations of the afferent neurones continue to grow in length, the principal differential ipns now taking place in the rhombic brain are those affecting the intermediate neurone systems.

The first of these to be considered is the further differentiation of the system of intersegmental neurones (p. 435). The earlier development of this system has been seen to involve especially the basal plate and the further development of the latter leads to the complete differentiation of the formatio reticularis which especially represents this system in the epichordal brain. It has already been seen (p. 474) that many of the intermediate neurones representing the beginning of this system seem to be at first heteromeric and form an internal arcuate system of fibers similar to those seen in the cord (pp. 473,477). They increase in number toward the median line and are especially numerous in the basal plate, where they, together with the medial efferent neurones (XII and VI cranial nerves), form an eminence of the mantle layer corresponding to the ventral gray column of the cord ([[#Fig411|Fig. 411]]). Many of the axones of these cells of the arcuate system cross the septum medullae, thus marking the beginning of the raphe, and form on each side a longitudinal bundle in the septal marginal layer ([[#Fig411|Fig. 411]]). These longitudinal bundles correspond to the first formation of the ventral funiculi of the cord. They must not, of course, be confused with the pyramids which appear much later. Whether these longitudinal bundles are also partly formed of axones of tautomeric cells is uncertain. Later, as the anterior horn swellings grow and the depth of the septum medullae and of the septal marginal layers increases (compare p. 484), more longitudinal fibers appear in the latter, the new ones apparently being added ventrally. Others also appear more laterally in the marginal layer (Figs. 415, 416 and 417). (Compare cord, p. 477-) At this time, also, fibers enter the marginal layer bordering the surface (as distinguished from the septal), pass along parallel with the surface, cross the septum, and proceed to various parts of the marginal layer of the opposite side. These fibers are the first external arcuate fibers as opposed to the prec eding internal arcuate fibers which traverse the mantle layer (gray) in the arcuate part of their course ([[#Fig415|Fig. 415]]).

The majority of the longitudinal fibers entering the septal marginal layers during the second month occupy approximately the position of the future mesial formatio reticularis alba (white reticular formation) and correspond in position to the fibers of the medial longitudinal fasciculi and reticulo-spinal tracts in the adult medulla, representing probably the same system as the medial part of the ventro-lateral funiculi of the cord (medial longitudinal fasciculi, reticulo-spinal and ventro-medial ground bundles of the cord). The medial longitudinal fasciculi are in part descending fibers from higher levels described later.

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'''Fig. 411. Half of a transverse section of the medulla of a 10.2 mm human embryo.''' His.

In the basal plate, between the medial and lateral efferent nuclei, there are, even at the beginning of the fifth week, not only the efferent neurones and the heteromeric (commissural) neurones already mentioned, but other neuroblasts whose axones have a radial direction, i.e., toward the periphery. (Figs. 411 and 414.) The interlacing of these with the arcuate fibers forms the first indication of the formatio reticularis grisea (gray reticular formation). Later, longitudinal fibers are present here, giving rise to a condition more fully corresponding to that in the adult, analogous also to the condition in the lateral funiculi of the cord, especially in the processus reticularis.

In the region of the auditory segment an important neurone group appears which is possibly a differentiation of the extreme dorso-lateral portion of the basal plate. This is Deiters' nucleus, which apparently receives vestibular and cerebellar fibers and sends uncrossed descending bundles along the outer lateral part of the reticular formation and also ascending and descending crossed and uncrossed fibers along its outer mesial portion (part of the medial longitudinal fasciculus) . This nucleus thus represents, apparently, like the nucleus ruber and nucleus of Darkschewitsch (below), a differentiated portion of the intersegmental neurones in especial connection with suprasegmental efferent fibers which thereby act on many brain and cord segments.

The great development of the reticular formation here and caudally possibly causes a ventro-lateral displacement of the contained nucleus ambiguus and efferent facial nucleus and consequently the arched or hook-shaped course of their root fibers as seen in transverse section (Streeter) . At the same time, the nucleus of the VI, which originally was caudal to the VII, migrates cranially, carrying the facial efferent roots with it. This gives rise to the genu facialis (Streeter, [[#Fig412|Fig. 412]]).

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'''Fig. 412. Diagram illustrating the development of the genu of the facial nerve in the human embryo.''' The drawings show the right facial nerve and its nucleus of origin, in three stages: the youngest, A, being a 10 mm. embryo, and the oldest, C, a new-born child. The relative position of the abducens (VI) nerve is represented in outline; its nerve trunk is not shown, as the structures represented are seen from above. Streeter.

In the mid-brain ([[#Fig413|Fig. 413]]), what appears to represent the basal plate forms an eminence, the tegmental swelling. Later there is differentiated from this the reticular formation of this region, containing various nuclei and traversed by radial, longitudinal and arcuate fibers, many of the latter arising from the later differentiating dorsal portions (corpora quadrigemina) of the lateral mid-brain walls. An important neurone group of the reticular formation system which appears in this region is the nucleus of Darkschewitsch. Its descending axones form a part of the medial longitudinal fasciculus and probably appear at the end of the first month. The nucleus ruber is probably differentiated from the forward extremity of the tegmental swelling which overlaps into a prechordal region ([[#Fig425|Fig. 425]]). Its axones (crossing as ForeVs decussation and forming the rubro-spinal tract) probably develop early. This neurone group apparently owes its great development principally to its close association with the cerebellum. These two long descending intersegmental tracts as they grow downward envelop the differentiating reticular formation of more caudal regions of brain (and cord) and thereby come to occupy an external position in the fully differentiated reticular formation.

The reticular formation is thus composed of a gray portion containing the neurone bodies and shorter tracts and a white portion composed of the longer tracts. Axones from certain nuclei (especially N. ruber, N. of Darkschewitsch and N. of Deiters) form long, principally descending, tracts which envelop the gray reticular formation mesially (medial longitudinal fasciculus including fibers from nuclei of Darkschewitsch and Deiters as well as other reticulospinal fibers) and laterally (rubro-spinal, lateral uncrossed tract from Deiters nucleus and other reticulo-spinal fibers) and constitute the white reticular formation. These long tracts descend to the cord and there similarly envelop its ventro- lateral ground bundles.

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'''Fig. 413. Transverse section through the mid-brain of a 10.2 mm human embryo.''' His.

While the above differentiation of the reticular formation has been taking place, changes in the alar plate have begun which lead to the formation of terminal nuclei of peripheral afferent nerves, as well as terminal nuclei of other tracts, all of which send fiber bundles to suprasegmental structures.

The formation of the receptive nuclei of the afferent nerves of peripheral (segmental) structures is complicated by the fact that the central continuations of the peripheral afferent nerves are not confined to their own respective segments but form longitudinal tracts which continue to grow upward (columns of Goll and Burdach) or downward (descending solitary, vestibular and trigeminal tracts) passing into other segments and overlapping externally structures already in process of formation there. In each segment, then, the terminal nuclei of the afferent nerves of that segment must be distinguished from the terminal nuclei of afferent elements from other segments. The latter are external or added to the former and are differentiated from additional proliferations of neuroblasts of the alar plate. In addition to these nuclei, there are certain nuclei forming links between the two great suprasegmental structures, the pallium and cerebellum. These nuclei are the olive* and pons nudei, both of which form afferent cerebellar bundles and which are differentiatec. by still further proliferations and migrations of alar plate neuroblasts.

It has already been seen that the afferent peripheral nerves (IX and X) of the visceral segment form (together with descending fibers of the VII) the tractus solitarius. This is at first (5th week) short, but in six weeks has reached the cord. The terminal nucleus of the tractus solitarius is differentiated irom the neuroblasts of the medial portion of the alar plate. The course of the axones of this nucleus is not known. Judging from comparative anatomical grounds, they would not follow the fillet pathway (C. J. Herrick). The most caudal part of this nucleus is the nucleus commissuralis at the lower apex of the fourth ventricle.

The formation of the other terminal nuclei lying in the region of this segment is begun by the further developments of the alar plate already alluded to. These are initiated by an expansion and consequent folding of its border (formation of the rhombic lip, p. 483). followed by further cell-proliferation, leading to fusion of these folds and copious formation of neuroblasts in this region. These neuroblasts represent fresh accessions to the neuroblasts already formed in the mantle layer of the more medial part of the alar plate. This latest development of the border portions of the alar plate is the last step in the progressive development of the neural tube from the medial portion (basal plate) to the lateral (dorsal) border of the lateral walls of the tube where further development ceases at the attachment to the roof plate (taenia). ([[#Fig414|Fig. 414]])

Many of the neuroblasts of the rhombic lip region migrate ventrally.t Some of those from the medial part of the swelling produced by the fusion of the rhombic lip folds (p. 483, migrate along the inner side of the tractus solitarius, while those from the lateral part of the swelling pass outside the tractus, which becomes thereby enclosed in the mantle layer (Fig. 415). Many of these neuroblasts continue their journey, passing along the outer side of the differentiating formatio reticularis, until they are arrested at the septal marginal layer ([[#Fig416|Figs. 416]] and [[#Fig417|417]]).

* This is conjectural. The origin of fibers to the inferior olivary nuclei is not known. The most conspicuous tract to the olive is von Bechterew's central tegmenlal trad. Purely a priori considerations might be adduced in favor of this being considered a descending tract from thalamic nuclei which in turn receive pallio-thalamic fibers. It may, however, arise from lower optic centers.

fit is, perhaps, an open question whether the formation of the lip is a fundamental feature in this last proliferation and invasion of neuroblasts from the border of the alar plate. The prominence of the rhombic lip in man is the early embryological expression of the future great development of parts subsequently formed from this portion of the neural wall, especially the cerebellum and neurone groups in connection with it.

From these neuroblasts which remain in situ near the dorsal border are developed the nucleus gracilis and nucleus cuneatus. The axones of these nuclei form internal arcuate fibers which decussate and form a bundle of longitudinal fibers in the opposite septal marginal layer ventral to the reticularis alba. This tract is the medial fillet whose fibers appear during the second month and is one of the afferent paths to suprasegmental structures (mid-brain roof and pallium). Other neuroblasts, which probably migrate further, form the substantia gelatinosa of Rolando. Axones of this group also form tracts representing afferent paths to suprasegmental structures (pallium). Neuroblasts which migrate further form, as already mentioned, afferent cerebellar connections. Those migrating to the septal marginal layer form there an L-shaped mass mesial to the root fibers of the XII cranial nerve (Fig. 417). This is the medial accessory olive. Fresh groups of neuroblasts, added laterally to these in streaks, form the inferior olivary nucleus, while others which have not advanced so far form the lateral nucleus. Axones of the olivary neuroblasts (olivo-cerebellar fibers) pass across the median line (seventh or eighth week) to the opposite dorsal border where they, together with axones from the lateral nuclei and the continuation from the cord of Flechsig's tract, form (end of the second month) the bulk of the restiform body (Fig. 417). At three months the olives have acquired their characteristic folded appearance.

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'''Fig. 414. Half of a transverse section of the medulla of a 9.1 mm human embryo (during the fifth week).''' His. The arrow is in the inner median sulcus. F. r. a., beginning of white reticular formation.

Owing to the later development and ventral migration of the alar plate neuroblasts, there are thus formed the various nuclei which lie external to the reticular formation in the adult. The continuations of ascending spinal cord tracts (Flechsig and Gowers) occupy the most external position on the lateral surface, and other cord continuations (medial fillets) the most external mesial positions. Later, however (fifth month), there is added ventral to the fillets the descending cortico-spinal fibers (pyramids). Their decussation takes place at the cervical flexure.

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'''Fig. 415. Half of a transverse section of the medulla of a 10.5 mm human embryo (end of fifth week).''' His.

By the external accessions from the alar plate above described, forming terminal nuclei of overlapping tracts from above (especially the nucleus of the spinal V) , the tractus solitarius becomes buried, as it were, hence its deep position in the adult. The great development of the reticular formation may contribute to this result. As the trigeminus is the most cephalic rhombic segment, its descending fibers are not overlapped by fibers from above and therefore occupy the most external position of all these descending peripheral systems.

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'''Fig. 416. Half of a transverse section through the medulla of a 13.6 mm. human embryo (beginning of sixth week).''' His. F. r. a., Beginning of white reticular formation in dorsal part of septal marginal layer. Another bundle has formed more ventrally (F. r. a. v.) .

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'''Fig. 417. Transverse section through the medulla of an 8 weeks' human embryo.''' His.

The terminal nuclei belonging to the auditory (acustico-facialis-abducens) segment are those of the vestibular and cochlear portions of the VIII nerve.

The development of these nuclei is not fully known, but they are derived from the alar plate, except possibly Deiters' nucleus (see p. 487), the nuclei of the later formed cochlear nerve occupying the more external position. The vestibular nuclei apparently send axones both to cerebellum and reticular formation. The cerebellum itself may be regarded as primitively a receptive vestibular structure (p. 436) and probably receives vestibular root fibers. The axones of the cochlear nuclei pass across the median line, along the ventral border of the reticular formation (second half of second month), forming the trapez'um. On the lateral boundary of the opposite reticular formation they ascend, forming the lateral fillet, to the suprasegmental posterior corpus quadrigeminum. Accessions are received from the superior olive, in which some of the trapezium fibers terminate.

The alar plate of this segment also forms the substantia gelatinosa and the anterior portions of the olivary nuclei in this region. The various remaining tracts assume the same positions as further caudally.

Later, the pyramids are added ventrally to the fillet, and the great development of the pons leads to it's covering the ventral surface of part of this region. Owing to the late development of the pons and pyramids, the trapezium is thus uncovered and lies on the ventral surface of the rhombic brain during the third month. It is permanently uncovered in the dog and cat.

In the trigeminus segment, the terminal nucleus of the afferent portion of this nerve is probably similarly formed from the alar plate. Its axones decussate, probably joining the fillet, and proceed to the thalamus, which is connected with the pallium. Descending axones from cells in the mid-brain roof form part of the trigeminus known as its descending or mesencephalic root. The view has been advanced (Meyer, Johnston) that these are afferent neurones equivalent to certain dorsal horn cells found in some adult and embryonic Vertebrates and representing spinal ganglion cells which have become included in the neural tube instead of becoming detached with the rest of the neural crest (compare p. 422).

In front of the lateral recess another extensive development of the alar plate occurs, evidenced by the large rhombic lip of this region. The neuroblasts thus differentiated form the enormously developed pontile nuclei whose axones pass across the median line (fifth month) to the opposite cerebellar hemisphere, forming the middle cerebellar peduncle or brachium pontis. The pons extends over the ventral surface of the cephalic part of the medulla and over the ventral surface of part of the mid-brain. It receives fibres from various parts of the neopallium, which form a great part of the pes pedunculi or crusta. A still greater development of the alar plate forms the cerebellum.

In the mid-brain region, the reticular formation already described (p. 487) is enveloped ventrally and laterally by the upward extension of the medial and lateral fillets, the whole comprising the tegmentum. Ventral to this are added later the pons and the descending cortico-pontile, cortico-bulbar and corticospinal bundles forming here the pes pedunculi or crusta (probably during the fifth month).

The alar plate of the mid-brain region forms the corpora quadrigemina (mid-brain roof).

The further changes in the gross morphology of the medulla are due mainly to further growth of structures already present. The nuclei of the dorsal columns by their increase cause the swellings on the surface of the medulla known as the clava and cuneus, and likewise by their increase in size cause a secondary dorsal closing in of the caudal apex of the fourth ventricle which formerly extended to the cervical flexure. The tuber culum of Rolando is produced by the growth of the terminal nucleus of the spinal V, and the restiform body largely by the development of the afferent cerebellar fibers ([[#Fig419|Fig. 419]]).

The growth of the olivary nuclei produces the swellings known as the olives. The above mentioned accession of the descending cerebrospinal tracts to the ventral surface is indicated by the pyramids.

In the floor of the ventricle there is a longitudinal ridge each side of the median line occupied by swellings produced by the nucleus of the XII and, further forward, the nucleus of the VI, together with other nuclei (intercalatus, funiculus teres and incertus, Streeter) which are not well understood. The furrow forming the lateral boundary of this area is usually taken to be the representative of the sulcus limitans and consequently the area in question would be the basal plate. Lateral to it is a triangular area with depressed edges the ala cinerea. It represents a region where portions of the vagoglossopharyngeal nuclei (dorsal efferent and terminal nuclei of fasciculus solitarius) lie near the surface. Possibly a secondary invasion by surrounding more recently differentiated nuclei may account for their apparent partial retreat from the surface. It is possible that the ala cinerea may be regarded not so much as a part of the alar plate, but that it or rather the branchial nuclei involved in its formation represents an independent intermediate region corresponding to the intermediate region in the cord (J. T. Wilson). The remaining portion of the alar plate, in -the floor, is apparently represented principally by the acoustic, especially the vestibular, field.

In the development of the segmental brain there are thus the following overlapping stages: (i) The differentiation of the inner, mantle and marginal layers. (2) The primary neural apparatus, consisting of (a) the peripheral segmental neurones, the central processes of the afferent neurones entering the alar or receptive plate, the efferent neurone bodies forming two main series of nuclei in the basal plate, and (b) intersegmental neurones composing the reticular formation in which the long tracts occupy external positions.

The further differentiation, from the alar plate, of terminal nuclei for the afferent peripheral segmental neurones, the axones of the terminal nuclei forming afferent tracts to suprasegmental structures. These tracts and other later forming afferent suprasegmental tracts with their nuclei are laid down external to the. reticular formation. (4) Formation of efferent (chiefly thalamic(?) mid-brain and cerebellar) suprasegmental tracts which act upon the intersegmental neurones or reticular formation. (5) Accession at a late stage of development of a descending system of fibres from the neopallium. These lie ventral to the preceding structures.

==The Cerebellum==

It has already been pointed out that at an early period (three weeks) the anterior boundaries of the thin expanded roof plate of the rhombic brain form two lines converging anteriorly to the median line where the roof plate is represented by the usual narrow portion connecting the two alar plates (Fig. 418). It has also been pointed out that the pontine flexure produces on the dorsal surface a deep transverse fold in this thin roof, into which vascular tissue grows later forming the chorioid plexus (Fig. 410). At this stage, the continuations of the alar plates of the medulla form two transverse bands which, when viewed laterally, are vertical to the general longitudinal axis of this part of the brain (Fig. 448). At the same time, the rhombic lips are formed along the caudal border of these bands and the latter become musm thickened into the two rudiments of the cerebellum, a H IB considerable portion of which may be derived from the

I: fj lips. These rudiments are thus two transverse and vertical swellings and are connected across the median line by the roof plate. The attachment (taenia) of the

<div id="Fig418"></div>
[[File:Bailey418.jpg|thumb|Fig. 418. Dorsal view alar plate of this region to the roof plate of the fourth ventricle is at first along its caudal edge. Later, by the folding back and fusion of this border to form the rhombic lips, the attachment is carried forward. Still later, by the growth of the cerebellar rudiment, it is rolled backward and under, as described below. The rudiments subsequently fuse across the median line, thus forming externally a single transverse structure, but internally a paired dorsal median projection of the lumen marks the location of the uniting roof plate (comp. Fig. 420).]]

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'''Fig. 418. Dorsal view of that part of the brain caudal to the cephalic flexure (human embryo of 3d week, 2.15 mm).''' Hh. Cerebellum; i, isthmus; M, mid-brain; Rf, Nh, medulla. Compare with Fig. 416. His.

While the structure thus formed expands enormously in a lateral direction, in its subsequent development its greatest growth is in a longitudinal direction. The effect of this is that the continuations of the cerebellum forward (velum medullare anterius) and backward (velum medullare posterius) into the adjoining, brain walls of the isthmus and medulla are comparatively fixed points and are completely overlapped by the spreading cerebellum, producing an appearance in sagittal section as though they were rolled in under the latter structure (comp. Fig. 370, F). Another result of this longitudinal growth is the formation of fissures running across the organ, transversely to the longitudinal brain axis. First, lateral incisures separate two caudal lateral portions, the flocculi (Fig. 419), the median continuation of which, the nodule, is finally rolled in on the under side of the cerebellum as explained above. Another transverse fissure, the primary fissure, beginning in the median part and extending laterally, separates an anterior lobe from a middle lobe, the former comprising the future lingula, centralis and culmen and their lateral extensions. The anterior portion is rolled forward under the anterior part of the cerebellum. Another transverse fissure next appears in the median part (secondary fissure} which later extends (peritonsillar) to the floccular incisure, and thereby completes the demarcation of a posterior lobe, including not only the flocculus and nodule, but also the tonsilla and uvula, which are also rolled backward and under. The result of this transverse fissuration would be the production of a cerebellum resembling that of certain forms below Mammals where the cerebellum is well developed (Selachians, Birds). A complicating factor, however, is the great growth of certain lateral portions of the middle lobe, forming the future cerebellar hemispheres (Fig. 419), which causes also a lateral overlapping and rolling inward of adjoining parts. This growth is the chief factor in the division of the cerebellum into vermis and hemispheres and is correlated with the development of the neopallium (p. 436 and Fig. 371).

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'''Fig. 419. Dorsal view of the cerebellum and medulla of a 5 months' human fetus.''' Kollmann.

The early histological development of the cerebellum has been most closely studied in Bony Fishes (Schaper) and there is every reason to suppose that the processes taking place in the human cerebellum are essentially the same. In that part of the alar plate forming the rudiment above described, the cells proliferate, forming first a nuclear layer with the dividing cells along its ventricular surface, and a non-nucleated outer or marginal layer. Later, owing to beginning migration and differentiation, there is formed the usual mantle layer, representing a differentiation of part of the original nuclear layer and thereby forming the three layers: an inner, a mantle and a marginal. The outer cells of the mantle layer increase in size and differentiate into the cells of Purkinje, snaller cells within forming the granular layer. The earliest stage of differentiation of the Purkinje cells has not been accurately described, but the axones of the neuroblasts evidently proceed (end of fifth month) toward the ventricular surface instead of entering the marginal layer. In this way the fibrous layer (white matter) comes to lie within instead of on the outer surface as in the cord, and, to some extent, in the medulla. There is thus formed the outer gray matter or cortex. The axones of the Purkinje cells form the great bulk of the centrifugal fibers of the cerebellar cortex. The marginal layer becomes ultimately the outer or molecular (plexiform) layer of the adult cerebellum.

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'''Fig. 420. Diagram representing the differentiation and migration of the cerebellar cells in a teleost.''' The arrows indicate the migration of cells from the borders of the cerebellar rudiment into the marginal layer; these cells probably all differentiate into nerve cells. Clear circles, indif ferent cells; circles with dots, neuroglia cells (except in marginal layer); shaded cells, epithelia* cells; circles with crosses, epithelial cells in mitosis (germinal cells); black cells, neuroblasts; Z* lateral recess; M, median furrow, above which is roof plate; R, floor of 4th ventricle (IV), Schaper.

It has been seen that in the other parts of the tube development begins in the medial parts of the lateral plates and thence advances toward their dorsal borders, which actively develop after the corresponding stages have ceased in the medial portions. The same is true of the cerebellar rudiment. In this, the edges which border on the thin roof plate, i.e., those parts adjoining the lateral recesses, the main roof of the fourth ventricle and the roof plate interposed between the two original lateral cerebellar rudiments, are the last to proliferate. The cells thus formed spread into the marginal layer of the earlier developed parts and by further proliferation form a nucleated layer of considerable thickness (Fig. 420). This complication is apparently essentially similar to that described above in the development of the medulla. From the cells of this invasion are formed a part, at least, of the granule cells, as well as the basket cells and other cells which remain in the marginal (molecular) layer. These are all association cells of the cerebellum.

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'''Fig. 421. Scheme showing the various stages of position and form in the differentiation of granule cells from the outer granular layer.''' Cajal.

:A, Layer of undifferentiated cells; B, layer of cells in horizontal bipolar stage; C, partly formed molecular (plexiform) layer; D, granular layer; b, beginning differentiation of granule cells; c, cells in mo no polar stage; d, cells in bipolar stage; e,f, beginning of descending dendrite and of unipolarization of cell; g,h, i, different stages of unipolarization or formation of single process connecting with the original two processes; j, cell showing differentiating and completed dendrites; k, fully formed granule cell.

The cerebellum reaches its full histological development very late; after birth in many Mammals. These last postnatal stages of development naturally involve principally those cells proliferated last and which lie in the marginal layer. These have been studied by means of the Golgi method in new-born Mammals by Cajal and others. The majority of these cells form granule cells by means of a progressive migration and differentiation, as shown in the accompanying Fig. 421. Each cell first develops a single horizontal process, then another, thus becoming a horizontal bipolar cell. Following this, the cell body migrates past the Purkinje cells into the granular layer, remaining in connection with the original processes by a single process. There are thus formed the axone of the granule cell with its bifurcation into two horizontal processes, the parallel fibers of the molecular layer. This mode of formation is thus similar to the unipolarization of the cerebrospinal ganglion cell. The dendrites begin to be formed during the migration, branch when the cell body reaches the granular layer and there finally attain the adult form. Other undifferentiated cells in the marginal layer send out horizontal processes the collaterals of which envelop the Purkinje cell bodies, and form the baskets. The place vacated, so to speak, by the migrating granules, is filled at the same time by the developing dendrites of the Purkinje cells. These at first show no regularity of branching, but subsequently differentiate into the definite branches of the adult condition, at the same time advancing toward the periphery ([[#Fig422|Fig. 422]]). When they reach this, the migration of the granules is completed and the molecular layer is definitely formed. This condition, evidenced by the disappearance of the outer granular layer, is usually reached in Mammals within two months after birth, but in man not until the sixth or seventh year. There are observations indicating that animals possessing completely developed powers of locomotion and balancing at birth have more completely differentiated cerebella at that time. The axones of the Purkinje cells form many embryonic collaterals which are afterward reduced in number.

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'''Fig. 422. Section through cerebellar cortex of a dog a few days after birth''' Showing the partial development of the dendrites of two cells of Purkinje. Cajal.

:A, external limiting membrane; B, external (embryonic) granule layer; C, partly formed molecular (plexiform) layer; D, granular layer; a, body of cell of Purkinje; &, its axone; c, and d, collaterals with terminal arborizations (e).

Of the centripetal fibers to the cerebellum, those from the inferior olives cross the median line of the medulla about the seventh or eighth week, and thence advance to the vermis, reaching their final destination during the third month. The fibers from the pontile nuclei (middle peduncle) do not develop until considerably later (end of the fourth month), the time of their reaching their destination in the cerebellar hemispheres not being definitely known. Many at least of the centripetal fibers do not reach their full development in Mammals till birth or after. Some of these fibers (climbing fibers) form arborizations around the inferior (axone) surface of the Purkinje cell bodies and later creep upward, enveloping the upper surface instead, and finally the dendritic branches. Other centripetal fibers (mossy fibers) ramifying in the granular layer are varicose fibers, at first otherwise smooth. From the varicosities a number of branches are given off which later become abbreviated and modified into the shorter processes of the adult condition. This final differentiation occurs simultaneously with the final differentiation of the dendrites of the granule cells with which they come into connection. The glia elements apparently develop in a manner essentially similar to their development elsewhere.

The development of the internal nuclei of the cerebellum has not been thoroughly investigated. The nucleus dentatus is well developed at the end of the sixth foetal month. Eminences passing forward and ventrally along the sides of the isthmus are the earliest indications of the superior peduncles* formed later by the axones of the cells of these nuclei.

==Corpora Quadrigemina==

The mid-brain roof is an expansion of the alar plate of the mid-brain. Later this differentiates into the anterior and posterior corpora quadrigemina. In the former, by the usual ventricular mitoses (germinal cells), a nuclear layer is formed with a non-nucleated marginal layer external to it which becomes the outer or zonal layer. Still later the neuroblast or mantle layer is differentiated, there being an unusually thick inner layer. The further development has not been closely studied in man. Owing to the diminished importance of the anterior corpora quadrigemina (p. 437) the neuroblasts do not differentiate into the well marked "spread out" layers characteristic of the optic lobes of many Vertebrates. This is probably due to a lack of development of their association neurones.

The fibers of the optic tracts grow toward the anterior corpora quadrigemina in the marginal layer forming the anterior brachia. When they reach the anterior corpora quadrigemina, they leave the marginal layer and penetrate the gray matter forming the most external fiber layer. The medial (and some lateral) lemniscus fibers enter more deeply than the optic. Neuroblast axones grow toward the ventricle, turn internally to the lemniscus fibers, cross (Meynert's decussation) , and proceed as the predorsal tracts to the segmental brain and cord, lying ventral to the medial longitudinal fasciculi.

==The Diencephalon==

The stage of development of the diencephalon at four weeks has already been mentioned (p. 448). (Figs. 423, 433 and 434.) In the lateral walls the principal feature is the presence of a furrow, the sulcus hypothalamicus, which beg : ns ventrally as an extension of the optic recess and extends dorsally and caudally toward the mid-brain. A branch of it extends to the posterior part of the foramen of Monro. This is the sulcus Monroi. The sulcus hypothalamicus is sometimes regarded as the representative in this region of the sulcus limitans. It is doubtful whether it has the same morphological value as the latter. Such a comparison is seen a priori to be difficult when it is considered that this region is in the most highly modified part of the brain tube, lacking motor peripheral apparatus, and that it is also the end region of the tube where all longitudinal divisions would naturally merge. The sulcus deepens till the end of the second month (Fig. 429). Later it becomes shallower, but appears to persist till adult life. The region of the diencephalon ventral to the sulcus, as already mentioned, is termed the pars subthalamica or hypothalamus. The ventral part of the optic stalk forms a transverse groove in the floor, the preoptic recess, caudal to which is a ridge or fold, the chiasma swelling, in which the fibers of the optic chiasma later appear.* Caudal to this is the recess or invagination of the floor, representing the postoptic recess and the beginning of the infundibulum (Figs. 424 and 425) . Its extremity later becomes extended into the infundibular process, the posterior part of which in the fifth week comes into contact with the hypophyseal (Rathke's) pouch. This is a structure formed from the stomodaeal epithelium and is connected with the latter by a stalk. The pouch, which is at first a flat structure, develops two horns which envelop the infundibulum. The cavity of the end of the infundibular process becomes nearly shut off from the rest of the infundibular cavity. The process penetrates the upper part of the pouch and then bending reaches its posterior surface and ends blindly. In the second half of the second month epithelial sprouts, which become very vascular, begin to appear, first in the lateral parts of the pouch, next the brain, and then extending through the pouch and finally nearly obliterating its cavity (third month). The shape of the organ (the hypophysis) formed by the union of these two parts is subsequently changed by its relations to surrounding parts. Its posterior lobe is derived from the infundibular portion, its anterior lobe from the pouch.

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'''Fig. 423. Transverse section through the diencephalon of a 5 weeks' human embryo.''' Dp., Roof plate; Ma., mammillary recess; P.s. hypothalamus; S.M., sulcus hypothalamicus; Th., thalamus. His.

* According to Johnston, the chiasma is formed in front of the optic recess which would then be represented by the postoptic recess. In this case the chiasma would be regarded as falling in the region of the telencephalon instead of forming the optic part of the hypothalamus (comp. Figs. 364 and 433).

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'''Fig. 424. Lateral view of a model of the brain of a 10.2 mm human embryo (middle of 5th week).''' His.

Diencephalon Thalamus Pineal region

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'''Fig. 425. Median view of the right half of a model of the brain of a 10.2 mm human embryo (middle of 5th week).''' Compare Fig. 424. His.

An expansion of the floor of the brain caudal to the infundibulum has been mentioned as the mammillary region. Subsequently there is formed from its cephalic part another evagination, the tuber cinereum. The mammillary region forms the mammillary bodies. The region caudal to the mammillary region later receives many blood vessels, thereby becoming the posterior perforated space.

At the end of the fourth week the roof plate of the diencephalon is smooth. At about this time the greater part of the roof expands, forming a median longitudinal ridge (Fig. 426). This ridge, which remains epithelial throughout life, is broader at its anterior end where it passes between the beginning pallial hemispheres. As the roof plate expands further, the anterior part is next thrown into longitudinal folds. The ridge forms the epithelial lining of the tela chorioidea of the third ventricle (diatela). By further growth and vascularization of its mesodermal covering at the beginning of the third month, there is formed the chorioid plexus of the third ventricle (diaplexus). Lateral extensions of the tela form the chorioid plexuses of the lateral ventricles (see p. 5 17) . In the fifth week a protrusion appears at the caudal end of the median ridge which is the beginning of the epiphysis. Soon after this, the furrow which forms its caudal boundary extends forward along the upper part of the sides of the walls, marking off a fold which is the lateral continuation of the median protrusion. From the median protrusion is later formed the pineal body, while from the lateral folds are formed the pineal stalk, and in front the habenula, with its contained nucleus (ganglion) habenulce, and the stria medullaris. Still further caudally, the anterior part of the mid-brain forms a horseshoe-shaped fold the arms of which extend forward over the diencephalon, ventral to the pineal folds. The median part of this fold forms the anterior corpora quadrigemina. From its lateral extensions are formed the anterior brachia of the anterior corpora quadrigemina, the pulmnar and the lateral and medial geniculate bodies, all of which (pulvinar ?) later receive optic fibers. The transverse furrow which forms the boundary between the rudiments of the pineal body and of the anterior corpora quadrigemina marks the location of the future posterior commissure (Figs. 426, 427 and 428).

The part of the roof anterior to the pineal fold, as already stated, forms the tela chorioidea of the third ventricle. Certain folds appear in it, however, which are more clearly indicated in later stages of embryonic development than in the adult and which probably represent structures already mentioned as common to the vertebrate brain ("cushion" of the epiphysis, velum transversum, paraphysis?) (p. 4 2 4 and Fig. 364).

From the above it is evident that at the close of the fifth week the rudiments of the various parts of the diencephalon are already well marked. These rudiments are principally indicated by foldings of the walls, there being no very strongly marked differences of thickness except the early differentiation between the median and lateral plates. From this time on, both general and local thickenings of the lateral walls occur. This indicates a rapid proliferation of the cells, especially a differentiation of the nerve cells and consequent formation of masses of gray and white matter. Another factor affecting the diencephalon is the subsequent growth backward over it of the cerebral hemispheres.

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'''Fig. 426. Dorsal view of a model of the brain of a 13.6 mm human embryo (beginning of 6th week).''' The dorsal part of the pallium on each side has been removed. Compare with Figs. 427 and 428 . His.

During the second month, the lateral walls become thickened, forming a prominence on the inner surface of each side. This reduces much of the cavity of the third ventricle to a cleft and in the third or fourth month a fusion of a portion of these two projections takes place, forming the commissura mollis or massa intermedia. The condition at this stage is shown in Fig. 429. Later this protrusion thrusts the lateral structures above described (the pulvinar, geniculate bodies and brachia) to the side, the cavity of the lateral geniculate body being obliterated. The prominence itself extends to the tegmental swelling (see Figs. 4 2 9-30) and there thus arises the possibility of direct connections between these two structures. There can, then, be distinguished in the diencephalon three regions, a hypothalamic region, as already described, an epithalamic region comprising the pineal body, ganglia habenulae and related structures, and finally the thalamus proper. In the latter, the geniculate bodies already mentioned constitute a metathalamic portion, while the portion derived from the thickened part, which is continuous anteriorly with the corpus striatum, differentiates various nuclei, especially those which receive the general somatic sensory fibers (medial lemniscus or fillet), and other nuclei in relation to definite centers of the pallium. The thalamus is thus strongly developed, owing to its containing the nuclei which receive the general sensory (ventro-lateral nuclei), acoustic (medial geniculate bodies), and optic (lateral geniculate bodies) systems of fibers and which in turn send fibers (thalamic radiations) to the pallium. These thalamic nuclei do not receive fibers probably until after the middle of the. second month. About this time the thalamic radiations begin to be formed from the thalamic nuclei and grow toward the corpus striatum which they reach toward the end of the second month. With the first appearance of the cortical layer of the developing neopallium (see p. 512) they penetrate the corpus striatum and pass to the cortex, forming the beginning of the internal capsule, and corona radiata. It has already been pointed out (p. 437) that the great development of the thalamus and its radiations is more recent phylogenetically and is due to the newly acquired connections with the neopallium.

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'''Fig. 427. Lateral view of the model of the brain of a 13.6 mm. human embryo (beginning of 6th week)'''. F, Beginning of frontal lobe; T, beginning of temporal lobe. His.

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'''Fig. 428. From a model of the brain of a 13.6 mm human embryo, right half, seen from the left side.''' His, Spalt'eholz,

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'''Fig. 429. Median sagittal section of the brain of a 7.5 weeks' human embryo.''' Aq. S., Aquaeductus Sylvii; C. c., fold between mid- and interbrain; C.m., commissura mollis; C. s., corpus striatum; H. b., tegmental swelling; R.g., geniculate recess; R. i., recessus infundibuli; R. o., recessus (prae-?) opticus; S.h., habenular evagination; 5. M. } sulcus hypothalamicus; S.p., pineal evagination; T. T., thalamus. His.

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'''Fig. 430. Brain of a human foetus 'in the 3d month, right half, seen from the left.''' His, Spalteholz,

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'''Fig. 431. Adult human brain, right half, seen from the left, partly schematic.''' Spalteholz.

Before the development of these neopallial connections, other tracts have begun to appear which represent older epithalamic and hypothalamic connections existing practically throughout the Vertebrates (pp. 437 and 438) . Some of the hypothalamic connections are the mammillo-tegmental fasciculus which appears early in the second month, the thalamomammillary fasciculus (Vicq d'Azyr's bundle), which appears later, and the bundles from the rhinencephalon (p. 475) and archipallium (columns of the jornioc, middle of fourth month, p. 521). In the hypothalamic region is also differentiated the corpus Luysii, connected by fiber bundles with the corpus striatum and tegmentum. Epithalamic connections are represented by bundles from anterior olfactory regions (stria medullaris, seventh week), by the commissure, habenularis, and by bundles to caudal regions (fasciculus retroflexus of Meynert to the interpeduncular ganglion, middle of second month), (pp. 437 and 475.) The posterior commissure fibers are formed early in the second month in the fold between mid- and inter-brain (Fig. 429). (Fig. 432 )

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'''Fig. 432. Construction of the brain of a 19 mm. human embryo (7.5 weeks).''' Showing the stage of development of some of the principal fiber-systems. His.

:C.C., posterior commissure; F. s., tractus solitarius; F. t., fasciculus spinalis trigemini (spinal V); K, nuclei of dorsa! funiculi of cord; L., medial longitudinal fasciculus; M., fasciculus retroflexus of Meynert; Ma., mammillary bundle; n. i., nervus intermedius; O., olive; Ol., olfactory nerve; S., fillet; St., stria medullaris thalami; T., thalamic radiation; T. o., tractus opticus; V, Gasserian ganglion; VII, facial nerve and geniculate ganglion; VIII, ganglia of acoustic nerve; IX, N. glossopharyngeus; X, N. vagus.

==The Telencephalon (Rhinencephalon, Corpora Striata and Pallium)==

To understand the development of this part of the brain it is necessary to keep firmly in mind certain relations which are laid down at a comparatively early stage. Some of these relations are shown in the diagram of the inner surface of a model of a brain of four weeks. At this stage the pallium is unpaired, i.e., there is no median furrow separating the two halves of the pallial expansion. The various boundaries of the pallium in one side are (i) the median line uniting the two halves of the pallial expansion (Fig. 433, be) ; (2) the boundary line or line of union with the thalamus lying caudally (pallio-thalamic boundary) (Fig- 433> cd) ; (3) the boundary between pallium and corpus striatum (striopallial boundary) (Fig. 433, bd) . The boundaries of the future corpus striatum are (i) the median (Fig. 433, ab), (2) the strio-pallial (Fig. 433, bd), (3) the strio-thalamic or peduncular (Fig. 433, de) and (4) the strio-hypothalamic (Fig. 433, a<0- The internal prominence which is the rudiment of the corpus striatum, has three limbs or crura, (i) a ridge proceeding forward (anterior crus), which corresponds externally to the furrow (external rhinal furrow) foiming the lateral boundary of the anterior olfactory lobe, (2) a middle crus corresponding to the constriction separating the two olfactory lobes, and (3) a posterior crus corresponding to the posterior boundary of the posterior olfactory lobe. This latter is merged with the earlier furrow separating the telencephalon from the thalamus and hypothalamus (peduncular furrow). What may be called the main body of the corpus striatum, from which these limbs radiate, soon becomes expressed externally by a shallow depression in the lateral surface of the hemispheres immediately dorsal to the olfactory lobes. This depression is the first indication of the fossa Sylvii (Fig. 427).

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'''Fig. 433. From a model of the brain of a human embryo at the end of the first month, right half, seen from the left.''' His, Spalteholz.

The boundaries of the pallial hemisphere above indicated are identical with the boundaries of the future foramen of Monro.

The median lamina uniting the two halves of the pallium and the two corpora striata may be termed the lamina terminalis and represents the roof plate and floor plate of this region. The point of meeting of the roof plate and floca plate at the end of the tube is often taken to be at the recessus neuroporicus ; and the lamina terminalis or end wall of the neural tube, more strictly speaking, is limited to the median wall ventral to this point. Here it will be understood as including the median wall to the point where the pa'llio-thalamic boundary begins, marked later |py the angulus prathalamicus of His (see p. 517 and Fig. 442).

===Rhinencephalon===

The term rhinencephalon is a convenient one for those basal structures of the fore-brain which are in most intimate connection with the olfactory nerve. The term has been extended by some to include the pallial olfactory structures. For descriptive purposes it is here used in the more limited sense.

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'''Fig. 434. Lateral view of outside of brain shown in Fig. 433.''' His.

At the fourth week, as already indicated (p. 5 16 . Fig. 434) , there is a slight longitudinal furrow on the external surface, marking the ventral limit of the pallial eminence. The part of the brain ventral to this furrow is the rhinencephalon, Somewhat later the latter becomes better marked off, the fissure forming its boundary on the lateral surface being the external rhinal fissure (Fig. 424). Later the mesial side is also marked off by an extension of the fissure around on the mesial side (medial rhinal fissure) and also by a notch, the incisura prima, a continuation of which later ascends along the middle part of the median surface of the hemispheres and is known as the (interior arcuate fissure (fissura prima of His). (Fig. 442.) The existence of a fissura prima in early stages, however, is doubtful. At about this time, the rhinencephalon shows a beginning division into anterior and posterior portions, the anterior and posterior olfactory lobes, the whole structure assuming a bean-shape (comp. p. 512) (Fig. 427). On the lateral surface immediately above this constriction is the beginning concavity in the lateral surface of the hemispheres which marks the earliest appearance of the fossa Sylvii. The external rhinal fissure, as it becomes more pronounced, may be regarded as an extension forward of the fossa (anterior crus of the corpus striatum) . On the mesial surface the incisura prima marks this constriction. With the further curvature of the hemispheres, the anterior lobe becomes bent back under the posterior (third month), but later is again directed forward. It contains a diverticulum of the fore-brain "cavity. The cavity of the posterior lobe is not so well marked off and is bounded by the corpus striatum and the inward projection of the incisura prima. (Figs. 424, 425, 427, 428 and 442.)

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'''Fig. 435. Ventral view of the brain of human foetus at the beginning of the 4th month.''' Kollmann.

The olfactory nerve at the end of five weeks has reached the anterior lobe on its ventral and posterior side. The lobe develops into the receptive centei 5 for the nerve the olfactory bulb; into the stalk in which the secondary olfactory tract proceeds; and also into a triangular area where the tract divides the trigonum. The posterior olfactory lobe develops into the anterior perforated space and an eminence known as the lobus pyriformis which becomes reduced later (comp. Fig. 3 70, G and H). From it is developed the gyms olfactorius lateralis, connected with the lateral division of the olfactory tract and thegyri ambiens and semilunaris (Fig. 435). On the mesial wall, the posterior lobe is especially connected with the region between the anterior arcuate fissure and the lamina terminalis (trapezoid area of His, parolfactory or preterminal area of G. Elliot Smith) (Fig. 442). Part of this mesial region represents the anterior portion of the archipallium (comp. Fig. 370, G and H and p. 482).

===Corpora Striata and Pallium===

The leading feature of the development of this part of the brain is the great expansion of the pallial hemispheres. That part of the brain wall marked externally by the fossa Sylvii and internally by the body of the corpus striatum, and especially that part where the corpus striatum is continuous with the thalamus (peduncular part) , may be considered as a fixed point from which the pallial walls expand in all directions, anteriorly, dorsally and posteriorly, i.e., in both transverse and longitudinal directions. At first, this expansion causes the pallial hemispheres to assume a bean-shape with the hilum at the fixed point (Fig. 427). The anterior end curves downward and forms the frontal lobe with its enclosed cavity (anterior horn of the lateral ventricle). The posterior end curves downward caudally and forms the temporal lobe with the descending horn of the lateral ventricle. At the same time, owing to the great expansion in a transverse plane of each pallial eminence, the median lamina uniting them (Figs. 425 and 426) not sharing in this growth, there are formed the hemispheres with their cavities, the lateral ventricles, and the great longitudinal fissure between the hemispheres. Later, vascular mesodermal tissue fills this fissure, forming the falx cerebri. The paired cavities of the pallium are connected with the unpaired end-brain cavity (aula) by the foramina of Monro, the boundaries of which are the same as those of the pallium described above (p. 508).

At first the walls of the telencephalon, like those of other parts of the tube, are epithelial in character and nearly uniform in thickness. By proliferation there is formed a several-layered epithelium differentiated into an inner nuclear layer and an outer marginal layer. Later a mantle layer is differentiated. The hemispheres are late in development and until the end of the second month the walls are thin and simply show the above three layers. Toward the end of the first month a greater activity in cell proliferation takes place in the basal portion of the telencephalon which thickens into the corpus striatum. At eight weeks there first appears on the external surface of the corpus striatum, a cortical layer of cells lying next the marginal layer and separated from the inner layer by an intermediate layer comparatively free of cells and known as the fibrous or medullary layer (see p. 524). The differentiation thus begun extends gradually around the circumference of the hemispheres until the mesial surface is reached. This differentiation permanently ceases at the medial pallial margin. The cortical layer does not extend as far as the medullary layer, thus leaving an uncovered medullary layer on the mesial hemisphere wall. As a result of this, there is in this region, passing toward the median line, (i) a region covered with a cortical layer (limbus corticalis of His); (2) an uncovered medullary layer (limbus medullaris); (3) a fibrous transitional zone (the t&nia) passing into (4) a membranous zone, the roof plate.

This process resembles that taking place in other parts of the neural tube, in which there is the same progressive development from the ventral portion of the lateral wall to the dorsal border of the same, where the latter passes into the roof plate which is either ependymal or expanded into a thin membrane.

The longitudinal growth of the hemispheres naturally affects the form of a number of its structures. As already mentioned, this growth consists in an elongation around a fixed point, which may be regarded as located on its ventral border, the result of this being a curving down in front and behind this point. This is especially marked in the caudal half which thereby becomes curled first ventrally and then forward, thus forming a spiral. This growth in length is interstitial, i. e., due to expansion of the intermediate parts, and pari passu with it there is an elongation not only of the corpus striatum and structures in the mesial hemisphere wall (hippocampal formation, corpus callosum, chorioid plexus of lateral ventricle), but also of adjacent thalamic structures (stria terminalis or semicircularis), as described later.

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'''Fig. 436. View of the inside of the lateral wall of anterior part of fore-brain. Human embryo of about 4.5 weeks.''' His.

:C, Corpus striatum; H, pallium; h. R, posterior olfactory lobe; L, lamina terminalis; O, recessus (prae-?) opticus; R. i., recessus infundibuli; S. M.. sulcus hypothalamicus; St, hypothalamus; T, thalamus; v. R., anterior olfactory lobe.

The early divisions of the corpus striatum have been mentioned, and also the relations of its parts with the rhinencephalon. The anterior end of the corpus striatum at this period and later shows a longitudinal division into three portions, a lateral, a middle and a medial, due to the original division into three limbs described above (p. 508). (Figs. 436, 437, and 438.) With the elongation backward of the hemisphere the corpus striatum also becomeselongated, being drawn out and curled around the peduncle or stalk of the hemisphere and forming a thickening along the elongated wall. This caudal prolongation of the striatum is its cauda (tail) and extends to the tip of the inferior horn (Figs. 437 and 438). The medial portion of the corpus striatum forms a triangular projection (Figs. 426 and 428) the edge of which is directed toward the foramen of Monro.

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'''Fig. 437. View of inside of the lateral wall of lateral ventricle of a human foetus at beginning of third month.''' His.

:Bb, bulbus olfactorius; C. L, lateral limb of corpus striatum; C.m., medial segment (consisting of the middle and inner limbs) of the corpus striatum. The furrow between these two parts opens into the anterior olfactory lobe; hRl., posterior olfactory lobe; L./., frontal lobe; L. o. y occipital lobe; Og. } olfactory nerve; R. i., recessus infundibuli; R. o., recessus (prae-?) opticus; St., stalk of hemisphere (strio-thalamic junction); V.I., lateral ventricle; v.Rl.+Bb, anterior olfactory lobe.

to some, there is a, fusion of the striatum, the medial wall of the hemisphere and the anterior part of the thalamus. According to others, the increase in bulk of this region is produced by a simple thickening of the walls, thus causing a flattening out or shallowing of the grooves marking the junctions of striatum and thalamus on the ventricular surface, and between medial hemisphere wall and thalamus externally (Fig, 439). The effect is much the same whether accom plished by apposition and fusion or by interstitial thickening, massive connections being formed which consist mainly of fibers connecting hemispheres and thalamus, the foramen of Monro at the same time being changed in form to a slit. From the metathalamic region the fibers of the optic and acoustic pathways grow forward into the hemispheres (see also p. 507) . entering more caudally and forming the retro- and sub-lenticular portions of the internal capsule (comp. p. 507). That part of the thalamic radiation from the anterior portion of the thalamus (fillet pathway) also forms a part of the internal capsule as described on p. 507. Later, the internal capsule is completed by the growth from the pallium of descending fibers from the neopallial cortex, through the striatum to the pes. By these various traversing fibers the striatum is divided into the nucleus lenticularis or lentiformis and the nucleus caudatus. The posterior arm of the internal capsule is formed by fibers passing between and thus separating thalamus and lenticularis (Figs. 439 and 440).

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'''Fig. 438. Dorsal view of the brain of a 3 months' (45 mm) human foetus.''' The dorsal part of each cerebral hemisphere has been removed. Kollmann.

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Fig. 439. 1, 2 and 3, Schematic horizontal sections through human embryonic fore-brains at different stages of development; 4, vertical section through fore-brain at about same stage as 1. Goldstein.

:a, That part of the lateral ventricle lying between the corpus striatum and the junction of medial hemisphere wall and thalamus (leading into the inferior horn); b, furrow or trough between mesial hemisphere wall and thalamus, produced by backward extension of hemisphere; c. /., internal capsule; P.M., foramen of Monro; &, external surface at junction of mesial hemisphere wall and thalamus; Str., corpus striatum; Th., thalamus; U, place where mesial hemisphere wall continues into the thalamus wall (junction of hemisphere wall and thalamus) ; U 1 , place where mesial hemisphere wall is continuous with lateral hemisphere wall.

:In 1, owing to the thickening of U and growth of the corpus striatum, these two are brought into apposition, as indicated by the dotted lines on the right, and apparently fuse, obliterating a and producing the condition shown in 2 and 3. In 2 and 3 the position of the former space a is indicated by the dotted lines a a' By comparison with 4, it will be seen that this obliteration by apparent fusion is actually produced by a filling up from the bottom of a (indicated faintly by dotted lines on the right in 4). The thickening of thfe walls at this region also produces a shallowing of b (indicated by dotted lines on the right in i). The principal cause of this general thickening is the passage of the fibers of the thalamic radiation to the hemispheres and, later, of fibers from hemisphere to pes, forming the internal capsule (4, 2 and 3).

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'''Fig. 440. Lateral view of the brain of a 3 months' (42 mm) human foetus.''' The lateral wall of the left cerebral hemisphere has been removed. His, Kollmann.

==The Archipallium==

During the fifth week, following the stage shown in Figs. 433 and 434, the pal Hal evaginations or hemispheres have become much more pronounced and consequently the foramina of Monro much better defined. A comparison will show that the boundaries of the foramen of Monro are essentially unaltered. Anteriorly it is bounded by the medial wall connecting the two hemispheres, posteriorly by the boundary between pallium and thalamus, ventrally by the corpus striatum and junction of it and thalamus (Figs. 425 and 441).

At the beginning of the sixth week the foramen of Monro has changed somewhat in shape. The pallio-thalamic part of its boundary passes forward and forms the above-mentioned (p. 5 10) acute angle (angulus praethalamicus) with that part of the wall uniting the two hemispheres (lamina terminalis). The latter wall descends to the region of the optic recess. The inferior part of the foramen is partly closed by the medial part of the corpus striatum as already described. (Comp. Figs. 441, 426 and 428.) In the ependymal mesial wall of the hemispheres just below the taenia, described above, there arises a folding inward, which begins anteriorly near the angulus praethalamicus and proceeds caudally along the upper (pallio-thalamic) border of the foramen of Monro. This infolding is the chorioid fissure. In the ependymal mesial wall there are now the following: limbus chorioideus (the infolded part) and a small strip of the ependyma wall below the fold, the lamina infrachorioidea (Fig. 442). This invagination soon becomes very deep, resulting in the formation of a doublelayered ependymal fold (the chorioid fold, plica chorioidea) lying in the lateral ventricle over the corpus striatum (Figs. 441, 426 and 444). Later, vascular mesodermal tissue passes in from the falx between the lips of this fold and thereby forms the chorioid plexus of the lateral ventricles. The chorioid fissure is at first quite short, but becomes elongated (Fig. 443) with the above-described posterior elongation of the hemisphere of which it is a part, and thus extends into the inferior horn of the temporal lobe. (Figs. 443 and 444.)

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'''Fig. 441. Transverse section through fore-brain of a 16 mm embryo (six to seven weeks).''' His.

Toward the end of the second month, according to some authorities (His) , but not until considerably later, according to others (Hochstetter, Goldstein), another furrow appears in the limbus corticalis above and parallel to the chorioid fissure, and known as the posterior arcuate fissure. This fissure does not extend at first as far forward as the chorioid, but extends farther caudally, arching downward in the temporal lobe around the caudal end of the chorioid fissure (Fig. 443) . The posterior arcuate fissure is a total fissure, involving the whole wall and producing a fold on the inner surface of the medial hemisphere wall (plica arcuata). The temporal or caudal part of this whole formation persists in the adult without much further change. The fissure here becomes the hippocampal fissure separating the fascia dentata from the gyrus hippocampus; the part rolled in by the hippocampal fissure produces the eminence in the lateral ventricle known as the cornu ammonis or hippocampus major; the edge of the limbus corticalis forms the fascia dentata; the limbus medullaris or exposed fibrous part is thefimbria which is continued by its thinning edge or tania fimbria into the ependymal or epithelial portion (lamina chorioidea) of the chorioid plexus of the lateral ventricle. The chorioid plexus is attached by the taenia chorioidea and lamina infrachorioidea (here the lamina affixa) to the brain wall, usually near the junction of corpus striatum and thalamus, thereby forming a part of the wall of the inferior horn of the lateral ventricle. At this line of junction of thalamus and hemisphere wall is formed the stria terminalis. The fimbria is continuous anteriorly with the posterior pillar of the fornix. (Fig. 444.)

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'''Fig. 442. Diagram of a graphic reconstruction of the mesial hemisphere wall of a 16 mm human embryo (about six weeks).''' His, Ziehen. Cavities are dotted, cut surfaces are lined.

:Apt, Angulus praethalamicus; Atr, preterminal area; Fpr, anterior arcuate fissure (fissura prima); Frhl, mesial termination of lateral rhinal fissure; hRh, posterior olfactory lobe (tuberculum olfactorium + substantia perforata anterior) ; Lt, lamina terminalis (lined) ; Vmr, depression between the two olfactory lobes; vRh, anterior olfactory lobe (bulbus olfactorius + tractus olfactorius + trigonum olfactorium).

The anterior part of the hippocampal formation above described undergoes further modifications, due principally to the development of commissural fibers in this region. Some of these commissural fibers connect the representatives on each side of the hippocampus (limbus corticalis) of this region, forming the fornix commissure, but most of them (corpus callosum) connect the rest of the cortical areas (neopallial areas) of the two hemispheres.

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'''Fig. 443. Graphic reconstruction of the mesial hemisphere wall of a human foetus (fourth month).''' His, from Quain's Anatomy.

:c and v, Anterior and posterior parts of pre terminal area; li, lamina infrachorioidea; km, limbus or border of mesial hemisphere wall (gyrus dentatus and fimbria) between hippocampal and chorioid fissures; P, " stalk " of hemisphere.

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'''Fig. 444. Diagram of a transverse section through the fore-brain of a human foetus (fourth month).''' To show the relations of the margins of the mesial walls of the hemispheres. His t from Quain's Anatomy.

:Cs., corpus striatum; fi., limbus medullaris (fimbria); /a., limbus corticalis (gyrus dentatus); h.f. t hippocampal fissure; Th., thalamus

There are two views regarding the formation of these commissures. According to one view, the first commissural fibers appear in the upper (dorsal) part of the lamina terminalis. The latter subsequently expands pari passu with the expansion of the corpus callosum. The commissural fibers are thus confined to the original walls connecting the two hemispheres. According to the other view, there is a secondary fusion of the mesial hemisphere walls and in these fusions the fibers cross. The first fibers appear during the third month and form at first a small band in the upper part of the lamina terminalis (Fig. 443) . These fibers come partly from the limbus corticalis (fornix commissural fibers) and partly from other parts of the cortex (callosal fibers), in either case traveling along the intermediate layer. According to the fusion view, the exposed intermediate layers (limbi medullares) fuse where the fibers cross. This fusion can easily be imagined by conceiving the opposite surfaces in question to be brought together in the upper part of Fig. 444. It is more probable, though, that not only the first fibers cross in the lamina terminalis, but that the later ones also cross in extensions of the latter. There are three views regarding the further development of the corpus callosum. The first is that all parts are represented at this stage, future growth being by intussusception of fibers; the second is that the part first formed represents the genu, the rest being added caudally; the third (His) is that this first formed part represents the middle portion of the callosum, both anterior (genu and rostrum) and posterior (splenium) portions being subsequently added (Figs. 443 and 445). This latter view is indicated in Fig. 445, the later additions being shaded darker.

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'''Fig. 445. Graphic reconstruction of the mesial hemisphere wall of a 120 mm foetus (end of four months).''' His, from Quain's Anatomy. 6, Fimbria; cs , cavity of septum pellucidum ("fifth" ventricle, ventricle of Verga); Icm, limbus corticalis (gyrus dentatus); P, stalk of hemisphere; v, outline of cavity of hemisphere (lateral ventricle).

As the callosal fibers connect the limbi medullares, the limbus corticalis and the arcuate fissure, corresponding to the gyrus dentatus and hippocarr pal fissure of the temporal lobe, lie dorsal to the callosum. The limbus corticalis is reduced to a mere vestige (indusium griseum and strict Lancisi) on the dorsal surface of the corpus callosum the fissure becoming the callosal fissure. The part of the limbus medullaris ventral to the corpus callosum, corresponding to the fimbria of the temporal lobe, forms the posterior pillars and body of the fornioc.

++++++++++++++++++++++++++++++++++
These relations are shown in the following table from His (slightly modified):

++++++++++++++++++++++++++++++++++

Fibers from the hippocampus enter the fimbria and pass forward in the posterior pillars and body of the fornix. In or near the lamina terminalis these fibers of the fornix descend, forming the anterior pillars of the fornix, and thence pass back of the anterior commissure and caudally to the mammillary region.

They are joined by fibers from the dorsal surface of the callosum (fornioc longus), i.e., from the vestigial hippocampal formation, many of which also descend in front of the anterior commissure to the rhinencephalon. The triangular mesial area (septum pellucidum) included between callosum and fornix probably represents an extended part of the lamina terminalis or "commissure-bed," in which a cavity is formed, the so-called fifth ventricle and ventricle of Verga. A remnant of the hippocampal formation at the anterior end of the callosum is represented by the gyms subcallosus (Fig. 445).

==The Neopallium==

The hippocampal or cornu ammonis formation and preterminal area represent the older part of the pallium (archipallium) comp. pp. 438 and 439. This part of the pallium is olfactory in character, being mainly a higher center for the reception of secondary and tertiary olfactory tracts. In its extension backward and partial obliteration by the corpus callosum, its embryologic presents a striking similarity to its phylogenetic development (compare p. 438). The rest of the pallial hemispheres (neopallium) are occupied by the nonolfactory higher centers.

The further growth of the neopallial hemispheres leads to their extension backward, overlapping the caudal portions of the brain tube. In the course of this extension the occipital lobe and its cavity, the posterior horn of the lateral ventricle, are formed. The growth of various portions of the hemisphere surface is unequal, producing folds (convolutions) and fissures. This folding may be partly due to growth in a confined space, but especially important is the relation between gray and white matter. The gray matter, containing not only fibers but also neurone bodies, remains spread out in a comparatively thin layer, probably to accommodate associative connections. The white matter, on the other hand, increases in thickness. This leads to a folding of the outer layer. The position of these folds is probably partly determined by the local histological differentiation and growth of various cortical areas (p. 527). Only some of the earliest and most important of these folds will be mentioned here.

It has been seen (p. 509) that early in the development of the pallium a shallow depression appears on the external lateral surface of each hemisphere, the fossa Sylvii (Fig. 446). The bottom of this is the future insula. It is external to the corpus striatum and does not grow as rapidly as the parts bounding it, which consequently overlap it, forming its opercula. These bounding walls are formed by the fronto-parietal lobe on its upper side, by the temporal on its lower, and by the orbital on its anterior. The temporal and frontoparietal opercula begin about the end of the fifth month, the temporal at first growing more rapidly but later the fronto-parietal, thereby changing the direction of the Sylvian fissure from an oblique to the more horizontal angle characteristic of man as compared with the ape. In the meanwhile the development of the frontal lobe leads to its also overlapping the insula. If the frontal lobe fully develops, it forms a U-shaped operculum between the frontoparietal and the orbital, if it does not so fully develop it forms a V-shaped operculum, and a still less developed condition is shown by a Y-shaped arrangement in which the frontal lobe does not completely separate the fronto-parietal and orbital opercula. The opercula cover the fore-part of the Sylvian fossa during the first year. Conditions of arrested development are thus indicated by the Y-shaped anterior ascending branch of the Sylvian fissure coupled with an absence of the pars triangularis and also by a partial exposure of the island of Reil. In the ape the frontal operculum is absent and the island of Reil partly exposed.

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'''Fig. 446. Lateral view of the brain of a human foetus at the beginning of the 4th month.''' Kollmann.

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'''Fig. 447. Median view of the left half of the brain of a human foetus at the end of the 7th month.''' Kollmann.

Toward the end of the third month the calcarine fissure appears, producing on the ventricular surface the eminence known as the calcar avis. At the beginning of the fourth month the parieto-occipital fissure unites with it forming the cuneus. The parieto-occipital reaches the superior border of the hemispheres by the sixth or seventh month. At the sixth month the fissure of Rolando (central fissure) appears. The condition of the surface of the hemisphere at the end of the seventh month is shown in Figs. 447 to 450.

The early histogenetic development of the pallial wall, resulting in the differentiation into the usual ependymal, mantle and marginal layers, has been mentioned. (Fig. 451). The next stage, already alluded to (p. 519), marks a difference in development between the pallium, as well as other suprasegmental structures, and the rest of the walls of the neural tube. This stage consists apparently in a further migration outward of the neuroblasts and their accumulation under the marginal layer, forming, at eight weeks, a definite layer of closely packed cells, the beginning of the cortex (Fig. 452). Later neuroblast migrations probably add to this layer. It has already been mentioned that the fibers of the thalamic radiation appear in the pallial walls about this time. They proceed internally to the cortical layer and thus mark the beginning of the fiber layer (medullary layer) which by later myelination becomes the white matter of the hemispheres.

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'''Fig. 448. Dorsal view of the cerebral hemispheres of a human foetus at the end of the 5th month.''' Kollmann.

The extension of the process of differentiation of the cortical layer from the region of the corpus striatum over the rest of the pallium has also been mentioned (p. 512). It is probable that the afferent pallial fibers (thalamic radiation) in their growth keep pace with this process. Those fibers from the lateral geniculate bodies proceed to the occipital region, those from the medial geniculate bodies to the temporal, and those from the ventro-lateral thalamic nuclei (continuation of the medial fillet) to the future postcentral region. The afferent pallial fibers are often termed the afferent or ascending projection fibers.

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'''Fig. 449. Lateral view of the right cerebral hemisphere of a human foetus at the end of the 5th month.''' Kollmann.

The axones of the neuroblasts of the cortical layer grow inward, entering the medullary layer. Their peripherally directed processes become the apical dendrites of the pyramid cells into which most of the cortical cells differentiate. According to Mall and Paton, this change of direction in the growth of the axone is due to a turning of the cell axis during its outward migration. It would seem more probable that the cells retain an original bipolar character and that the inner processes differentiate into axones instead of the cells going through a monopolar stage (pp. 454 and 455 and Fi s - 3^6 and 387). The axones of the cortical cells form either efferent or descending projection fibers, proceeding to other parts of the nervous system, or crossed (callosal) and uncrossed association fibers, connecting various cortical areas of the hemispheres. The basilar dendritic processes of the pyramid cells and the axone collaterals develop last. Many details of development of the cells in Mammals are not completed until afterbirth (Fig. 453).

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'''Fig. 450. Ventral view of the brain of a human foetus at the beginning of the sixth month.''' Retzius, Kollmann.

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'''Fig. 451. Section through the pallial wall of a two months' human foetus.''' His, Cajal. a, Layer of germinal cells; b, nuclear layer; c, mantle layer; d,' marginal layer; e, germinal cell

'''Fig. 452. Section through the pallial wall of a human foetus at the beginning of the third month.''' His, Cajal.

:a, Layer containing germinal cells; b, fibrous (medullary) layer (rudimentary white matter) ; c, layer of neuroblasts forming rudimentary cortical gray matter; d, marginal layer (future molecular layer) ; e, germinal cell; /, g, neuroblasts with radial processes. Spongioblasts and myelospongium are shown on the right side.

During the fourth and fifth fcetal months the cortical layer shows a differentiation into a denser outer and an inner layer. During the sixth and seventh months a differentiation and grouping of the nerve cells begins which results in the formation of six cortical layers (Brodmann). These are: (1) the zonal layer (marginal layer, molecular layer of adult), (2) the external granular layer (layer of small pyramid cells of adult), (3) pyramid layer (medium and large pyramid cells), (4) internal granular layer, (5) ganglionic layer (internal pyramid cells), (6) multiform layer (polymorphous cells). By various local modifications of this six-layered cortex the differentiation of the various histological areas of the adult cortex is brought about. In the calcarine region of the occipital lobe, in the sixth month, the internal granular layer differentiates into two layers between which is formed the line of Gennari which contains terminations of the fibers from the lateral geniculate bodies, representing the visual pathway. This area is the visual cortex. In the temporal (future transverse gyri) and postcentral regions, areas are differentiated which mark the reception of the terminations of the fibers of the acoustic and somaesthetic (medial fillet) pathways. These areas are thus, respectively, the auditory cortex and the somcesthetic (general bodily sensation) cortex. (Cf. Fig. 371.)

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[[File:Bailey453.jpg|600px]]

'''Fig. 453. Section through cortex of a mouse foetus before birth.''' Showing later stages of differentiation of pyramid cells. Golgi method. Cajal. a, large pyramid cells; b, c. medium-sized and small pyramid cells; d, beginning collaterals of, e y axis-cylinders or axones; /, horizontal cell of molecular layer. Basal dendrites of pyramid cells are beginning to appear.

In the precentral region, the internal granular layer becomes merged with the adjoining layers and practically disappears, the two inner layers become more or less fused and in them certain cells develop to a great size forming the layer of giant pyramid cells. It is the axones of these cells, in all probability, which proceed as the pyramidal tracts through the middle part of the internal capsule and pes to the epichordal segmental brain and cord. The area in which these cells lie is the motor cortex (cf. Fig. 371). Descending axones develop similarly from cells in the calcarine area, possibly here also from large pyramidal cells of the fifth and sixth layers (solitary cells of Meynert), which probably pass to the anterior colliculus (operating there upon reflex eye mechanisms) .

In the whole pallium there are thus four great projection fields, differentiated both by their histological structure and their connections. These are (i) the archipallial olfactory area with mesial ascending and descending connections ; (2) the visual; (3) the acoustic; (4) the somatic. The systems of projection fibers of the three neopallial fields are lateral. The visual and acoustic fields represent certain specialized and concentrated groups of receptors (rods and cones, hair cells of organ of Corti) upon which stimuli of a certain definite nature (light and sound waves), from distant objects, are focussed by means of accessory apparatus (eye, ear). The somatic area represents receptors scattered over the whole organism. In the visual and acoustic mechanisms, the efferent element is small or lacking in both peripheral apparatus and cortical areas, in the somatic the efferent element is large and is represented cortically by an area (motor, precentral area) distinct from that of the receptive portion (somaesthetic, postcentral area). Gustatory and other visceral areas have not been well determined (vicinity of archipallium ?) .

These four primary sensori-motor fields are probably the first differentiated of the various pallial cortical areas. This is evidenced by the myelination (comp. p. 464) which first involves the projection fibers of these areas (at or soon after birth, Flechsig), the afferent projection fibers probably myelinating before the efferent (Figs. 454 and 455).

The process of myelination next spreads over areas adjoining the primary areas, the intermediate areas of Flechsig. Descending projection fibers from these areas in the frontal, temporal and occipital lobes are probably represented by the cortico-pontile systems of fibers, securing cerebellar regulation of pallial reactions. The presence of other fibers connecting with thalamic nuclei is probable, but knowledge of their develoDment and connections is very incomplete.

The cells whose axones form descending or efferent projection fibers constitute only a small fraction of the cortical cells. The great majority are association cells whose axones, or collaterals, pass across the median line in the lamina terminalis as the callosal fibers already mentioned (p. 520) or pass to distant or near parts of the same hemisphere. In general, these develop later than the projection neurones and the completion of their development is carried to a much later period. Variations which arise in their differentiation and arrangement probably contribute largely to the formation of various histological areas which develop at different periods. These local inequalities of growth probably constitute a factor in the production of the convolutions appearing later than those already mentioned in connection with the primary areas. The last areas to myelinate, the terminal areas of Flechsig, are poor in projection fibers and are thus composed largely (entirely ?, Flechsig) of association cells. It is the extent of these last developing areas which constitutes the principal difference between the human cortex and that of related forms. These pallial areas are those which continue to grow in human development. Myelination in the cortical areas may continue for twenty years or so. It is a significant fact that the last areas to develop are comparatively poor, even when completely developed, in both cells and fibers (Campbell). The association neurones thus probably follow the same order of development as the projection systems. As their development spreads from the primary receptive areas (perceptions?), the incoming stimuli receive a more and more extended associative "setting" (psychologically, the "meaning" or "significance" of perceptions?), extensive associations between the various areas being provided by the extension of their development to the terminal areas (rendering possible the association of symbols: mental processes?).

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'''Fig. 454. Diagram of cortical areas of mesial surface of pallium as determined by the myelogenetic method.''' Flechsig, from Quain's Anatomy. For explanation see Fig. 455.

The general biological significance of this late development of the pallium and especially of its associative mechanisms has already been alluded to. These "added" parts of the nervous system are the most modifiable mechanisms of the human organism; they are those mechanisms which perform its newest and most highly adaptive adjustments. The other parts of the nervous system are fixed at birth, but the cerebral hemispheres are still plastic for the reception and recording of individual experience. Such experience symbolized and formulated (spoken, written, etc.) is transmitted to the next generation, as already pointed out (p. 440)- An example of the far-reaching consequences of this capacity of the pallium is the prolonged period of infancy and education of man.

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'''Fig. 455. Diagram of cortical areas of lateral surface of pallium as determined by the myelogenetic method.''' Flechsig, from Quain's Anatomy. The numerals indicate, in a general way. the order of myelination. The primary areas (1-10) are indicated by dots, the intermediate areas (11-31) by oblique lines and the terminal or final areas (32-36) by clear spaces.

==Anomalies==

Those anomalies of the nervous system involving more general developmental anomalies (cyclopia, anencephaly, cranioschisis, spina bifida, etc.) are dealt with in the chapter on Teratogenesis (XX) . Owing to the fact that the nervous system consists of parts which are more or less separated, and yet connected and interdependent, it is in certain respects affected differently from the other organs when portions of it are injured or inhibited in development. Thus an injury or inhibition in development of one part of the nervous system may, because of the dependence upon this part of other perhaps distant parts, affect the development of the latter. Even in the adult, injury of an axone leads to the disappearance of that portion of the axone distal to the point of injury; it may also lead to the disappearance of the entire neurone where regeneration is not possible. Such an injury during development will not only cause a disappearance of the whole neurone, but it may also lead to the disappearance of other neurones forming links in the same functional pathway. Thus a developmental defect involving the central area will not only lead to absence of the pyramidal tract, but also to partial atrophy of the corresponding fillet bundles. When one cerebellar hemisphere fails to develop, there results a correlated defect in its centripetal and centrifugal pathways. The opposite inferior olive is practically absent, as is also the central tegmental tract leading to that olive. The pontile nuclei of the opposite side, the middle peduncle leading from them to the affected cerebellar hemisphere, and the fibers in the pes which pass to the pontile nuclei in question are likewise suppressed, and the superior peduncle and red nucleus are absent or reduced. In this case it is evident that the correlated atrophy affects at least two neurones in the pathways leading to and from the cerebellum. This illustrates the far-reaching character of correlated developmental defects in the nervous system arising from the nature of the connections between various portions of the system.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_18|Special Sense]]

==References for Further Study==

BARDEEN, C. R.: The Growth and Histogenesis of the Cerebrospinal Nerves in Mammals. Am. Jour, of Anat., Vol. II, No. 2, 1903.

DEJERINE, J.: Anatomic des centres nerveux. Tome I, Ch. 2 and 3.

EDINGER, L.: Vorlesungen iiber den Bau der nervosen Zentralorgane. Seventh Ed.

EDINGER, L. The Relations of Comparative Anatomy to Comparative Psychology. Jour. ofComp. N enrol, and Psychol., Vol. XVIII, No. 5, Nov., 1908.

FLECHSIG, P. : Einige Bemerkungen iiber die Untersuchungsmethoden der Grosshirnrinde insbesondere des Menschen. Berichten der math.-phys. Klasse d. Konigl. -Sachs. Gesellsch. d. Wissensch. zu Leipzig. 1904. See also Johns Hopkins Hosp. Bull, Vol. XVI, 1905, pp 45-49.

HARDESTY, I. : On the Development and Nature of the Neuroglia. Am. Jour, of Anat., Vol. Ill, No. 3, July, 1904.

HARRISON, R. G. : Further Experiments on the Development of Peripheral Nerves. Am. Jour, of Anat., Vol. V, No. 2, May, 1906.

HARRISON, R. G.: Observations on the Living Developing Nerve Fiber. Anat. Record. Vol. I, No. 5, 1907.

HARRISON, R. G.: Embryonic Transplantation and Development of the Nervous System. Anat. Record, Vol. II, No. 9, 1908.

HERRICK, C. J.: The Morphological Subdivision of the Brain. Jour, of Comp. Neurol. and Psychol., Vol. XVIII, No. 4, ipo 8

His, W.: Zur Geschichte des menschlichen Riickenmarkes und der Nervenwurzeln. Abhandl. der math.-phys. Klasse der Konig. -Sachs. Gesellsch. d. Wissensch., Bd. XIII, 1887.

His W Zur Geschichte des Gehirns, sowie der centralen und periphenschen Nerven bahnen' beim menschlichen Embryo. Abhandl. d. math.-phys. Klasse d. Konig.-Sachs. Gesellsch. d. Wissensch., Bd. XIV, 1888.

His, W.: Die Neuroblasten und deren Entstehung im embryonalen Mark. Abhandl. d. math.-phys. Klasse d. Konig. -Sachs, d. Wissensch., Bd. XV, 1890. Also Arch. f. Anat. u. Physiol., Anat. Abth., 1889.

His, W.: Ueber.die Entwickelung des Riechlappens und des Riechganglions und liber diejenige des verlangerten Markes. Verhandl. d. Anat. Gesellsch. zu Berlin, 1889. Also Abhandl. d. math.-phys. Klasse d. Konig.-Sdchs. Gesellsch. d. Wissensch., Bd. XV, 1889.

His, W.: Die Entwickelung des menschlichen Rautenhirns vom Ende des ersten bis zum Beginndesdritten Monats. I. verlangertesMark. Abhandl. d. math.-phys. Klasse d. Konig.Sachs. Gesellsch. d. Wissensch., Bd. XVII, 1891.

His, W.: Die Entwickelung des menschlichen Gehirns wahrend der ersten Monate. Leipzig, 1904.

JOHNSTON, J. B.: The Nervous System of Vertebrates. 1906.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Bd. II, 1907.

VON KUPPFER, K. : Die Morphogenie des Centralnervensystems. In Hertwig 's Handbuch d. vergleich. u. experiment. Entwickelungslehre der Wirbeltiere. Bd. II, Teil III, Kap. 8, 1905.

MARBURG, O.: Mikroskopisch-topographischer Atlas des menschlichen Zentralnervensystems, 1904*

MEYER, A.: Critical Review of the Data and General Methods and Deductions of Modern Neurology. Jour. ofComp. Neurol., Vol. VIII, Nos. 3 and 4, 1898.

NEUMAYER, L.: Histo- und Morphogenese des peripheren Nervensystems, der Spinalganglien und des Nervus sympathicus. In Hertwig's Handbuch der vergleich. und experiment. Entwickelungslehre der Wirbeltiere, Bd. II, Teil III, Kap. 10, 1906.

RAMON Y CAJAL, S. : Sur 1'origine et les ramifications des fibres nerveuses de la moelle embryonnaire. Anat. Anz., Bd. V, Nos. 3 and 4, 1890.

RAMON Y CAJAL, S. : A quelle epoque apparaissent les expansions des cellules nerveuses de la moelle epiniere du poulet? Anat. Anz., Bd. V, Nos. 21 and 22, 1890.

RAMON Y CAJAL, S.: Textura del sistema nervioso del hombre y de los vertebrados. Madrid, 1899-1904. Also translation into French by Azoulay, 1910-11.

RAMON Y CAJAL, S.: Nouvelles observations sur 1'evolution des neuroblasts, avec quelques rernarques sur 1'hypothese neurogenetique de Hensen-Held. Anat. Anz., Bd. XXXII, Nos. i, 2, 3 and 4, 1908.

SCHAPER, A.: Die morphologische und histologische Entwickelung des Kleinhirns der Teleostier. Morph.Jahrbuch, Bd. XXI, 1894.

SCHAPER, A.: Die friihesten Differenzierungsvorgange im Centralnervensystems. Arch f. Entw.-Mechan., Bd. V, 1897.

SMITH, G. E.: On the Morphology of the Cerebral Commissures in the Vertebrata, etc. Trans. Linnoean Soc. of London, 2d Ser. Zoology, Vol. VIII, Part 12, 1903. See also articles by same author in Jour, of Anat. and Physiol.

{{Ref-Streeter1905}}

{{Ref-Streeter1908pns}}

ZIEHEN, TH.: Die Morphogenie des Centralnervensystems der Saugetiere. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere. Bd. IL Teil III, Kap. 8, 1905.

ZIEHEN, TH.: Die Histogenese von Him- und Riickenmark. Entwickelung der Leitungsbahnen und der Nervenkerne bei den Wirbeltierer-. In Hertwig's Handbuch der vergleich. u. experiment Entwickelungslehre der Wirbeltiere, Bd. II, Teil III, Kap. IX, 1905,

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[[Category:Neural]]

Book - Text-Book of Embryology 16

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{{Bailey 1921}}
{| class="wikitable mw-collapsible mw-collapsed"
! Online Editor - Integumentary 
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| [[File:Mark_Hill.jpg|50px|left]] The links below are to both current and historic notes on [[Integumentary System Development]].

{{Integumentary Links}}
|}
=The Development of the Integumentary System =

The integument consists of the skin and certain accessory structures. The skin is composed of the dermis (or corium) and the epidermis. The accessory structures comprise the hairs, nails, sudoriferous glands, sebaceous glands, and mammary glands. The epidermis (or epithelial layer) and all the accessory structures are derived from the ectoderm; the dermis is mesodermal in its origin. Other appendages of the skin such as scales, feathers, claws, hoofs, and horns which are found only in the lower animals, are ectodermal derivatives and belong in the same class as the accessory structures in man.

==The Skin==

===The Epidermis===

The embryonic ectoderm consists primarily of a single layer of cells (Fig. 72). During the latter part of the first month, the single layer gives rise to two layers, of which the outer is composed of irregular flat cells and is known as the epitrichium or periderm, the inner or basal, of larger cuboidal cells which are the progenitors of the epidermal cells and of the accessory structures. The epitrichial cells later become dome-shaped and acquire a vesicular structure, the nuclei becoming less distinct. They persist until the middle of foetal life and are then cast off and mingle with the secretion of the newly formed sebaceous glands as a constituent of the vernix caseosa (see p. 412) . The epidermal cells, constantly increasing in number, soon come to form several layers (4 to 6 in the sixth month). The innermost layer rests upon the basement membrane and is composed of cuboidal or columnar cells rich in cytoplasm ; the outer layers consist of irregular cells with clearer contents and less distinct nuclei.

As development proceeds, the basal layer gives rise to several layers which, together constitute the stratum germinativum. The cells of the innermost layers are constantly proliferating and thus forming new cells which are pushed toward the surface. During the seventh month keratohyalin granules appear in two or three layers which are then known collectively as the stratum granulosum. The clearer cells of the superficial layers undergo a process of degeneration by which their contents are transformed into a horny substance, the nuclei becoming fainter and finally disappearing. These modified or degenerated cells, which are constantly being cast off and replaced by others from the deeper layers, constitute the stratum corneum (Fig. 354). In the thick epidermis, on the palms of the hands and the soles of the feet, for example, a few layers of cells just outside of the stratum granulosum become specially modified (keratinized) to form the stratum lucidum.

===The Dermis===

In the first month the {{dermis}} is represented by closely arranged, spindle-shaped mesenchymal (mesodermal) cells underlying the epidermis, and is separated from the latter by a delicate basement membrane. This mesenchymal tissue gives rise to fibrous connective tissue which, about the third month, becomes differentiated into two layers the dermis proper and the deeper subcutaneous tissue. The papillae develop as little projections of the dermis which grow into the stratum germinativum of the epidermis. In some of these, many blood vessels appear, while in others nerve endings (tactile corpuscles of Meissner) develop, thus giving rise to vascular and nerve papillae. Usually a considerable amount of fat develops in the subcutaneous tissue. Some of the mesencnymal cells of the dermis are transformed into smooth muscle cells which are found in connection with the hairs (arrectores pilorum) , in the scrotum (tunica dartos) , and in the nipples.

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'''Fig. 353. Longitudinal section through the end of the middle finger of a 5 months human foetus.''' Bonnet.

The dermis has generally been considered as a derivative of the cutis plates (p. 131) which, with the myotomes, constitute the outer walls of the primitive segments, but it is probable that the outer walls of the segments are transformed wholly into muscle tissue (McMurrich).

The pigment in the dermis develops in the form of granules in the connective tissue cells; that in the epidermis appears as granules in the cells of the deeper layers (white races) or of all the layers (dark races). Whether the pigment in the epidermis arises independently or is carried from the dermis by wandering cells is not known.

==The Nails==

The {{nail}}s are derivatives of the epidermal layer of the ectoderm, and correspond morphologically to the claws and hoofs of lower animals. The epidermis on the end of each finger and toe forms a thickening, known as the primitive nail, which is encircled by a faint groove (Zander). This occurs about the ninth week. Later the nail area migrates to the dorsal side of the digit and becomes somewhat sunken below the surface of the surrounding epithelium (Fig. 353). These observations have led to the conclusion that primarily the nails in man occupied positions on the ends of the digits, corresponding to the positions of the claws in lower forms. Furthermore, the fact that the nails (or their anlagen) are at first situated on the ends of the digits and subsequently migrate dorsally would exolain the innervation of the nail region by the palmar (and plantar) nerves.

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'''Fig. 354. Vertical section of the skin of a mouse embryo of 18 mm.''' Showing early hair germs. Maurer.

After the dorsal migration of the nail area, the epithelium and dermis along, the proximal and lateral edges become still more elevated to form the nail wall, the furrow between the latter and the nail being the nail groove. At the distal edge of the nail area, the epithelium becomes thickened to form the so-called sole plate, which is probably homologous with the more highly developed sole plate in animals with hoofs or claws. The epithelium of the nail area increases in thickness, and, as in the skin, becomes differentiated into three layers (Fig. 353). The outer layers of cells become transformed into the stratum corneum. The cells of the next deeper layers, which acquire keratin granules and constitute the stratum lucidum, degenerate and give rise to the nail substance. Thus the nail is a modified portion of the stratum lucidum. The layers of epithelium beneath the nail form the stratum germinativum, which, with the subjacent dermis, is thrown into longitudinal ridges.

After its first formation, the nail is covered by the stratum corneum and the epitrichium, the two together forming the eponychium. The epitrichium soon disappears; later the stratum corneum also disappears with the exception of a narrow band along the base of the nail.

The formation of nail substance begins during the third or fourth month in the proximal part of the nail area. The nail grows from the root and from the under surface in the region marked by the whitish color (the lunuld). New keratinized cells are added from the subjacent stratum germinativum and become degenerated to form new nail substance which takes the place of the old as the latter grows distally.

==The Hair==

The {{hair}}s, like the nails, are derivatives of the epidermal layer of the ectoderm. In embryos of about three months, local thickenings of the epidermis appear (beginning in the region of the forehead and eye-brows) and grow obliquely into the underlying dermis in the form of solid buds the hair germs (Fig. 355, I, II). As the buds continue to elongate they become club-shaped and the epithelium at the end of each molds itself over a little portion of the dermis in which the cells have become more numerous and which is known as the hair papilla (Fig. 354).

As the epidermal bud grows deeper, its central cells become spindle-shaped and undergo keratinization to form the beginning of the hair shaft; the peripheral layers constitute the anlage of the root sheath (Fig. 355, III, IV). The hair shaft grows from its basal end, new keratinized cells being added from the epithelium nearest the papilla as the older cells are pushed toward the surface of the skin. The surface cells of the hair shaft become flattened to form the cuticle of the hair (Fig. 355, V). The hairs appear above the surface about the fifth month. Of the cells of the root sheath, those nearest the hair become scale-like to form the cuticle of the root sheath; the next few layers become modified (keratinized) to form Huxley's and Henle's layers. Outside of these is the stratum germinativum, the basal layer of which is composed of columnar cells resting upon a distinct basement membrane. The stratum germinativum is continued over the tip of the papilla, where its cells give rise to new cells for the hair shaft (Fig. 355, V).

The connective tissue around the root sheath becomes differentiated into an inner highly vascular layer, the fibers of which run circularly, and an outer layer, the fibers of which extend along the sheath. The two layers together constitute the connective tissue follicle.

The first formed hairs, which are exceedingly fine and silky, develop in vast numbers over the surface of the embryonic body and are known collectively as the lanugo. This growth is lost (beginning before birth and continuing during the first and second years after), except over the face, and is replaced by coarser hairs. These in turn are constantly being shed during the life of the individual and replaced by new ones. The new hairs probably in most cases develop from the old follicles, the cells over the old papillae proliferating and the newly formed hairs growing up through the old sheaths. In some cases, however, new follicles are formed directly from the epidermis and dermis. In some of the lower Mammals, new hair germs appear as outgrows from the sheaths of old follicles, thus giving rise to tufts of hair. The arrectores pilorum muscles arise from the dermal (mesenchymal) cells and become attached to the follicles below the sebaceous glands.

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'''Fig. 355. Five stages in the development of a human hair.''' Stohr.

:a, Papilla; b, arrector pili muscle; c, beginning of hair shaft; d, point where hair shaft grows through epidermis; e, anlage of sebaceous gland; l, hair germ; g, hair shaft; h, Henle's layer; i, Huxley's layer; k, cuticle of root sheath; /, inner root sheath; m, outer root sheath in tangential section; n, outer root sheath; o, connective tissue follicle.

==The Glands of the Skin==

===The Sebaceous Glands===

These structures usually develop in connection with hairs. From the root sheath a solid bud of cells grows out into the dermis (Fig. 355, IV) and becomes lobed. The central cells of the mass undergo fatty degeneration and the products of degeneration pass to the surface of the skin through the space between the hair and its root sheath. The more peripheral cells proliferate and give rise to new central cells which in turn are transformed into the specific secretion of the gland, the whole process being continuous. On the margins of the lips, on the labia minora'aridon the glans penis and prepuce, glands similar in character to the sebaceous glands arise directly from the epidermis independently of hairs.

===The Sudoriferous Glands===

The sweat glands : begin to develop during the fifth month as solid cylindrical growths from the deeper layers of the epidermis into the dermis (Fig. 353). Later the deeper ends of the cylinders become coiled and lumina appear. The lumina do not at first open upon the surface but gradually approach it as the deeper epidermal layers replace the more superficial.

===The Vernix Caseosa===

During foetal life the secretion of the sebaceous glands becomes mingled with the cast-off epitrichial and epidermal cells to form the whitish oleaginous substance (sometimes called the smegma embryonum) that covers the skin of the new-born child. It is collected especially in the axilla, groin and folds of the neck.

===The Mammary Glands===

In embryos of six to seven mm, or even less, a thickening of the epidermis occurs in a narrow zone along the ventro-lateral surface of the body (Strahl). In embryos of 15 mm this thickening, known as the milk ridge, extends from the upper extremity to the inguinal region (Kallius, Schmidt). Later the caudal end of the ridge disappears, while the cephalic portion becomes more prominent. The further history of the ridge has not been traced, but in embryos considerably older the anlage of each gland is a circular thickening of the epidermis in the thoracic region, projecting into the underlying dermis. It seems most probable that this local thickening represents a portion of the original ridge, the remainder having disappeared. Later the central cells of the epidermal mass become cornified and are cast off, leaving a depression in the skin (Fig. 356). In embryos of 250 mm a number of solid secondary buds have grown out (Fig. 357). These resemble the anlagen of the sweat glands, to which they are generally considered as closely allied (Hertwig, Wiedersheim and others), and represent the excretory ducts. Continued evaginations from the terminal parts of the excretory ducts form the lobular ducts and acini. The acini, however, are scarcely demonstrable in the male, and not even in the female until pregnancy. Lumina appear by a separation and breaking down of the central cells of the ducts and acini, the peripheral cells remaining as their lining.

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'''Fig. 356. Vertical section through the anlage of the mammary gland of a human foetus of 16 cm.''' Bonnet.

Late in foetal life, or sometimes after birth, the original depressed gland area becomes elevated above the surface to form the nipple. The excretory ducts (15 to 20 in number) which at first opened into the depression, thus come to open on the surface of the nipple. In the area around the nipple the areola numerous sudoriferous and sebaceous glands develop, some of which come to open into the lacteal ducts. Sometimes rudimentary hairs appear. Other glands known as areolar glands (of Montgomery) resembling rudimentary mammary glands also develop from the epidermis of the areola.

After birth the mammary glands continue to grow slowly in both sexes up to the time of puberty. After this they cease to grow in the male, and then atrophy. In the female, growth of the glandular elements goes on, but very slowly, and usually a considerable amount of fat develops in the surrounding tissue, causing the enlargement of the breasts.

===The Mammary Glands of Pregnancy===

Even in the female, as stated before, acini are scarcely demonstrable until pregnancy. The mamma consists mostly of connective tissue and fat, with scattered groups of duct-like tubules. During pregnancy the tubules give rise to the acini by a process of evagination, the cells increasing in number by mitosis. Toward the end of pregnancy each excretory duct and its smaller ducts and acini form a distinct lobe with a relatively small amount of connective tissue. The epithelium is low or cuboidal, and fat begins to accumulate, in the seventh or eighth month, as droplets in the basal parts of the cells. The droplets increase in number and in size, approaching the inner end of the cell, until finally the cell is practically filled. At the beginning of lactation the fat escapes into the lumen of the acinus, leaving a bit of ragged cytoplasm with a nucleus. This regenerates into a cell capable of further activity; and it is probable that the same cell may become filled with fat and discharge its contents several times during lactation.

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'''Fig. 357. Vertical section of the anlage of the mammary gland of a human foetus of 25 cm.''' Nagel.

During pregnancy and lactation the acini also contain leucocytes which have wandered through the epithelium from the surrounding tissue. These contain fat droplets and are known as colostrum corpuscles.

At the end of lactation the acini atrophy and disappear, the lobules becoming masses of connective tissue and fat, which contain groups of duct-like tubules and which are so closely joined with one another that they are indistinguishable as lobules.

==Anomalies==

===Anomalies of the Skin===

The epidermis may develop to an abnormal degree over the entire surface of the body, forming a horny layer which is broken only where the skin is folded by the movement of the members of the body a condition known as hyperkeratosis. Or the abnormal development may give rise to irregular patches of thick epithelium ichthyosis. In either case, hairs and sebaceous glands are usually absent over the affected areas.

Occasionally pigment develops in excess over larger or smaller areas of the skin, giving rise to the so-called ncevi pigmentosi. In some cases, on the other hand, there is total or almost total lack of pigment in the skin and hair (usually accompanied by defective pigmentation of the iris, chorioid and retina) a condition known as albinism. There are also instances of partial albinism. The influence of heredity in albinism is doubtful, for albinos are usually the children of ordinary parents.

The angiomata (lymphangiomata, haemangiomata) found in the skin are due to dilated lymphatic or blood channels, the color in haemangiomata being due to the haemoglobin in the blood.

Dermoid Cysts. The congenital dermoid cysts not infrequently found in or under the skin are usually situated in or near the line of fusion of embryonic structures, as in the region of the branchial arches, along the ventral body wall and on the back. During the fusion of adjacent structures, portions of the epidermis become constricted from the parent tissue and come to lie in the dermis, where they continue to grow and produce cystic masses and sometimes give rise to hairs and sebaceous glands'. This type of dermoid is to be distinguished from that found for example in the ovary, in which derivatives of all three germ layers are present (see Chap. XX).

===Anomalies of the Epidermal Derivatives===

Occasionally hair develops in profusion over areas of the skin that naturally possess only a fine, silky growth, such, for example, as a woman's face. Or nearly the entire body may be covered by an unusual amount of hair. Such conditions known as hypertrichosis possibly represent the persistence and continued growth of the lanugo (p. 410) and in this sense are to be regarded as the result of arrested development (Unna, Brandt). Congenital absence of the hair (hypotrichosis, alopecia) is a rare anomaly and is usually accompanied by defective development of the teeth and nails.

Sebaceous cysts, generally regarded as due to accumulation of secretion in the sebaceous glands, sometimes probably represent remnants of displaced pieces of epidermis apart from the hairs (Chiari).

Supernumerary mammary glands (hypermastid) and nipples (hyperthelia) are not infrequently present in both males and females. They are usually situated below the normal mammae (rarely in the axillary region), in a line drawn from the axilla to the groin, and probably represent persistent and abnormally developed portions of the milk ridge (see p. 412). In very rare cases a supernumerary gland develops in some other region (even on the thigh). If the mammary glands are morphologically allied to the sweat glands (p. 413), these misplaced mammae are suggestive of anomalous development of some of the sweat gland anlagen.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_17|Nervous System]]

==References for Further Study==

BROUHA: Recherches sur les di verses phases du developpement et de Pactivite de la mammelle. Arch, de Biol., T. XXI, 1905.

BONNET, R. : Die Mammarorgane im Lichte der Ontogenie und Phylogenie. Ergebnisse d. Anat. u. Entwick., Bd. II, 1892; Bd. VII, 1898.

KALLIUS, E. : Ein Fall von Milchleiste bei einem menschlichen Embryo. Anat. Hefte, Bd. VIII, 1897.

{{Ref-KeibelMall1910}}

KRAUSE, W.: Die Entwickelung der Haut und ihrer Nebenorgane. In Hertwig's Handbuch d. vergleich. u. experiment. Entwick elungslehre der Wirbeltiere, Bd. II, Teil I, 1902.

OKAMURA, T.: Ueber die Entwickelung des Nagels beim Menschen. Arch. f. Dermatol. u. Syphilol., Bd. XXV, 1900.

PIERSOL, G. A. : Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

SCHMIDT, H.: Ueber normale H.yperthelie menschlicher Embryonen und tiber die erste Anlage der menschlichen MilchdrUsen uberhaupt. Morphol. Arbeiten, Bd. XVII, 1897.

SCHULTZE, O.: Ueber die erste Anlage des MilchdrUsen Apparates. Anat. Anz. } Bd. VIII, 1892.

STOHR, P.: Entwiokelungsgeschichte des menschlichen Wollhaares. Anat. Hefte, Bd. XXIII, 1903.

STRAHL, H.: Die erste Entwickelung der Mammarorgane beim Menschen. Verhandl. d. Anat. Gesellsch., Bd. XII, 1898.

ZANDER, R.: Bie friihesten Stadien der Nagelentwickelung und ihre Beziehungen zu den Digitalnerven. Arch. f. Anat. u. PhysioL, Anat. Abth., 1884.

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[[Category:Integumentary]][[Category:Mammary Gland]]

Book - Text-Book of Embryology 15

2024-01-25T01:05:06Z

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{{Template:Bailey 1921}}

=The Development of the Urogenital System=

No other system in the body presents such peculiarities of development as the urogenital system. In the first place, it is exceedingly complicated on account of its many parts. It is derived from both mesoderm (mesothelium and mesenchyme) and entoderm. The urinary portion develops into a great complex of ducts for the carrying off of waste products. The genital portion in both sexes becomes highly specialized for the production and carrying off of the sexual elements. In the second place, instead of one set of urinary organs developing and persisting, three sets develop at different stages. The first set (the pronephroi) disappears in part, but leaves certain structures which are used, so to speak, in the development of the second. The second set (the mesonephroi) disappears for the most part, leaving, however, some portions which are taken up in the development of the genital organs and other portions which persist as rudimentary structures in the adult. The third set (the metanephroi or kidneys) develops in part from the second and in part is of independent origin. These conditions" afford one of the most striking examples of the repetition of the phylogenetic history by the ontogenetic, or, in other words, of von Baer's law that an individual, in its development, has a tendency to repeat its ancestral history; for the first and second sets of urinary organs in the human embryo represent systems that are permanent in the lower Vertebrates. In the third place, the ducts of the genital organs are not homologous in the two sexes. In the male the ducts (deferent duct, duct of the epididymis, efferent ductules) are derived from the second set of urinary organs; in the female they (the oviducts) are derived from other ducts which develop in the second set of urinary organs, but which are not functionally a part of the latter.

==The Pronephros==

The pronephros, with the pronephric duct, is the first of the urinary organs to appear. In embryos of 2-3 mm. there are two pronephric tubules on each side, situated at the level of the heart. Although their mode of origin has not been observed in the human embryo, it is probable, judging from observations on lower Vertebrates, that they arise as evaginations of the mesothelium. The part of the mesothelium involved is that adjacent to the intermediate cell mass (Fig. 305) . (The intermediate cell mass is the portion of the mesoderm intervening between the primitive segments and the unsegmented parietal and visceral layers; p. 99.) The more cephalic of the two tubules becomes hollow and opens into the ccelom; the more caudal is merely a solid cord of cells. Neither tubule forms any connection with the pronephric duct. At each side of the root of the mesentery a small elevation, which projects into the ccelom, probably represents a rudimentary glomerulus. A glomerulus in the lower Vertebrates, where the pronephros develops to a much greater degree than in Mammals, contains tortuous vessels derived from branches of the aorta (Fig. 306). The mesonephros (p. 359), beginning to develop almost as soon as the pronephros and in the same relative position, forms a ridge which projects into the coelom. The pronephric tubules thus become embedded in the mesonephric ridge.

The pronephric duct begins to develop about the same time as the tubules. It appears as a longitudinal ridge on the outer side of the intermediate cell mass at the level of the heart and projects into the space between the mesoderm and ectoderm. The ridge is at first solid but soon acquires a lumen, and gradually extends to the caudal end of the embryo where it bends medially to open into the gut. The origin of the caudal portion of the duct is a matter of dispute. It comes in contact and fuses with the ectoderm, but whether in the higher animals the fusion is secondary or signifies a derivation from the ectoderm has not been determined. When first formed, the entire duct lies on the outer side of the intermediate cell mass, but later becomes embedded in the mesonephric ridge.

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'''Fig. 305. Transverse section of a dog embryo with 19 primitive segments.''' Bonnet. Section taken through sixth segment.

The pronephric tubules are but transient structures and have no functional significance in man and the higher Vertebrates. The ducts, however, remain and become the ducts of the second set of urinary organs, the mesonephroi.

The significance of the pronephros can be understood only by reference to the conditions in the lower animals. In the latter the pronephros acquires a relatively higher degree of development than in the higher forms. The tubules are segmentally arranged and are preset in many segments of the body. They open at their outer ends into the ducts, and at their inner ends into the coelom through ciliated funnel-shaped mouths or nephrostomes. Little masses of mesoderm, containing tortuous vessels derived from branches of the aorta, form glomeruli which project into the ccelom. Waste products are removed from the blood through the agency of the glomeruli and are collected in the ccelom. They are then taken up by the pronephric tubules and carried away by the ducts. In some of the Round Worms there is not even a longitudinal duct, but the tubules open directly on the outer surface of the body. In the lowest Fishes all the tubules on each side open into a longitudinal duct which opens into the cloaca. In these lower forms of animal life the pronephroi constitute the permanent urinary apparatus. In the ascending scale the mesonephroi appear (higher Fishes, Amphibia) and assume the function of carrying off waste products. The pronephroi also develop, but to a lesser degree. Still higher in the scale (Reptiles, Birds, Mammals) the kidneys (metanephroi) appear and the mesonephroi lose their functional significance. But even in the very highest Mammals the pronephroi appear, in a very rudimentary form, in each individual in the earliest embryonic stages, thus repeating the ancestral history.

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'''Fig. 306. Diagram of the pronephric system in an amphibian.''' Bonnet.

:CceL, Coelom; Glom., glomerulus, containing ramifications of a branch of the aorta; Nch., notochord; Pron. t., pronephric tubule.

==The Mesonephros==

The mesonephroi, which constitute the second set of urinary organs, appear in embryos of 2.6-3.0 mm., immediately following the pronephroi. They begin to develop just caudal to the pronephric tubules and in the same relative position as the latter, that is, in the intermediate cell mass. Condensations<sup>*</sup> appear in the mesenchyme and become more or less tortuous. At their inner ends they form secondary connections with the mesothelium and at their outer ends they join the pronephric duct which now becomes the mesonephric (or Wolffian) duct. The cells acquire an epithelial character, lumina appear, and the tortuous mesenchymal condensations thus become true tubules. Their connections with the mesothelium soon disappear (Fig. 307).

:<sup>*</sup>The term " condensation " is here used to mean increased density of tissue due mainly to proliferation of cells.

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'''Fig. 307. From a transverse section of a sheep embryo of 21 days (15 mm.)''' Showing the developing mesonephros. Bonnet.

After the tubules are formed, other condensations of the mesenchyme appear near their inner ends. A branch from the aorta enters each condensation and breaks up into a number of smaller vessels which ramify inside, the entire structure thus becoming a glomerulus. Each glomerulus pushes against the corresponding tubule, the latter becoming flattened and then growing around the glomerulus. In this way the glomerulus becomes surrounded by two layers of epithelium, except at the point where the vessels enter, and the whole structure the Malpighian corpuscle resembles very closely a renal corpuscle of the adult kidney. Waste products are removed from the blood through the agency of the glomeruli and are carried to the ducts by the mesonephric tubules (Fig. 307). The tubules themselves increase in length and become much coiled. Secondary and tertiary tubules also develop and become branches of the primary. Whether these develop from condensations of the mesenchyme or as buds from the primary tubules has not been determined. Each tubule consists of two parts (1) a dilated part around the glomerulus, composed of large flat cells and forming Bowman's capsule, and (2) a narrower coiled part leading from the glomerulus to the duct and composed of smaller cuboidal cells (Fig. 307). The primary mesonephric tubules are arranged segmentally, one appearing in each segment as far back as the pelvic region. Thus the intermediate cell mass may be considered as a series of nephrotomes, corresponding to the sclerotomes and myotomes. The segmental character is soon lost, however, owing to the inequality of growth between the mesonephros and the other segmental structures, and to the development of the secondary and tertiary tubules. As stated above, the first mesonephric tubules appear immediately caudal to the pronephros From this point their formation gradually progresses in a caudal direction as far as the pelvic region. By the further development of the primary and by the addition of the secondary and tertiary tubules and the glomeruli, the mesonephros as a whole increases in size and forms a large structure which projects into the ccelom on each side of the body, forming the so-called mesonephric or Wolffian ridge. It reaches the height of its development in the human embryo about the fifth or sixth week, at which time it extends from the region of the heart to the pelvic region (Fig. 308). Each organ is attached to the dorsal body wall by a distinct mesentery which, at its cephalic end, also sends off a band to the diaphragm the diaphragmatic ligament of the mesonephros. The peritoneum is reflected over the surface of the mesonephros, and on the ventro-medial side the mesothelium becomes thickened to form the genital ridge (p. 374; Figs. 276 and 308). The mesonephric ducts are embedded in the lateral parts of the organs and extend throughout practically T their entire length. Since the ducts are identical with the pronephric ducts, they open at first into the caudal end of the gut, or cloaca (p. 355; Fig. 322). At a little later period, when the urogenital sinus is formed, they open at the junction of the latter with the bladder (Fig. 325). Still later they open into the sinus itself (p. 370) . A description of their further development is best deferred to the section on the male genital organs, since they become the genital ducts (p. 386).

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'''Fig. 308. Human embryo of 5 weeks.''' The ventral body wall has been removed to disclose the mesonephroi. Kollmann.

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'''Fig. 309. Diagram representing certain persistent portions of the mesonephros in the male''' (see table). Kottmann.

The mesonephroi function as urinary organs during the period of their existence in the embryos of all higher Vertebrates. Excretory products are conveyed directly to the tubules by means of the glomeruli instead of being deposited in the ccelom and then taken up by the tubules, as is the case in functional pronephroi (p. 356). The main excretory ducts are the same as in the pronephroi. Aside from the vessels in the glomeruli the mesonephroi are exceedingly vascular organs. Large and small branches of the posterior cardinal veins ramify among the tubules (Figs. 276 and 194). The blood undergoes purifying processes in its close contact with the tubules and is returned to the heart by the posterior cardinals, or, after the cephalic ends of the latter atrophy, by the subcardinals and the inferior vena cava (see p. 225; also Fig. 194, B). There is thus present a true renal portal system, similar to the hepatic portal system.

Although the mesonephroi become large functional organs during the earlier stages of development, they atrophy and disappear for the most part, coincidently with the appearance and development of the kidneys. The degeneration begins during the sixth or seventh week and goes on rapidly until, by the end of the fourth month, little remains but the ducts and a few tubules. The degenerative processes consist of (1) an ingrowth of connective tissue among the tubules, (2) atrophy of the epithelium of the tubules, and (3) atrophy of the glomeruli, The portions which remain differ in the two. sexes, and since the remnants are taken up in the formation of the male and female genital organs it seems best to discuss them more fully under those heads (pp. 383,386). The accompanying table, however, will give a clue to their fate (see also Figs. 309 and 310). A [[Book_-_Text-Book_of_Embryology_15#Table07|more comprehensive table]] will be found on p. 393.

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'''Fig. 310. Diagram representing certain persistent portions of the mesonephros in the female''' (see table).
:Epo. /., Longitudinal duct of the epoophoron; Epo. t., transverse ductules of the epoophoron; O. t. a. t ostium abdominale tubae; Ovd., oviduct; X represents a small duct which, if present, leads from the epoophoron to one of the fimbriae of the oviduct.

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The significance of the mesonephroi, which, as well as the pronephroi, are present in the embryos of ail higher Vertebrates, can be understood only by referring to the conditions in the lower Vertebrates. In the majority of the Fishes and in the Amphibia the mesonephroi constitute the functional urinary organs of the adult and possess essentially the same structure in the embryos of higher forms. Beginning in the Reptiles and continuing up through the series of Birds and Mammals, another set of urinary organs the kidneys develops. The mesonephroi also develop in these forms, even to a high degree, thus repeating the ancestral history, but retain their original function only in the earlier embryonic stages.

==The Kidney (Metanephros)==

The kidneys are the third set of urinary organs to develop. They assume the function of the mesonephroi as the latter atrophy, and constitute the permanent urinary apparatus. Each kidney is derived from two separate anlagen which unite secondarily. The epithelium of the ureter, renal pelvis, and straight renal tubules (collecting tubules) is derived from the mesonephric duct by a process of evagination. The convoluted renal tubules and glomeruli are derived directly from the mesenchyme, and in this respect resemble the mesonephric tubules and glomeruli.

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'''Fig. 311. From a reconstruction of the anlage of the kidney (metanephros) of a human embryo at the beginning of the 5th week.''' Schreiner.

The Ureter, Renal Pelvis and Straight Renal Tubules. During the fourth week (in embryos of about 5 mm.) a small, hollow, bud-like evagination appears on the dorsal side of each mesonephric duct near its opening into the cloaca. The evagination continues to grow dorsally in the mesenchyme toward the vertebral column, and at the same time becomes differentiated into two parts, a narrow stalk and a dilated terminal portion. The stalk is the forerunner of the ureter, the dilated end is the primitive renal pelvis (Figs. 311 and 313). When the dilated end reaches the ventral side of the vertebral column it turns and grows cranially between the latter and the mesonephros. The stalk (or ureter) elongates accordingly (Fig. 312).

About the fifth week, four evaginations from the primitive renal pelvis appear one cephalic, one caudal and two central (Figs. 312 and 314) . These may be considered as straight renal tubules of the first order. The distal end of each then enlarges to form a sort of ampulla, and from each ampulla two other evaginations develop, forming tubules of the second order. From the ampulla of each secondary tubule two tertiary tubules grow out; and this process continues in a similar manner until twelve or thirteen divisions occur, the final divisions occurring during the fifth month. The tubules grow into the mesenchyme which surrounds the pelvis and which forms the so-called metanephric blastema, or nephro genie tissue (Fig. 313).

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'''Fig. 312. From a reconstruction of the anlage of the kidney of a human embryo of 11.5 mm.''' Schreiner.

If the straight tubules were to remain in this condition, only four would open directly into the pelvis, corresponding with the four primary evaginations. In the adult, however, many hundreds open into the pelvis; consequently extensive changes of the early condition must take place. These changes are similar to the process by which the proximal ends of some of the blood vessels come to be included in the wall of the heart (p. 214). The proximal ends of the tubules become wider, the pelvis swells out, and the walls of the tubules become included in the wall of the pelvis. In certain parts of the pelvic wall this process goes on until deep bays the calyces are formed, into which a large number of tubules open. In the other parts of the wall the process does not go so far, thus leaving promontories the renal papilla upon which larger tubules or papillary ducts open. The adult renal pelvis thus consists of the primitive pelvis plus the proximal ends of the straight tubules.

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'''Fig. 313. From a transverse section of a human embryo at the beginning of the 5th week.''' The plane of the section is indicated in Fig. 311. Schreiner.

The Convoluted Renal Tubules and Glomeruli. As stated above, the metanephric blastema or nephrogenic tissue surrounds the renal pelvis and the straight tubules. It represents a condensation of the mesenchyme and is destined to give rise to the convoluted tubules and glomeruli. The cells of the blastema in the region of the ampullae of the terminal straight tubules acquire an epithelial character and become arranged in solid masses (Fig. 315). Each mass unites with an ampulla and acquires a lumen, which becomes continuous with the lumen of the straight tubule, then elongates and forms an S-shaped structure (Figs. 316 and 317). The loop of the S nearer the straight tubules elongates still more and grows toward the pelvis, parallel with the straight tubules, to form Ifenle's loop. The part between Henle's loop and the straight tubule elongates and becomes convoluted to form the proximal part of a convoluted renal tubule (second convoluted tubule) . The part between the distal end and Henle's loop elongates and becomes convoluted to form the distal part of a convoluted renal tubule (first convoluted tubule) (Figs. 318 and 319).

To avoid confusion it may be well to call attention to the fact that what has here been called the proximal part of a convoluted tubule corresponds with what is usually described as the second or distal convoluted tubule, and that the distal part of a convoluted tubule corresponds with the first or proximal convoluted tubule. In histology the distal and proximal convoluted tubules are spoken of in relation to the renal corpuscle, but in development it is more convenient to speak of the terminal part of a tubule as its distal part.

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'''Fig. 314. From a model of the primitive renal pelvis and the evaginations which form the cephalic, central and caudal straight renal tubules of the first order.''' Human embryo of 4.75 months. Compare with Fig. 350. Schreiner

A glomerulus develops in connection with the extreme distal end of a convoluted tubule or, in other words, with the distal loop of the S (p. 363). There occurs here a further condensation of the mesenchyme, into which grows a branch from the renal artery. This, as the afferent vessel of the glomerulus, breaks up into several arterioles, each of which gives rise to a tuft of capillaries. These tufts are separated from one another by somewhat more mesenchymal tissue than separates the capillaries within a tuft. The tufts with the associated mesenchymal tissue constitute a glomerulus, and it is the mesenchymal septa between the tufts that give to the glomerulus its characteristic lobulated appearance. The capillaries of each tuft empty into an arteriole, and the several arterioles unite to form the efferent vessel of the glomerulus, which passes out along side of the afferent vessel. The renal tubule becomes flattened on the side next the condensation of the mesenchyme, and as the glomerulus develops, the epithelium of the tubule grows around it except at the point where the blood vessels enter and leave. Thus a double layer of epithelium comes to surround the glomerulus, the space between the two layers being the extreme distal part of the lumen of a renal tubule. The inner layer is closely applied to the surface of the glomerulus and even dips down into the latter between the tufts. The outer layer forms Bowman's capsule, the flat epithelium of which passes over into the cuboidal epithelium of the "neck" of the tubule, and this in turn is continuous with the pyramidal epithelium of the distal convoluted tubule. The entire structure is a renal corpuscle. The formation of renal corpuscles begins in embryos of 30 mm. and continues until after birth.

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'''Fig. 315. Sagittal section of the anlage of the left kidney in a rabbit embryo of 15 days.''' Schreiner.
:The straight renal tubules (sections of which are shown) are embedded in the metanephric blastema. Condensations of the latter form the anlagen of the convoluted renal tubules. At the left of the figure several mesonephric tubules are shown.

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Fig. 316. From a section of the kidney of a human foetus of 7 months. Schreiner.

:Amp., Ampulla of a straight renal tubule; Con. r. t., anlagen of convoluted renal tubules, above and between which are two ampullae (compare Fig. 317); met. bl., metanephric blastema.

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Figs. 317, 318 and 319. From reconstructions of convoluted renal tubules in successive stages of development. Stoerk.

==The Renal Pyramids and Renal Columns==

The tubules arising from the four primary evaginations of the renal pelvis together form four distinct groups or primary renal (Malpighian) pyramids one cephalic, one caudal, and two central. The central pyramids are crowded in between the end pyramids, (cephalic and caudal) and do not develop as rapidly as the latter which soon bend around toward the ureter, thus resulting in the formation of the convex side of the kidney and a depression or hilus opposite (compare Figs. 314 and 320). Between these four pyramids the mesenchyme remains for some time as rather distinct septa, forming the primary renal columns (columns of Bertini) which are marked by corresponding depressions on the surface of the kidney and extend to the renal pelvis. The four primary pyramids may be considered as lobes (Fig. 320). It should also be stated that the parts of the tubules derived from the mesenchyme form the bases of the renal pyramids. Between the groups of straight tubules derived from evaginations of the second or third order (see p. 362) there are also septa of mesenchyme which divide each primary pyramid into two or three secondary pyramids. These septa may be considered as secondary renal columns (Fig. 321). Thus the entire kidney is divided into from eight to twelve secondary pyramids. Tertiary renal columns then divide incompletely the secondary pyramids into tertiary pyramids. These are apparent on the surface of the kidney and constitute the surface tabulation, but are not clearly denned in the interior.

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'''Fig. 320. Frontal section of the kidney of a human foetus of 3.75 months (10 cm).''' Hauch.

The formation of renal papillae (p. 363) corresponds to the formation of pyramids only to a certain point, for some of the tertiary pyramids appear only near the surface and consequently do not have corresponding papillae. This accounts for the fact that frequently the number of pyramids apparent on the surface does not correspond with the number of papillae. The surface lobulation is very plainly marked in kidneys up to and for a short time after birth. It then disappears and the surface becomes smooth. At the same time the connective (mesenchymal) tissue of the renal columns is largely replaced by the epithelial elements of the gland so that in the adult kidney the columns are not clearly denned.

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'''Fig. 321. Frontal section of the kidney of a human foetus of 19 weeks (17.5 cm).''' Hauch.

The capsule of the kidney is derived from the mesenchyme which surroum the anlage of the organ (Fig 315). This mesenchyme is transformed into fibroi connective tissue and a small amount of smooth muscle, forming a layer which closely invests the kidney and dips into the hilus where it surrounds the blood vessels and the end of the ureter. The connective tissue and muscle of the ureter are also derived from the mesenchyme.

==Cortex and Medulla==

As the convoluted renal tubules develop in the metanephric blastema (p. 363), they form a cap-like mass around the group of straight tubules. This is the beginning of the renal cortex. A true cortex, however, can be spoken of only after the appearance of the glomeruli (in embryos of 30 mm.). Its peripheral boundary is the capsule, and the renal corpuscles nearest the pelvis mark its inner boundary. The mass of straight tubules forms the bulk of the medulla. It does not at this stage contain Henle's loops, the latter developing later (during the fourth month). Both cortex and medulla increase until the kidney reaches its adult size. The cortex increases relatively faster than the medulla up to the seventh year; after this the increase is practically equal. The medullary rays are probably secondary formations, being formed by groups of straight tubules which grow out into the cortex; later, ascending arms of Henle's loops are added to these groups.

Some of the glomeruli of the first generation are much larger than any found in the adult. In some of the lower Mammals these "giant" glomeruli disappear and it is probable that the same occurs in the human embryo. Some of the tubules also degenerate and disappear. The cause of these phenomena is not known.

Changes in the Position of the Kidneys. As has already been described (p. 361), the kidney buds first grow dorsally from the mesonephric ducts toward the vertebral column. They then grow cranially, with a corresponding elongation of the ureters, and in embryos of 20 mm. they lie for the most part cranial to the common iliac arteries. This migration continues until the time of birth when the cephalic ends of both kidneys reach the eleventh thoracic vertebra. When the kidneys begin to move cranially the hilus is directed caudally. Later they rotate and the hilus is turned toward the medial sagittal plane.

Since the ureter, renal pelvis and straight tubules develop from the mesonephric ducts, and since the convoluted tubules and glomeruli develop directly from the same tissue as the mesonephric tubules, namely, the mesenchyme, the renal tubules may be said to represent the third generation of urinary tubules. But no definite reason for the appearance of the third generation can be given. The atrophy of the mesonephroi would, of course, make necessary the compensatory development of new structures; but this only carries the problem a step further back, for the cause of the atrophy of the mesonephroi is not clear. In regard to this atrophy, however, there is a suggestion of a cause in the fact that in the Amphibia the mesonephroi are in part used for conveying the sexual elements, which leaves the mesonephroi less free to function as urinary organs. Possibly the loss of freedom to function leads to the development of new structures the kidneys in the higher forms (Reptiles, Birds and Mammals). In these forms the kidneys assume the urinary function after the early embryonic stages, and only the ducts and a part of the tubules of the mesonephroi persist in the male to convey the sexual elements. Thus the persistent parts of the mesonephroi assume a new function as the old one is lost. But, on the other hand, complications arise on account of the fact that in the female the sexual products are carried off by another set of ducts (the Miillerian ducts), which develop in both sexes but disappear in the male, while the mesonephroi and their ducts disappear almost entirely.

==The Urinary Bladder, Urethra and Urogenital Sinus==

As described elsewhere, the allantois appears at an early stage as an evagination from the ventral side of the caudal end of the primitive gut (Fig. 244), grows out into the belly stalk, and finally becomes enclosed in the umbilical cord (p. 582). As the embryo develops, the proximal end of the allantois becomes elongated to form a stalk or duct which extends from the caudal end of the gut to the umbilicus (Fig. 247). The portion of the gut immediately caudal to the attachment of the allantoic duct becomes dilated to form the cloaca which at first is a blind sac, its cavity being separated from the outer surface of the embryo by the cloacal membrane (Fig. 322). The latter is composed of a layer of entoderm and a layer of ectoderm, with a thin layer of mesoderm between. The cloaca then becomes separated into two parts a larger ventral part which forms the urogenital sinus and a smaller dorsal part which forms the rectum. This Is accomplished by a fold or ridge which grows from the lateral wall into the lumen and meets and fuses with its fellow of the opposite side. The fusion begins at the cephalic end, in the angle between the allantoic duct and the gut, and gradually proceeds caudally until the separation is complete as far as the cloacal membrane. The mass of tissue forming the partition is called the urorectalfold (Fig. 323). The openings of the mesonephric ducts, which primarily were situated in the lateral cloacal wall (p. 359), are situated after the separation in the dorso-lateral wall of the urogenital sinus (compare Figs. 322, 323, 324). During the separation of the urogenital sinus from the rectum, certain changes take place in the proximal ends of the mesonephric ducts and ureters. The ends of the ducts become dilated and are gradually taken up into the wall of the sinus. This process of absorption continues until the ends of the ureters are included, with the result that the ducts and ureters open separately, the latter slightly cranial and lateral to the former. (Compare Figs. 324 and 325.) This condition is reached in embryos of 12 to 14 mm. The point at which these two sets of ducts open marks the boundary between a slightly larger cephalic part of the sinus, the anlage of the bladder, and a smaller caudal part which becomes the urethra and urogenital sinus (Fig. 325).

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'''Fig. 322. From a model of the cloaca and the surrounding structures in a human embryo of 6.5 mm'''. Keibel.

After the second month the bladder becomes larger and more sac-like, and the openings of the ureters migrate farther cranially to their final position. The lumen of the bladder is at first continuous with the lumen of the allantoic duct, but the duct degenerates into a solid cord of cells, the urachus. The latter degenerates still further and finally remains only as the middle umbilical ligament. It seems quite probable that the bladder is derived almost wholly from the cloaca. A small part arises from the inclusion of the ends of the mesonephric ducts. If any part is derived from the allantoic duct, it is only the apex. After the bladder begins to enlarge, the adjacent portion of the urogenital sinus becomes slightly constricted. This marks the beginning of the urethra. In the female the constricted part represents practically the entire urethra. In the male it represents only the proximal end, the other portion developing in connection with the penis (p. 398). The urogenital sinus is narrow and tubular at its junction with the urethra; more distally it is wider and is shut off from the exterior by the cloacal membrane. After the embryo reaches a length of 16 to 17 mm., the membrane ruptures and the sinus opens on the surface.

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'''Fig. 323. From a model of the cloacal region of a human embryo slightly older than that shown in Fig. 322.''' Keibel.
: The arrow points to the developing partition (uroectal fold) between the rectum and urogenital sinus. The opening of the mesonephric duct into the urogenital sinus is indicated by a small seeker.

The narrow part of the sinus is gradually taken up into the wider, resulting in the formation of a sort of -vestibule. In both sexes the urethra opens into the deeper end of the vestibule. In the male the mesonephric (seminiferous) ducts open near the external orifice. In the female the opening of the developing vagina is situated on the dorsal side near the external orifice.

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'''Fig. 324. From a reconstruction of the caudal end of a human embryo of 11.5 mm. (4^ weeks).''' Keibel.

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'''Fig. 325. From a reconstruction of the caudal end of a human embryo of 25 mm.''' (8i-g weeks). Keibel. The asterisk (*) indicates the urorectal fold.

The epithelium of the prostate gland is derived by evagination from the proximal part of the urethra. The first evagination appears during the third month. In the male the process continues to form a rather large gland; in the female the structure remains in a rudimentary condition. During the fourth month two evaginations arise from the urethra and develop into the bulbo-urethral (Cowper's) glands in the male, into the larger vestibular (Bartholin's) glands in the female.

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'''Fig. 326. Transverse section through the germinal epithelium of a pig embryo of n mm.''' Nagel.

:The larger cells in the epithelium represent the sex cells, the smaller ones the undifferentiated mesothelial cells.

From the course of development it is seen that the epithelium of most of the bladder, of the female urethra and proximal end of the male urethra, of the prostate, of the urogenital sinus, and of the bulbo-urethral and vestibular glands is of entodermal origin. A very small part of the bladder epithelium is of mesodermal origin, since the proximal ends of the mesonephric ducts, which are mesodermal derivatives, are taken up into the wall. All the connective tissue and smooth muscle associated with these organs are derived from the mesoderm (mesenchyme) which surrounds the anlagen.

==The Genital Glands==

The Germinal Epithelium and Genital Ridge.

At a very early stage in the formation of the mesonephros, a narrow strip of mesothelium extending along the medial surface becomes thicker and the cells become arranged in several layers (Figs. 276 and 308). Two kinds of cells can be recognized in this (i) small cuboidal cells with cytoplasm which stains rather intensely, and (2) larger spherical cells with clearer cytoplasm and large vesicular nuclei (Fig. 326). The latter are the sex cells; and the whole epithelial (mesothelial) band is known as the germinal epithelium. The sex cells are destined to give rise to the sexual elements in the female to the ova, in the male to the spermatozoa. In the earlier stages, however, it is impossible to determine whether the sex cells will give rise to male or female elements. The differentiation of sex and the corresponding histological differentiation of the sex cells occur at a later period.

In his earlier work on the ovary and testis in Mammals, Allen has observed in very early stages (pig embryos of 6 mm., rabbit embryos of 13 days) certain large cells, with large clear nuclei, in the mesenchymal tissue of the mesentery, outside oj the genital ridge. In his investigation of the chick, Swift has discerned the sex cells at the time when the primitive streak and primitive axis are being formed. They are located in the entoderm and in the space between entoderm and ectoderm in the anterior part of the germ wall. When the mesoderm appears in this region the sex cells enter this layer, then enter the blood vessels. They are apparently amoeboid. By the blood stream they are carried to all parts of the blastoderm and embryo. Later the cells accumulate in the vicinity of the coelomic angle and finally enter the thickened mesothelium (germinal epithelium) of the genital ridge.

Beard, Eigenmann, Rabl, Woods, and others, have described sex cells, undoubtedly homologous with the early sex cells mentioned above, as occurring in various regions of the embryos of certain Fishes. These investigators also assert that the sex cells become specialized and, so to speak, segregated at a very early period of development, even at the stage of blastomere formation. Beard contends that the early differentiated sex (or germ) cells are significant in the origin of certain teratomata (see Chapter on Teratogenesis).

The cells of the germinal epithelium increase in number by mitotic division and the sex cells continue to increase in number by proliferation of their own members since there are no intermediate stages between the two types. The germinal epithelium soon becomes separated into two layers (i) a superficial layer which retains its epithelial character and contains the sex cells, and (2) a deeper layer composed of smaller cells which resemble those of the mesenchyme and which give rise to a part, at least, of the stroma of the genital glands. The elevation formed by these two layers projects into' the body cavity from the medial side of the mesonephros and constitutes the genital ridge (Fig. 308). From the superficial epithelial layer, columns or cords of cells, containing some of the sex cells, grow into the underlying tissue. This ingrowth, however, does not occur equally in all parts of the genital ridge, for three fairly distinct regions can be recognized. In the cephalic end comparatively few columns appear, but these few grow far down into the underlying tissue and constitute the rete cords. In the middle region a greater number of columns grow into the stroma, forming the sex cords. In the caudal region there are practically no columns. At first the line of demarkation between the cell columns and the stroma is not clearly defined.

The changes thus far described are common to both sexes and are completed during the fourth or fifth week. The genital ridges or anlagen of the genital glands constitute "indifferent" structures which later become differentiated into either ovaries or testicles.

==Differentiation of the Genital Glands==

After the fourth or fifth week, certain changes occur in the genital ridges which differ accordingly as the ridges form ovaries or testicles. While the differences are at first not particularly obvious, there are four which become clearer as the changes progress, (1) If the ridge is to become a testicle, the cells of the surface epithelium become arranged in a single layer and become flat. (2) In a developing testicle a layer of dense connective tissue grows between the surface epithelium and the sex cords, forming the tunica albuginea.

(3) In a testicle there also appears a sharper line of demarkation between the cell columns and the stroma, and the latter shows a more extensive growth.

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'''Fig. 327. Transverse section of the left testicle of a pig embryo of 62 mm.''' Bonnet.

(4) Another feature of the testicle is that the sex cells begin to be less conspicuous and do not increase furth2r in size, but come to resemble the other epithelial elements. The ovarian characters are to a certain extent the opposite. (i) The surface epithelium does not become flattened. (2) A layer of connective tissue, corresponding to the albuginea of the testicle, grows between the epithelium and the deeper parts, but is of a looser nature. (3) There is a less sharp line of demarkation between the cell columns and the stroma. (4) The sex cells continue to increase in size and become more conspicuous. (Compare Figs. 327 and 328.)

During these processes of development, the anlage of each genital gland becomes more or less constricted from the mesonephros and finally is attached only by a thin sheet of tissue the mesovarium in the female or the mesorchium in the male (p. 389). At the same time the anlage grows more rapidly in thickness than in length and assumes an oval shape.

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'''Fig. 328. Longitudinal section of the ovary of a cat embryo of 94 mm.''' Semidiagrammatic. Coert.

==The Ovary==

As stated above, a layer of loose connective tissue, corresponding to the albuginea of the testicle, grows in between the surface epithelium and the cell columns (sex cords) and effects a more or less complete separation. The sex cords are thus pushed farther from the surface, become more clearly marked off from the surrounding stroma and constitute the so-called medullary 'cords. The cortex of the ovary at this stage is represented only by the surface (germinal) epithelium, which is composed of several layers of cells and contains numerous sex cells in various stages of differentiation (Fig. 329). The rete cords which arise in the cranial end of the "indifferent" gland (p. 374) come to lie in what will be the hilus of the ovary. The ovary may thus be said to be composed of two parts (i) the rete anlage and (2) the stratum germinativum. The latter is subdivided by the albuginea into (a) medulla and (b) cortex.

1 . The rete cords develop into a group of anastomosing trabeculae which constitute the rete ovarii, situated in the hilus but nearer the cephalic end of the gland (Fig. 328). They are the homologues of the rete testis. The cells composing them are smaller and darker than those of the medullary cords. Sprouts grow out from the rete cords and unite with the medullary cords and the mesonephric tubules. (The same process occurs in the testicle, where the rete cords give rise to the functional rete testis and straight seminiferous tubules.) In some of the cords lumina appear and are lined with irregular epithelium. Such a condition represents the height of their development in the ovary. From this time on, they degenerate and finally disappear. The time of their disappearance varies in different individuals; they usually persist until birth, sometimes until puberty.

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'''Fig. 329. Transverse section of the ovary of a fox embryo.''' Buhler in Hertwig's Handbuch. The large clear cells are the primitive ova.

Formerly it was thought that the rete cords were derived from the mesonephric tubules and entered the genital glands secondarily. More recent researches have demonstrated quite conclusively, however, that they are derivatives of the germinal epithelium and unite with the mesonephric tubules secondarily.

2 (a). The medullary cords are composed of small epithelial cells, contain a number of larger sex cells or primitive ova, and are surrounded by stroma (Figs. 329, 330). They are connected with the rete cords and in some places with the germinal epithelium. During foetal life they give rise to primary ovarian (Graafian) follicles; later they degenerate and finally disappear.

2(b). The cortex of the ovary, as stated above, at first consists of several layers of small, darkly staining cells, among which are many large, clearer sex cells or primitive ova (Fig. 329). From the epithelium, masses or cords of cells grow into the underlying tissue, carrying with them some of the primitive ova. These masses are known as Pfluger's egg cords. In some cases several ova are grouped together, forming egg nests (Fig. 330). The epithelial cells are the progenitors of the follicular cells and constantly undergo mitotic division. The primitive ova, on the other hand, increase in size and their nuclei show distinct intranuclear networks.

The egg cords become separated from the surface epithelium and are broken up so that in most cases a single ovum is surrounded by a single layer of epithelial cells. This constitutes a primary Graafian follicle. Rarely a follicle contains more than one ovum. In the case of the egg nests, the ova may become separated, or two or more may lie in one follicle. If two or more ova are present at first in any follicle, usually only one continues to develop and th( others either degenerate or are used as nutritive materials. In very rare cases, however, two ova may develop in a single follicle, but whether they reach maturity or not is uncertain. The formation of egg cords is usually completed before birth, but in some cases may continue for one or two years after birth. During the processes thus far described, the stroma also has been increasing, and the egg cords and follicles come to be separated by a considerable amount of connective tissue. The germinal epithelium becomes reduced to a single layer of cuboidal cells.

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'''Fig. 330. From a section through the ovary of a human foetus of 4 months.''' Meyer-Ruegg, Buhler. The large cells are the primitive ova.

Each primary ovarian follicle, containing a primitive ovum (egg cell, sex cell) , is composed of a single layer of flat or cuboidal cells, plus a layer of stroma which gives rise to the theca folliculi. As the ovum continues to enlarge, the follicular cells become higher and arranged in a radial manner (Fig. 331, a) . By proliferation, the follicular cells come to form several layers, the innermost layer retaining the radial character and forming the zona radiata. The inner or basal ends of the cells of the zona radiata become clear to form the zona pellucida. In the latter, radial striations appear which have been described as minute channels in the cells, through which nutriment may pass to the ovum. After the follicular epithelium has become several layers thick, a fluid substance known as the liquor folliculi, and probably derived from the cells themselves, comes to lie in little pools among the cells (Fig. 33 1, b and c ) . While the follicle as a whole enlarges, these pools gradually coalesce and form a single large pool which fills the interior of the follicle (Fib. 331, d). Thus the epithelium is crowded out toward the periphery where it forms a layer several cells in thickness, known as the stratum granulosum. The ovum itself, with the zona radiata and some other surrounding cells, is also crowded off to the periphery of the follicle. The little elevation of the stratum granulosum in which the ovum is embedded is known as the cumulus ovigerus or germ hill (see Fig. i).

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'''Fig. 331. Four stages in the development of the ovarian (Graafian) follicle.''' From photographs of sections of a cat's ovary Hertwig. The ovum is not shown in a, b and c.

The primary ovarian follicles at first lie rather near the surface of the ovary, but as they enlarge and as the ovary enlarges they come to lie deeper. As the follicle approaches maturity it increases greatly in size (5=*= mm.) and finally extends through the entire thickness of the cortex, its theca touching the tunica albuginea.

In speaking of the development of the follicles, it must be remembered that they develop slowly and do not reach maturity until near the age of puberty, and furthermore that one, or very few at most, reach maturity at the same time. In other words, when one follicle has reached m iturity there are all intermediate stages of development between this and the primitive follicles. When a follicle reaches maturity it ruptures at the surface of the ovary and the ovum is set free (p. 24). The ovum itself undergoes certain changes by which the somatic number of chromosomes is reduced one-half (p. 16). It then unites with the mature spermatozoon, which also contains one-half the somatic number of chromosomes, and forms the starting point, so to speak, for a new individual. At this point the processes by which an individual is carried through its life period from its beginning as a fertilized ovum to the time when it produces the next generation of mature sexual elements are ended. The developmental cycle of one generation is complete.

It has been estimated that approximately 36,000 primitive ova appear in each human ovary. Since, as a rule, only one ovum escapes from the ovary at menstrual period or between two succeeding periods, it is obvious that the vast majority of these never reach maturity. They probably degenerate, and, as matter of fact, atretic follicles may be found in an ovary at any time.

==Corpus Luteum==

After the rupture of the mature follicle at the surface the ovary and the escape of the ovum and liquor folliculi, blood from the rup tured vessels fills the interior of the follicle and forms a clot the corpus hcemorrhagicum. The cells of the stratum granulosum proliferate and , migrate into the clot and gradually form a mass which replaces the blood. It is held by some that the cells are derived from the theca folliculi. Whatever their origin, they become infiltrated with a fatty substance known as lutein. Trabeculae of connective tissue grow into the mass of cells, carrying small blood vessels with them. The (lutein) cells disintegrate and the products of disintegration are probably carried off by the blood, and finally the entire corpus luteum is transformed into a mass of connective tissue.

Whether the escaped ovum is fertilized or not has an influence upon the development of the corpus luteum. In case of fertilization, the corpus luteum becomes quite large, increasing in size up to the fourth month of pregnancy, and then degenerates. In case the ovum is not fertilized, the corpus luteum remains smaller. In both cases, however, the histological changes are essentially the same.

==The Testicle==

The processes that give rise to the "indifferent" genital glands have been described (p. 373 et seq.}. It has also been stated that there appears during the fourth or fifth week a structure that forms one of the characteristic features of the testicle. This is a layer of dense connective tissue which develops beneath the surface epithelium and constitutes the tunica albuginea (p. 375), and which separates the surface epithelium from the sex cords (Fig. 327) . The epithelium becomes reduced to a single layer of flat cells, although the cells on the tip of the gland usually remain high until after birth. Naturally this epithelium is continuous around the hilus of the testicle with the epithelium (mesothelium) of the abdominal cavity. Within the gland are the sex cords the progenitors of the convoluted seminiferous tubules, which become quite distinctly marked off from the stroma by a basement membrane. In the hilus region lie the rete cords the progenitors of the rete testis and the straight seminiferous tubules (Fig. 327) . The rete cords of the testicle are homologues of the rete cords of the ovary, and are derivatives of the germinal epithelium on the cephalic portion of the "indifferent" gland (p. 374).

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'''Fig. 332. From a section of the testicle of a human foetus of 35 mm'''. Showing a developing convoluted seminiferous tubule. Meyer-Ruegg, Biihler.

The sex cords at first are solid masses composed of several layers of cells. The latter are of two kinds, as in the ovary (i) smaller, darkly staining indifferent cells, and (2) larger, clearer sex cells (Fig. 332). The sex cells lose their clearness and come to resemble again the undifferentiated epithelial cells. They represent the spermatogonia, which correspond to the primitive ova. The spermatogonia proliferate very rapidly and become much more numerous than the epithelial cells. The sex cords become more and more coiled during development and anastomose with one another near the convex surface of the testicle. Beginning after birth and continuing up to the time of puberty, lumina appear in them by displacement of the central cells, and they thus give rise to the convoluted seminiferous tubules. The supporting cells (of Sertoli) are probably derived from the undifferentiated epithelial cells.

The details of the further development of the spermatogonia to form the the spermatozoa have been described in the Chapter on Maturation. At this point, that is, with the formation of the spermatozoon, the life cycle from a mature male sexual element in an individual to a mature male sexual element in an individual of the succeeding generation is completed.

The rete cords constitute an anastomosing network of solid cords of small, darkly staining cells, situated in the hilus region. These cords later acquire irregular lumina, which are lined with cubpidal cells, and form the rete testis. Evaginations grow out from the rete and fuse with the ends of the convoluted tubules, thus forming the straight tubules. On the other hand, outgrowths from the rete unite with the tubules in the cephalic portion of the mesonephros, so that a direct communication is established between the convoluted seminiferous tubules and theinesonephric tubules. There is thus formed the proximal part of the efferent duct system of the testicle (Fig. 327). That portion of the tunica albuginea in which the rete testis lies, becomes somewhat thickened to form the mediastinum testis.

The stroma of the testicle is derived for the most part from the mesenchyme of the "indifferent" gland or genital ridge. Probably a smaller part is derived from the germinal epithelium (see p. 374)- During development, however, the glandular elements increase more rapidly than the stroma, so that in the adult they predominate. There is a tendency for the convoluted tubules to become arranged in groups which are separated by trabeculae of connective tissue radiating from the mediastinum. The interstitial cells of the stroma are direct derivatives of the connective tissue cells (Fig. 332).

==Determination of Sex==

The views regarding the determination of sex are discussed in the chapter on Maturation (page 21) in connection with the question of Mendelian heredity.

The Ducts of the Genital Glands and the Atrophy of the Mesonephroi.

In the Female. Strictly speaking, the ovaries are ductless glands; for neither developmentally nor anatomically are the ducts which convey their specific secretion directly connected with them. Furthermore, these ducts are in part transformed into certain organs for the reception and retention of both kinds of sexual elements. In other words, the ducts in part become specially modified to form the vagina and uterus, of which the latter serves as an organ of maintenance for the embryos of the next generation.

The ducts originate in connection with the mesonephroi, and are known at first as the Mullerian ducts. They appear in both sexes alike but persist only in the female. In the lower Vertebrates they are split off from the mesonephric ducts. In the higher forms, however, their mode of origin is not known with certainty, but the present evidence favors the view that they arise independently of the mesonephric ducts. They appear in human embryos of 8-14 mm. The mesothelium on the lateral surface of the cephalic end of each mesonephros becomes thickened and then invaginates or dips into the underlying mesenchyme. By proliferation of the cells at its tip, the invaginated mass grows caudally as a duct parallel with and close to the mesonephric duct. The two ducts come to be embedded in a ridge which at the cephalic end of the mesonephros is situated laterally, but toward the caudal end bends around and comes to lie ventrally. Beyond (caudal to) the mesonephros the ridge is attached to the lateral body wall, and near the urogenital sinus it meets and fuses with its fellow of the opposite side (Fig. 333).

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'''Fig. 333. From a transverse section through the pelvic region of a human embryo of 25 mm. (8 -9 weeks).''' Keibel.

The two Mullerian ducts, contained in the ridges, also approach each other and fuse. The fusion begins in embryos of 25 to 28 mm. (end of second month), and about the same time they open into the dorsal side of the urogenital sinus. The relations of the Mullerian and mesonephric ducts are different in different parts of their courses. At the cephalic end the Miillerian lies dorsal to the mesonephric, but farther back it runs more laterally, then ventrally, and finally opens into the urogenital sinus on the medial side of the mesonephric duct.

==The Oviduct==

The single part of each Mullerian duct gives rise to the oviduct. The opening at the cephalic end remains as the ostium abdominale tuba, which from the beginning communicates directly with the abdominal cavity (ccelom) and never becomes connected with the ovary (Fig. 328). The rim of the opening sends from three to five projections into the abdominal cavity to form the primary fimbria. Secondary branches grow out from these and form the numerous fimbriae of the adult oviduct. The part of each

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'''Fig. 334. Right half of the pelvic region of a female human foetus of 7 months.''' Nagel.

Mullerian duct between the fimbriated end and the fused caudal end, grows in length as the embryo develops, but not proportionately, so that in the adult the oviduct is relatively shorter than in the embryo. At first it is lined with simple cylindrical epithelium, but later the cells become cuboidal, and during the second half of f octal life acquire distinct cilia. The connective tissue and muscle of the oviduct are derived from the mesenchyme that primarily surrounds the Miillerian duct.

In connection with one of the fimbriae of the oviduct there is sometimes found a small vesicle lined with ciliated epithelium, forming the non-stalked hydatid (of Morgagni), which possibly represents the extreme cephalic end of the Miillerian duct (Fig. 342). In this case the permanent ostium of the tube would be of secondary origin.

==The Uterus and Vagina==

The fused caudal ends of the two Mullerian ducts form the anlage of the uterus and vagina, which is a single medial tube opening into the urogenital sinus (Fig. 325). During the third month certain histological changes bring about a differentiation between the cephalic end or uterus and the caudal end or vagina. The simple columnar epithelium of the vaginal portion changes to stratified squamous, and during the fourth month the lumen becomes closed. Near the external orifice a semicircular fold appears, which represents the hymen (Fig. 334). During the sixth month the lumen reappears by a breaking down of the central cells. The epithelium of the uterus, primarily high columnar, becomes lower and toward the end of foetal life acquires cilia. Many irregular folds appear in the mucosa of the vagina, a smaller number in the uterus (Fig. 334). Some of the folds in the uterus constitute the regular plica palmata of the cervix. The uterine glands represent evaginations from the epithelial lining. They do not begin to develop until after birth (one to five years), and their development is usually not completed until the age of puberty.

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'''Fig.335. Transverse section through the ovary and broad ligament of a human foetus of 3 months.''' Nagel.

The muscle and connective tissue of the walls of the uterus and vagina are derived from the mesenchyme which surrounds the Mullerian ducts. The muscle develops relatively late (after the fourth month of foetal life).

==Atrophy of the Mesonephroi==

By far the greater part of each mesonephros degenerates and disappears, and the parts that do persist are rudimentary and possess no functional significance. The cephalic portion leaves ten to twenty coiled tubules which terminate blindly at one end and at the other end open into a common duct that represents the cephalic end of the mesonephric duct. These tubules constitute the epoophoron (parovarium, organ of Rosenmiiller) which comes to lie in the mesosalpinx between the oviduct and the mesovarium, and later in the mesentery between the oviduct and the ovary (Fig. 335). At the height of their development the tubules are lined with columnar, ciliated epithelium. The rete cords of the ovary (rete ovarii, p. 377) during their development unite with the tubules in the cephalic portion of the mesonephros, but later disappear. The epoophoron is homologous with the tubules of the head of the epididymis in the male.

The caudal portion of the mesonephros leaves a few tubular remnants which come to lie in the broad ligament near the hilus of the ovary. These constitute the paroophoron which is homologous with the paradidymis in the male (Fig. 335). They may disappear before birth or may persist through life.

The mesonephric duct also leaves certain remnants which are situated (i) in the broad ligament, (2) in the lateral wall of the uterus, (3) in the lateral wall of the vagina, and (4) in the tissue lateral to the external genital opening. These remnants are known as the canals of Gartner, and they naturally lie in the course of the duct in the embryo. All the rudimentary structures derived from the mesonephroi and their ducts are extremely variable.

In the Male. In the male all the efferent ducts of the genital glands, except the rete testis, are derived from the mesonephroi and their ducts. As described earlier in this chapter (p. 381) , the rete testis acquires a connection with some of the tubules in the cephalic end of the mesonephros and with the sex cords or anlagen of the convoluted and straight seminiferous tubules (see Fig. 327). This establishes a communication between the seminiferous tubules and the tubules of the mesonephros. Those mesonephric tubules with which the rete testis unites persist as the efferent ductules (or vasa eff erentia) . The latter form a set of coiled ducts which are situated in the head of the epididymis and which open into the cephalic part of the mesonephric duct (Fig. 309). They are homologous with the epoophoron in the female.

The next succeeding portion of the mesonephric duct becomes the duct of the epididymis which in its tortuous course constitutes the bulk of the body and tail of the epididymis and passes over into the caudal portion of the mesonephric duct. The latter portion becomes the deferent duct (vas def erens) . The caudal end of the deferent duct forms the ejaculatory duct which opens into the urogenital sinus. The seminal vesicles appear during the third month as lateral evaginations from the ejaculatory ducts.

The portions of the mesonephros not involved in the formation of the duct system of the testicle atrophy and for the most part disappear. They leave certain tubules, however, which persist as rudimentary structures connected with the testicle. In the cephalic end, some of the tubules persist in part and come to lie among the efferent ductules, being either attached to the latter or unconnected, and forming the appendage of the epididymis. The caudal part of the mesonephros leaves a few tubules which come to lie near the head of the epididymis and form the paradidymis (or organ of Giraldes), the tubules of which are lined with columnar, ciliated epithelium. Near the transition from the duct of the epididymis to the deferent duct there is almost invariably a tubule (sometimes branched) which also represents a remnant of the mesonephros and is known as the aberrant ductule. It usually opens into the duct of the epididymis, but may lie free in the tissue around it (Fig. 309).

==Atrophy of the Mullerian Ducts==

These ducts persist in the female and become the oviducts, uterus and vagina; in the male they degenerate and disappear almost entirely. The degeneration begins about the time they open into the urogenital sinus (embryos of 25 to 28 mm.) ; by the time the embryo reaches a length of 60 mm. only the extreme cephalic end and the caudal third remain, and at 90 mm. the entire duct is gone except the extreme ends. The cephalic end persists as the appendix testis (or hydatid of Morgagni) (Figs. 309, 341). The caudal end persists as the utriculus prostaticus (uterus masculinus).

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'''Fig. 336. Urogenital organs in a human embryo of 17 mm. (6 weeks).''' Kollmann's Alias.

Changes in the Positions of the Genital Glands and the Development of their Ligaments.

During the early stages of development the genital glands testicles or ovaries are situated far forward in the abdominal cavity. During the eighth week they lie opposite the lumbar vertebrae. During the succeeding months, up to the time of birth, they gradually move caudally to the positions they occupy in the adult. This migration is brought about, to some extent at least, by the influence of certain bands of tissue which are primarily like mesenteries. As the mesonephros develops and projects into the body cavity it comes to be attached along the dorsal body wall, lateral to the dorsal mesentery, by a sheet of tissue which is called the mesonephric mesentery. Cranial to the mesonephros, this mesentery is continued as the diaphragmatic ligament of the mesonephros, which as the name indicates, is attached to the diaphragm; caudally it is continued to the inguinal region as the inguinal ligament of the mesonephros (Fig. 336). The genital gland lies on the medial side of the mesonephros and is attached to the latter by a sort of mesentery which becomes the mesovarium in the female or the mesorchium in the male. The cephalic portions of the ducts (Miillerian and mesonephric) lie close together in a ridge on the lateral surface of the mesonephros; as they pass caudally they extend around to the ventral surface of the mesonephros and approach the medial line, and finally, in the pelvic region, the two ridges meet and fuse, forming the socalled genital cord (Fig. 333). The genital cord thus contains the mesonephric and Miillerian ducts, the latter fusing to form a single tube (the anlage of the uterus and vagina, p. 385). It also contains the umbilical arteries.

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'''Fig. 337. From a dissection of the pelvic region of a male human foetus of 21 cm.''' Kollmann's Atlas.

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'''Fig. 338. From a dissection of the scrotal region of a human foetus of 25 cm.''' Kollmann's Atlas.

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'''Fig. 339. From a dissection of the pelvic region of a female human foetus of 7.5 cm.''' Kollmann's Atlas.

Such a condition is found in embryos of about eight weeks. From this time on, the processes of development follow divergent lines in the two sexes, the differences becoming more marked from month to month. Certain structures persist and othersdisappear, according to the sex. The mesenteries and ligaments undergo metamorphoses and the genital glands migrate caudally.

==Descent of the Testicles==

As the mesonephros atrophies, its mesentery and the mesentery of the testicle are combined to form a single band of tissue which, of course, is continuous with the inguinal ligament. The latter now becomes the so-called gub.ernaculum testis (Hunteri), a strong band or cord composed of connective tissue and smooth muscle. Its cephalic end is attached to the epididymis; its caudal end pierces the body wall in the inguinal region and is attached to the corium of the skin (Fig. 337). It plays an important part in the descent of the testicle. The descent is brought about through the principle of unequal growth. As the body grows in length, the gubernaculum grows much less rapidly and, since the caudal end of the latter is fixed, the natural result is the drawing downward of the testicle. This takes place gradually, and at the end of the third month the testicle lies in the false pelvis; at the end of the sixth month close to the body wall at the inguinal ring.

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'''Fig. 340. Diagrammatic representation of the urogenital organs in the "indifferent" stage.''' Hertwig.

During the third month a second factor in the descent of the testicle appears. This is an evagination of the peritoneum at the point where the gubernaculum pierces the body wall. The evagination at first is a shallow depression, known as the processus vaginalis peritonei, but continues to burrow through the body wall and causes an elevation in the skin which is destined to become one side of the scrotum (see p. 396) . The opening of the peritoneal sac into the body cavity is the inguinal ring. In its descent the testicle passes through the inguinal ring and comes to lie in the elevation in the skin or scrotum (ninth month) . Whether its passage into the scrotum is the result of a traction by the gubernaculum is not certain. The inguinal ring then closes by apposition of its walls and the testicle lies in a closed sac which has been pinched off, so to speak, from the body cavity (Fig. 338).

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Fig. 341. Diagram of the development of the male genital organs from the "indifferent" anlagen. Hertwig.

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'''Fig. 342. Diagram of the development of the female genital organs from the "indifferent" anlagen.''' Hertwig. These diagrams should be compared with Fig. 340. The dotted lines represent the organs in the relative positions they occupy in the adult (with the exception of the Mullerian duct in the male and the mesonephric duct in the female, which ducts disappear for the most part).

Since the testicle is invested by peritoneum from the beginning of its development, it must be understood that in its passage into the scrotum it passes along under the peritoneum. Consequently when it reaches the scrotum it is surrounded by a double layer of peritoneum, the tunica vaginalis propria.

The descent of the testicle also produces marked changes in the course of the deferent duct. Primarily the (mesonephric) duct extends cranially from the urogenital sinus in a longitudinal direction. But as the testicle migrates, the cephalic end of the duct is drawn caudally so that in the adult the deferent duct extends cranially from the scrotum to the ventral side of the urinary bladder and then bends caudally again to open into the urethra.

==Descent of the Ovaries==

The ovaries undergo a change of position corresponding to the descent of the testicles, although the change is not so extensive. Primarily the Miillerian and mesonephric ducts lie in a ridge on the surface of the mesonephros (p. 383). As the mesonephros and its duct atrophy, the Miillerian duct (oviduct) comes to lie in a fold, the mesosalpinx, which is attached to the mesovarium (Fig. 335) . At the same time the mesovarium becomes directly continuous with and really a part of the inguinal ligament. The latter corresponds, of course, to the gubernaculum testis, and plays a role in the descent of the ovaries. It may be conveniently divided into three parts, (i) a cephalic part which is attached to the hilus of the ovary, (2) a middle part which extends from the ovary to the uterus, forming the ovarian ligament, and (3) a caudal part which extends from the uterus to the inguinal region, forming the round ligament of the uterus (Fig. 339). The round ligament pierces the body wall and is attached to the corium of the skin. At the point where it passes through the body wall there is a slight evagination of the peritoneum, the diverticulum of Nuck, which corresponds to the processus vaginalis peritonei in the male.

The ovaries gradually migrate caudally from their original position into the false pelvis (third month) and thence into the true pelvis (at birth) . Obviously no traction can be exerted upon them by the round ligament (or caudal part of the inguinal ligament) , since the latter extends from the uterus to the inguinal region. Their descent into the pelvic seems to be due to the unequal growth of the ovarian ligaments, or in other words, to the fact that the ovarian ligaments grow proportionally less than the surrounding parts. During their descent the ovaries become embedded in the broad ligaments of the uterus, which represent further development of the peritoneal folds of the genital cord. In this way the mesovarium becomes merged with the broad ligament.

On pages 390 and 391 are three diagrammatic representations of the changes that take place in the genital systems of the two sexes. Fig. 340 represents the "indifferent" stage in which all the embryonic structures are present; Fig. 341 represents the changes that occur in the male; Fig. 342 represents the changes that occur in the female. A careful study of the diagrams will assist the student materially in understanding the processes of development which have been described in the preceding paragraphs.

Below is a table that is meant to set forth briefly the various structures which belong to the internal genital organs in the two sexes, and which are derived from the structures in the "indifferent" stage. The words in italics are the names of structures that persist in a rudimentary form.

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==The External Genital Organs==

In addition to the internal organs of generation, to which the description has thus far been confined, certain other structures appear on the outside of the body to form the external genitalia. In the case of these also there is an " indifferent" stage from which the courses of development diverge in the two sexes.

During the sixth week a depression appearing on the ventral surface of the caudal end of the body indicates the position of the cloacal membrane (p. 370). This becomes surrounded by a slight elevation, produced by the thickening of the mesoderm which is known as the genital ridge (Fig. 343). The cephalic side of the ridge becomes raised still farther above the surface, forming a distinct protrusion, the genital tubercle. The tubercle continues to increase in size, and the distal end forms a knob-like enlargement. Along the ventral (or rather caudal) side a groove appears, which extends distally as far as the base of the enlarged end. The ridges along the sides of the groove increase in size and form the genital folds. In the meantime a second pair of elevations appears lateral to the genital folds to form the genital swellings (Fig. 344).

After the cloacal membrane ruptures, a single opening is produced which leads from the exterior into the cloaca. This opening is then separated by the further growth of the urorectal fold (p. 370) into the opening of the urogenital tract and the anal opening. The caudal part of the fold then enlarges to form the perineal body, which serves to push the anus farther away from the genital ridges. The latter, together with the genital tubercle and swellings, all of which lie in the immediate vicinity of the urogenital opening, constitute the anlagen of the external genital organs (Fig. 345). These at this time are in the "indifferent" stage, from which development proceeds in one of two directions, accordingly as the embryo is a male or a female. Up to the fourth month there is little difference between the structures in the two sexes. After this the differences become more and more obvious.

In the female the changes in the originally "indifferent" structures are comparatively slight. The genital tubercle grows slowly and becomes the clitoris. The enlarged extremity becomes more clearly marked off from the other part to form the glans clitoridis. The skin covering the glans is converted by a process of folding into a sort of prepuce. The genital folds, which bound the opening of the urogenital tract, become elongated and form the labia minora. The opening of the urogenital tract is the vestibulum vagina. The genital swellings enlarge still more than the genital folds, by a deposition of a considerable mass of fat in the mesenchyme, and become the labia majora. The latter are the structures (mentioned on p. 390) which mark the points at which the inguinal ligaments of the mesonephroi pierce the body wall, and are homologous with the scrotum in the male (Figs. 346 and 347).

In the male the "indifferent" anlagen undergo more extensive changes than in the female. The genital tubercle continues to grow more rapidly and forms the penis, which is homologous with the clitoris. The enlarged extremity becomes the glans penis, and an extensive folding of the skin over the glans forms the prepuce. The groove on the caudal or lower side of the tubercle elongates as the latter elongates and becomes deeper. Finally the ridge (or genital fold) on each side of the groove meets and fuses with its fellow of the opposite side, thus enclosing within the penis a canal the penile portion of the urethra. The groove is primarily continuous with the opening of the urogenital tract, and as the fusion takes place the penile portion forms a direct continuation of the internal (membranous and prostatic) portion of the urethra. The genital swellings also fuse and form the scrotum, the line of fusion in the medial line becoming the raphe (Fig. 348) . Primarily the inguinal ligaments of the mesonephroi are attached to the corium of the skin in the genital swellings, and as the testicles descend they pass through the inguinal ring into the scrotum. In a sense the scrotum represents an evagination of the body wall

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'''Figs. 343-348. Stages in the development of the external genital organs.''' Kollmann's Atlas.

:indifferent " stage embryo of 17 mm.; Fig. 344, " indifferent " stage embryo of 23 mm ; g. 345, " indifferent " stage embryo of 29 mm. (beginning of 3d month) ; Fig. 346, female embryo of 70 mm. (n weeks); Fig. 347, female embryo of 150 mm. (16 weeks); Fig. 348, male embryo of 145 mm. (16 weeks).

:An., Anus; CL, clitoris; Clo.and gen. /., cloaca and genital folds; Cl. m., cloacal membrane; Ext. y lower extremity; Gen. /., genital folds; Gen. r., genital ridge; Gen. sw., genital swelling; Gen. tub., genital tubercle; Gl. p., glans penis; Lab. ma., labium majus; Lab. mi., labiura minus; Ra., raphe of scrotum; Scr., scrotum; Ta., tail; Ug. s., urogenital sinus; Umb. c, umbilical cord.

==The Development of the Suprarenal Glands==

Although the suprarenal glands do not logically come under the head of the urogenital system, being neither functionally nor developmentally a part of the latter, it is most convenient to consider them in this chapter.

In Mammals including man these glands are composed of two parts which can be differentiated histologically and topographically the cortex and medulla. The cortex is composed of trabeculae and spheroidal masses of cells which do not have a strong affinity for the ordinary cytoplasmic stains am which contain granules of a fat-like substance known as lipoid granules. Th( medulla is composed of irregularly arranged sympathetic ganglion cells am other granular cells which, after treatment with chrome salts, acquire a pea brownish color. The brown cells are known as chromaffin (or phaeochrome) cells and their granules as chromaffin (or phaeochrome) granules. As cort( and medulla are distinct anatomically, they are also distinct developmentally, being derived from two distinct and different parent tissues which unite secondarily. Furthermore, it is an interesting fact that in the lower Vertebrates (Fishes) the two parts remain permanently separate; that in the ascending scale of animal life (Amphibia, Reptiles, Birds) they become more closely associated; and that finally (in Mammals) they unite to form a single glandular structure. In Mammals the phylogenetic history is repeated with remarkable precision during the development of an individual : The two parts arise separately, come closer together, and finally unite.

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'''Fig. 349. Section of a sympathetic ganglion in the coeliac region of a frog (Rana esculenta)''' Showing differentiating phaeochrome cells. Giacomini.

===The Cortical Substance===

The cortex is of mesothelial (mesodermal) origin. In embryos of five to six mm. the mesothelium at the level of the cephalic third of the mesonephros proliferates and sends buds or sprouts into the mesenchyme at each side of the root of the dorsal mesentery. These sprouts soon lose their connection with the parent mesothelium and unite with one another to form a rather compact mass of epithelial-like cells ventro-lateral to the aorta (Fig. 276). Frequently the two masses fuse across the medial line ventral to the aorta. They constitute the anlagen of the cortical substance of the two suprarenal glands. From the fact that in the lower forms they remain separate from the medullary substance and lie between the urinary organs, they are known as the inter renal organs.

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F'''ig. 350. From a transverse section of a 40 mm. pig embryo.''' Showing the growth of the medullary substance into the cortical substance of the suprarenal gland. The vessel in the center of the figure is the aorta. Wiesel.

===The Medullary Substance===

A little later than the appearance of the cortical anlage, the cells of some of the developing sympathetic ganglia become differentiated into two types (i) the so-called sympathoblasts which develop into sympathetic ganglion cells, and (2) phaochromoblasts which are destined to give rise to the phaeochome or chromafiin cells (Fig. 349). Hence the chromaffin cells are derivatives of the ectoderm, since the ganglia are of ectodermal origin.

They soon become more or less separated from the ganglia, migrate to the region of the cortical anlagen and then penetrate the latter in cord-like masses (Fig. 350). Finally these masses unite in the interior of the cortical substance to form a single compact mass (Fig. 351) . Along with the phaeochrome masses, sympathoblasts also are carried in and give rise to the sympathetic ganglion cells within the gland. The two types of cells together constitute the medullary substance. In the lower forms the phaeochrome masses remain separate from the cortical substance and are known as the suprarenal organs. In Mammals the two sets of organs (interrenal and suprarenal) unite to form the suprarenal gland.

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'''Fig. 351. Section of the suprarenal gland of a 119 mm pig embryo.''' Cor., Cortex; Cor.*, some cortical substance in the center of the gland; Med., medulla. Wiesel.

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[[File:Bailey352.jpg|thumb|'''Fig. 352. Diagram of the developing phaeochrome masses in a human foetus of 50 mm.''' A, Aorta; N ; . cortical substance (interrenal gland) ; U, ureter; R, rectum. Kohn.]]

At the time when the mesonephros is fully developed, the cortical substance forms a small oval body near its cephalic end. During the union of the cortex and medulla and the atrophy of the mesonephros, the suprarenal gland becomes more closely associated with the cephalic end of the kidney, and by the middle of the third month has practically reached its adult position. During the third month and the first half of the fourth month the glands increase in size and become relatively large structures, larger in fact than the kidneys. From the fourth month on, they grow proportionately less than the neighboring organs, and by the sixth month are about half as large as the kidneys. At birth the ratio of their weight to that of the kidneys is about 1:3; in the adult about 1:128.

While perhaps in a normal course of development all the anlagen are united in the adult suprarenal gland, it is not unusual to find accessory structures in various places. Some of these consist of cortical tissue only and are usually found in or near the capsule of the gland. Others may consist of both cortical and medullary substances, and are found in the vicinity of or embedded in the kidneys, in the retroperitoneal tissue near the kidneys, in the walls of neighboring blood vessels, or associated with the internal genital organs in the rete testis or epididymis, or in the broad ligament. These accessory structures may arise independently of the main gland, or they may be portions of the main gland which were separated during the union of the different anlagen of the latter and were carried away in the descent of the genital glands.

In addition to the chromamn tissue which enters into the formation of the main gland or of accessory glands, there are other small masses of this tissue which remain permanently associated with some of the prevertebral and peripheral sympathetic ganglia.

Recent researches have shown that the Carotid Skein (glomus caroticum, intercarotid ganglion, carotid gland), which formerly was believed to be a derivative of the epithelial lining of one of the branchial grooves, is of sympathetic origin and that the cells acquire the characteristic chromaffin reaction. These facts indicate that it is closely allied with the medullary substance of the suprarenal gland.

==Anomalies==

===The Kidneys===

Rarely is there congenital absence of both kidneys. More often there is a high degree of aplasia in both organs in otherwise well-developed children. In either case death necessarily soon follows. Not infrequently one kidney, usually the left, is poorly developed or absent and a compensatory enlargement of the other exists. Such malformations are due to deficient development of the organs, but the causes underlying the deficient development are obscure.

One of the most common malformations is the abnormal position of one or both kidneys (ectopia of the kidneys). Usually they occupy a position lower than the normal in the abdominal cavity, which indicates that they have failed, during development, to migrate forward to the normal limit (see p. 369). Very rarely one or both organs migrate beyond the normal limit, in which case they occupy positions cranial to the normal.

Not infrequently the lower ends of the two kidneys are fused across the medial line, giving rise to the so-called "horseshoe kidney." Two renal pelves and ureters are usually present. Occasionally the fusion is so extensive that a single flat mass is formed. This occupies a medial position or lies at either side of the medial line, and may be situated at the normal level or lower. The renal pelvis may be single or double, with one or two ureters. In cases of double ureters and pelves it seems most likely that the anlagen of the kidneys have fused secondarily, that is, after the evagination from the mesonephric ducts (p. 361) . In cases where the pelvis and ureter are single, the fusion may have occurred secondarily, although there is the possibility that only a single anlage appeared.

Occasionally in children and even in adults the kidneys show a distinct lobulation. This is due to the persistence of the lobulation that normally exists in the foetus (p. 367).

The kidney may be more or less movable owing to laxity of the surrounding tissue, or it may Refloating, in which case it has a distinct mesentery. These cases should be distinguished from those in which similar conditions have been acquired, usually as the result of trauma.

Congenital cysts of the kidney are not uncommon. They vary in size and number, sometimes being so numerous that they crowd out the greater part of the renal tissue. Rarely they are so large and numerous that the affected organ fills a large part of the abdominal cavity, resulting in serious or even fatal disturbances of the functions of other organs. There are three views concerning the origin of these cysts, (i) They may be the result of dilatation of certain renal tubules derived from the nephrogenic tissue, which failed to unite with the straight tubules (p. 363). (2) Inflammation in the medulla of the foetal kidney may effect a closure of the lumina of some of the tubules, with subsequent dilatation of the portions (tubules. or renal corpuscles) that are cut off from communication with the renal pelvis. (3) Normally some of the renal corpuscles and tubules degenerate (p. 369), and the,cysts may arise as dilatations of incompletely degenerated corpuscles or tubules or both. While these views appear reasonable, none of them has been proven. All three views express possibilities, and there is no good reason for believing that any one of them expresses the only possibility.

===The Ureters===

The renal pelvis is sometimes absent, the calyces uniting to form two or more tubes which in turn unite to form the ureter. This probably is the result of abnormal branching of the ureter during development and the failure of the ends of the branches to become dilated. Occasionally the ureter is double or triple throughout the whole or a part of its length. The most reasonable explanation of two or three complete ureters on either side is that two or three separate evaginations arose from the mesonephric duct (p. 361.) Where the tube is double in only a part of its length, an abnormal branching of the single original evagination is indicated. Atresia of one or both ureters is occasionally met with. This probably represents a secondary constriction after the ureter is formed since both ex-aginations are hollow from the beginning (p. 391), but the cause of the constriction is not understood. The atresia results in dilatation of the portion of the ureter on the side toward the kidney.

Abnormal situations of the openings are sometimes seen, the explanation of which is to be found in the relations of these tubes to the mesonephric ducts, to the cloaca, and to the Miillerian ducts. In the male the ureters may open into the seminal vesicles, the prostatic urethra, or the rectum. If one recalls that the ureter arises as an evagination from the mesonephric duct near the opening of the latter into the cloaca (p. 361), that the cloaca becomes separated into a dorsal part (the rectum) and a ventral part (the urogenital sinus) (p. 370), and that the proximal end of the mesonephric duct is so far taken up into the wall of the urogenital sinus (or bladder) that the ureter opens separately (p. 370), it is readily seen that any interference with these normal processes of development will result in abnormal opening of the ureter. If the ureter does not become separated from the mesonephric duct, it will open into the deferent duct (vas deferens), the latter being the proximal part of the mesonephric duct. And since the seminal vesicle is an outgrowth from the proximal end of the mesonephric duct, the opening of the ureter is likely to be associated with the vesicle^ If the separation between the ureter and mesonephric duct is complete, but the opening of the ureter does not migrate cranially on the wall of the bladder, the opening comes to lie in the wall of the prostatic urethra. If the wall (urorectal fold) separating the urogenital sinus and rectum is situated too far dorsally, the opening of the ureter comes to be in the wall of the rectum. (Consult Figs. 322, 323, 324, 325.)

In the female the ureters may open into the urethra, the vagina, or the uterus. The explanation of the opening into the urethra is the same as in the male (see preceding paragraph). The opening into the genital tract is probably to be explained on the ground that the ureters fail to migrate cranially along the wall of the urogenital sinus to the bladder, and as the fused ends of the Mtillerian ducts enlarge to form the uterus and vagina, the openings of the ureters are taken up into their walls.

===The Bladder===

Absence of the bladder is very rare. Abnormal smallness, due to imperfect dilatation of the urogenital sinus (p. 371), is not infrequent.

The urachus, which represents the portion of the allantoic duct between the bladder and the umbilicus (p. 371), not infrequently persists as a whole or in part, giving rise to certain anomalous conditions in the region of the middle umbilical ligament. The urachus may persist as a complete tube, lined with epithelium, thus forming a means by which urine can escape at the umbilicus. This condition is usually associated with obstruction of the urethra and is known as uracho-vesical fistula. The urachus may degenerate in part, leaving disconnected portions which frequently become dilated to form cysts.

Vesical fissure, the most serious malformation of the bladder, is associated with fissure of the lower abdominal wall. The edges of the cleft in the bladder are continuous with those of the cleft in abdominal wall, the integument being continuous with the lining of the bladder. In some cases the bladder is everted through the cleft, and the cleft may even be so extensive as to involve the external and internal genital organs. Vesical fissure is much more common in the male than in the female. No very satisfactory explanation of this malformation has yet been given. It is in some way connected with imperfect formation of the ventral abdominal wall resulting from influences acting at a very early period of development.

==The Urethra==

The urethra in both sexes may be abnormally small or abnormally large or partly occluded, owing to faulty development of the urogenital sinus. In the male the penile portion also may be malformed, being represented merely by a furrow on the lower side of the penis. This condition, known as hypospadias, is due to the incomplete fusion or lack of fusion between the genital folds along the lower side of the genital tubercle (p. 394). In extreme cases the defect may involve the scrotum and extend back as far as the prostate gland, the two halves of the scrotum being separated. Epispadias, in which the urethral cleft extends along the upper side of the penis (or the clitoris) is rare, and is usually associated with vesico-abdominal fissure. Its mode of origin is not understood.

===The Testicles===

One of the most common malformations affecting the male genital glands is the condition known as chryptorchism, in which the glands, instead of descending into the scrotum, are retained within the abdominal cavity. One or both testicles may be affected. They may occupy their original position far forward in the abdominal cavity or may be situated near the inguinal canal, or may lie at some intermediate point. The malposition is due to a failure in the normal descent into the scrotum (p. 389). The cause of the failure is obscure. Not infrequently the ectopic testicles atrophy or fail to develop properly at puberty.

Congenital absence of one or both testicles is rare. More frequently the gland or efferent system of ducts is defective in part, owing to imperfect development. In case of absence of the testicles the individual is small and poorly developed ; when the glands are imperfectly developed the individual is effeminate.

Cysts which are sometimes met with in the epididymis are possibly due t( dilatation of incompletely degenerated portions of the mesonephric tubules or Mullerian ducts. Teratoid tumors and chorio-epitheliomata are occasionally found in the testicle. For a further discussion of these see chapter on Teratogenesis (XX).

===The Ovaries===

Congenital absence of both ovaries is rare; defective development of one is more common. Either anomaly may occur with or without defects in the other genital organs. Occasionally the ovaries remain rudimentary, their function as egg-producing organs never being assumed. Malpositions, due to partial or complete failure in the normal descent into the pelvis (p. 392), are not infrequent. Sometimes, on the other hand, they descend to the inguinal canal and may even pass through the latter into the labia majora.

Ovarian cysts occur frequently. Some of these (follicular cysts) may arise during, postnatal life as dilatations of Graafian follicles. Others probably arise during foetal life in the same manner. Certain other forms of ovarian tumors, known as cystadenomata, are possibly to be considered as derivatives of the epithelium of the medullary cords which in normal cases disappear entirely (p. 377; also Fig. 328). A discussion of the origin of teratoid tumors of the ovary will be found in the chapter on Teratogenesis (XX).

===The Oviducts, Uterus and Vagina===

Absence of the oviducts is usually associated with malformations of other parts of the genital tract. On the other hand, normal oviducts may be present in conjunction with defective uterus and vagina. Atresia may occur at the uterine or fimbriated end, or at any intermediate point.

The majority of the malformations of the uterus and vagina can be attributed to defective processes of development in the caudal ends of the Miillerian ducts. It will be remembered that the caudal ends of these ducts normally fuse to form a single medial tube which opens into the urogenital sinus, and which constitutes the anlage of the uterus and vagina (p. 385; Fig. 325). It is obvious that any defect in this fusion will result in some degree of duplicity in the two organs in question. The fusion may be almost complete, the resulting abnormality being merely a small pocket which forms, at each side of the fundus, a continuation of the cavity of the uterus. There may be a greater degree of imperfection in the fusion, resulting in a partial division of the uterus into two horns bicornuate uterus. The wall between the two Mullerian ducts may remain patent in the entire uterine portion of the tract, thus giving rise to a bipartite uterus. If the wall between the ducts remains intact throughout both uterine and vaginal portions, the result is a complete division of the uterovaginal tract uterus didelphys. Occasionally the uterine portion of one Mullerian duct may fail to develop properly and becomes a solid cord, resulting in an unicornuate uterus.

Not infrequently the uterus remains rudimentary infantile uterus. This anomaly is usually accompanied by stenosis of the vagina. Stenosis or other defects in the vagina may occur, however, when the uterus is normal. In rare instances the hymen is absent; in other cases it closes the entrance to the vagina a condition known as imperforate hymen.

Malformations of the uterus and vagina resulting from persistence of the cloaca and atresia of the anus are mentioned on page 326.

==Hermaphroditism==

--[[User:S8600021|Mark Hill]] 13:22, 17 January 2011 (EST) Note this is a historic term, now replaced with "intersex".

This condition implies a combination of the male and female sexual organs in one individual, accompanied by a blending ot the general characteristics of the two sexes When such an individual possesses both ovary and testicle, the condition is known as true hermaphroditism ; when the individual possesses ovaries or testicles, the condition is known as false hermaphroditism.

===True Hermaphroditism===

The presence of both ovary and testicle in one individual is one of the rarest anomalies in man. Furthermore, one or both of the organs are sexually immature. Three forms can be recognized (Klebs) :

1. Lateral hermaphroditism, in which an ovary is present on one side and a testicle on the other;

2. Unilateral hermaphroditism, in which both ovary and testicle are present on one side, either ovary or testicle, or neither, on the other side;

3. Bilateral hermaphroditism, in which both ovary and testicle are present on both sides.

In all these cases the general character of the body is of an intermediate type, sometimes tending toward the male, sometimes toward the female. The external genitalia are also of an intermediate type, with hypospadias, small penis, separate scrotal halves, and small vaginal orifice. The uterus usually shows some degree of duplicity.

===False Hermaphroditism===

In this type of hermaphroditism, in which either ovaries or testicles are present in an individual with mixed general sexual characteristics, two varieties can be recognized:

# Masculine false hermaphroditism, the more common, in which testicles are present but the external genitalia and general character of the body approximate the female;
# Feminine false hermaphroditism, in which ovaries are present but otherwise male characteristics predominate.

The causes underlying the origin of hermaphroditism are among the most obscure in teratogenesis. It is well known that up to the fourth or fifth week the anlagen of the sexual glands are histologically "indifferent," and later become differentiated into ovaries or testicles (p. 375). Since the secondary sexual characteristics are dependent upon the development of the primary, they also are brought out later. If the " indifferent " glands give rise to both ovaries and testicles, true hermaphroditism is the result; if they give rise to either ovaries or testicles but the external genitalia and general characteristics develop in the opposite direction, false hermaphroditism is the result. Thus the hermaphroditic condition is potentially present in every individual during the earlier stages of development; the most remarkable fact is that it is not more common.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_16|Integumentary]]

==References for Further Study==

ADAMI, J. G.: The Principles of Pathology. Vol. I, 1908.

AICHEL, O.: Vergleichende Entwickelungsgeschichte und Stammesgeschichte der Nebennieren. Arch.f. mik Anat., Bd. LVI, 1900.

{{Ref-Allen1904}}

BEARD, J.: The Germ-cells of Pristiurus. Anat. Anz., Bd. XXI, 1902.

BEARD, J.: The Morphological Continuity of the Germ Cells in Raja batis. Anat. Am., Bd. XVIII, 1900.

BREMER, J. L. : The Interrelation of the Mesonephros, Kidney and Placenta in different Classes of Mammals. Am. Jour, of Anat., Vol. XIX, 1916.

BONNET, R.: Lehrbuch der Entwickelungsgeschichte. Berlin, 1907.

{{Ref-Corner1919}}

EGGERTH, A. H.: On the Anlage of the Bulbo-urethral (Cowper's) and Major Vestibular (Bartholin's) Glands in the Human Embryo. Anat. Record, Vol. IX, 1915.

EIGENMANN, C. H.: On the Precocious Segregation of the Sex-cells of Micrometrus aggregatus. Jour, of MorphoL, Vol. V, 1891.

FELIX, W.: Entwickelungsgeschichte des Excretions-systems. Ergebnisse der Anat. u. Entunck., Bd. XIII, 1903.

FELLX, W., and BUHLER, A.: Die Entwickelung der Harn- und Geschlechtsorgane. In Hertwig's Handbuch d. vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. III. Teil I, 1904.

GAGE, S. P.: A Three Weeks' Human Embryo, with Especial Reference to the Brain and Nephric System. Am. Jour, of Anat., Vol. IV, 1905.

GERHARDT, U.: Zur Entwickelung der bleibenden Nieren. Arch. f. mik. Anat., Bd. LVII, 1901

HERTWIG, O. : Lehrbuch der Entwickelungsgeschichte des Menschen und der Wirbeltiere. Jena, 1906.

{{Ref-Hill1906}}

HUBER, G. C. : On the Development and Shape of the Uriniferous Tubules of Certain of the Higher Mammals. Am. Jour, of Anat., Vol. IV, SuppL, 1905.

KED3EL, F.: Zur Entwickelungsgeschichte des menschlichen Urogenitalapparatus. Arch.f. Anat. u. Physiol., Anat. Abth., 1896

KINGSBURY, B. F.: The Morphogenesis of the Mammalian Ovary: Felis domestica. Am. Jour, of Anat., Vol. XV, 1913.

KOHN, A.: Das chromaffine Gewebe. Ergebnisse der Anat. u. Enlwick., Bd. XII, 1903.

KOLLMAN, J. Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMAN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907, Bd. II.

MARCHAND, F.: Missbildimgen. In Eulenburg's Real-Encyclopddie der gesammten HeUkunde, Bd. XV, 1897.

McMuRRiCH, J. P.: JThe Development of the Human Body. Philadelphia, 1919.

MINOT, C. S.: Laboratory Text-book of Embryology. Philadelphia, 1903.

MORGAN, T. H.: ,The Cause of Gynandromorphism in Insects. Am. Naturalist, Vol. XLI, 1907.

NAGEL, W.: Ueber die Entwickelung des Urogenitalsystems des Menschen. Arch. f. Mik. Anat., Bd. XXXIV, 1889.

NAGEL, W.: Ueber die Entwickelung der Urethra und des Dammes beim Menschen. Arch.f. mik. Anat., Bd. XL, 1892.

NAGEL, W.: Ueber die Entwickelung des Uterus und der Vagina beim Menschen. Arch.f. mik. Anat., Bd. XXXVII, 1891.

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

POHLMAN, A. G.: The Development of the Cloaca in Human Embryos. Am. Jour, of Anat., Vol. XII, 1911.

POLL, H.: Die Entwickelung der Nebennierensysteme. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil I, 1905.

POLL, H.: Die Entwickelung der Nebennierensysteme. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil I, 1905.

RABL, C.: Ueber die Entwickelung des Urogenitalsystems der Selachier. Morphol. Jahrbuch, Bd. XXIV, 1896. Theorie des Mesoderms. Ueber die erste Entwickelung der Keimdruse. Morphol. Jahrbuch, Bd. XXIV, 1896.

SCHREINER, H. E.: Ueber die Entwickelung der Amniotenniere. Zeitschr. /. wissensch. Zoologie, Bd. LXXI, 1902.

SOULIE, A.: Sur le mechanisme de la migration des testicules. Comp. Rend, de la Soc. de Biol., Paris, Ser. 10, T. II, 1895.

SOULIE, A. : Recherches sur le developpement des capsules surrenales chez les vertebres superieurs. Jour. de. V Anat. et de la Physiol., T. XXXIX, 1903.

STOERK, O.: Beitrag zur Kenntnis des Aufbaus der menschlichen Niere. Anat. Hefte, Bd. XXIII, 1904.

SWIFT, C. H.: Origin and Early History of the Primordial Germ-cells in the Chick. Am. Jour, of Anat., Vol. XV, 1914.

SWIFT, C. H.: Origin of the Definitive Sex-cells in the Female Chick and their Relation to the Primordial Germ-cells. Am. Jour, of Anat., Vol. XVIII, 1915.

SWIFT, C. H.: Origin of the Sex-cords and Definitive Spermatogonia in the Male Chick. Am. Jour, of Anat., Vol. XX, 1916.

TANDLER, J.: Ueber Vornieren-Rudimente beim menschlichen Embryo. Anat. Hefte, Bd. XXVIII, 1905.

TAUSSIG, F. J. : The Development of the Hymen. Am. Jour, of Anat., Vol. VIII, 1908.

WIESEL, J.: Ueber die Entwickelung der Nebennieren des Schweins, besonders der Marksubstanz. Anat. Hefte, Bd. XVI, 1900.

WINIWARTER, H.: Recherches sur 1'ovogenese et 1'organogenese de 1'ovaire des Mammiferes. Arch, de Biol., T. XVII, 1900.

WATSON, E. M.: The Development of the Seminal Vesicles in Man^ Am. Jour, of Anat., Vol. XXIV, 1918.

WOODS, F. W.: Origin and Migration of the Germ-cells in Acanthias. Am. Jour, of Anat., Vol. I, No. 3, 1902.

{{Bailey_1921_Footer}}

[[Category:Renal]] [[Category:Bladder]] [[Category:Genital]]

Book - Text-Book of Embryology 13

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{{Template:Bailey 1921}}

=The development of the respiratory system=

The anlage of the respiratory system appears in human embryos of about 3.2 mm. A hollow, linear evagination the lung groove develops on the ventral side of the oesophageal portion of the primitive gut, extending caudally a short distance from the region of the fourth inner branchial groove. It was once thought that the evagination developed along practically the entire length of the oesophagus anlage, but more recent researches seem to prove that it is confined to the cephalic end. The lung groove soon becomes separated from the gut by a constriction which appears at the caudal end and gradually progresses forward. Thus there is formed a tube which lies ventral to the gut and which opens upon the floor of the latter at the boundary line between the oesophagus and pharynx (Figs. 282 and 246).

<div id="Fig282"></div>
[[File:Bailey282.jpg|600px]]

'''Fig. 282. Sagittal section of reconstruction of a human embryo of 5 mm.''' His, Kollmann.

From this simple tube the entire respiratory system develops. The cephalic end gives rise to the larynx, the opening into the gut being the aditus laryngis. The middle portion gives rise to the trachea. Two outgrowths from the caudal end of the tube, which appear about the time of separation from the oesophagus, develop into the bronchi and their continuations the lungs. The epithelial lining of the system is of course derived from the entoderm. The various kinds of connective tissue are derived from the mesoderm, since the anlage grows into the mesodermal tissue of the ventral mesentery.

==The Larynx==

The opening from the gut into the respiratory tube becomes surrounded by a U-shaped elevation the furcula which lies in the floor of the pharynx with its open end directed caudally. Toward the end of the first month each side of the opening (aditus laryngis) becomes elevated, forming the arytenoid ridge. From each of these a secondary elevation arises, forming the cuneiform ridge. The arytenoid ridges come so close together that they practically close the opening except at its cephalic side (Fig. 283). Along with the development of these ridges the apical portion of the furcula becomes a distinct transverse fold at the cephalic rim of the opening. This fold is the anlage of the epiglottis. Laterally the epiglottic fold becomes continuous with the arytenoid ridges, forming the ary epiglottic ridges (Fig. 283).

<div id="Fig283"></div>
[[File:Bailey283.jpg|600px]]

'''Fig. 283. From a reconstruction of the larynx of a human embryo of 28 days.''' Seen from above. Kattius.

During the fourth month a groove-like depression appears on the medial side of each arytenoid ridge, gradually becomes deeper, and leaves on each side of it a fold or lip which bounds the opening. The external lips those nearer ; the pharynx form the superior or false vocal cords; the internal lips form the true vocal cords. At the same time the opening into the larynx, which was closed by the arytenoid ridges, is reestablished. The depression between the vocal cords on each side becomes still deeper to form the ventricle, and a further outgrowth from the ventricle produces the appendage of like ventricle (the laryngeal pouch).

The mesodermal tissue external to the epithelium (entoderm) of the larynx gives rise to the various kinds of connective tissue including the laryngeal cartilages. By the end of the fourth week condensations appear in the mesenchymal tissue, which are the forerunners of the cartilages, but true cartilage does not appear until the seventh week. The anlagen of the thyreoid cartilage are two mesenchymal plates, one on each side, which are bilaterally symmetrical and correspond to the lateral parts of the adult cartilage (Fig. 284, A). These plates gradually grow ventrally and unite and fuse in the midventral line (Fig. 285) . Two centers of chondrification appear in each plate (Fig. 284, A,) and enlarge until the entire plate is converted into cartilage, the middle becoming elastic in character, the rest hyalin.

<div id="Fig284"></div>
[[File:Bailey284.jpg|600px]]

'''Fig. 284. From reconstructions of the mesenchymal condensations which represent the hyoid and thyreoid cartilages in an embryo of 40 days.''' A, Ventral view; B, lateral view from right. Kallius.
:Inf.hy., Inferior (greater) horn of hyoid; Sup.hy., superior (lesser) horn of hyoid; Thyr., thyreoid. The portions indicated by black lines represent chondrification centers.

<div id="Fig285"></div>
[[File:Bailey285.jpg|600px]]

'''Fig. 285. From a transverse section through the pharynx and larynx of a human embryo of 48 mm.''' Nicolas.

Originally the cephalic edge of each thyreoid plate is connected with the inferior horn of the hyoid cartilage (Fig. 284, B). This connection is subsequently lost, but a remnant of the connecting cartilage persists as the triticeous cartilage in the lateral hyothyreoid ligament. The anlagen of the arytenoid cartilages develop in the arytenoid ridges as condensations of the mesenchyme, which later are converted into true cartilage (Fig. 285). The apex and vocal process of each arytenoid become elastic, the main body becomes hyalin. The corniculate cartilages (cartilages of Santorini) are split off from the cephalic ends of the arytenoids and are of the elastic variety. The cricoid cartilage, like the others, is preceded by a condensation of mesenchyme. Chondrification begins on each side and then progresses around dorsally and ventrally until a complete hyalin ring is formed. From its developmental resemblance to the tracheal rings, the cricoid is sometimes regarded as the most cephalic of that series. The epiglottic cartilage develops in the epiglottic ridge as two separate pieces which subsequently fuse. It is of the elastic variety. The cuneiform cartilages (cartilages of Wrisberg) are split off from the two pieces of the epiglottic, and are of the elastic type.

Attempts have been made to determine which branchial arches are represented by the laryngeal cartilages. It seems quite definitely settled that the thyreoid is derived in part, at least, from the fourth arch. There is much doubt as regards the others, for there is great difficulty in determining their derivation in the human embryo, since the arches disappear at such an early stage. Furthermore, some of these cartilages may represent arches which are present in lower forms but do not appear in the higher Mammals.

The larynx is situated much farther cranially in the foetus and in the newborn child than in the adult. In a five months fcetus it extends into the nasopharyngeal cavity, whence it migrates caudally to its adult position. The laryngeal skeleton becomes ossified during postnatal life. Ossification begins in the thyreoid and cricoid cartilages at the age of eighteen to twenty years, and in the arytenoids a few years later. Three centers appear in the thyreoid one on each side near the inferior cornu and one in the medial line between the two wings. In the cricoid, ossification begins near the upper border on each side, in the arytenoids at the lower borders. Ossification usually begins earlier and proceeds more rapidly in the male than in the female.

As an example of the explanation which Embryology offers of certain peculiarities of structure in the adult, the case of the recurrent laryngeal nerve may be cited. The heart and aortic arches are primarily situated in the cervical region. At that time a branch of the vagus on each side, passes behind the fourth aortic arch to reach the larynx. As the heart and arches recede into the thorax, the nerve is pulled caudally between its origin and termination, so that in the adult the left nerve bends around the arch of the aorta and the right around the subclavian artery.

==The Trachea==

The portion of the original tube between the larynx and the two caudal outgrowths which form the bronchi and lungs, develops into the trachea. It lies ventral to the oesophagus and is surrounded by mesodermal tissue which is destined to give rise to the connective tis. 'ie, including the cartilage, of the adult trachea (Figs. 246 and 282). The development of the tracheal rings is very similar to that of the laryngeal cartilages. During the eighth or ninth week condensations appear in the mesenchyme, which are later transformed into hyalin cartilage. The rings are not complete but remain open on the dorsal side. At birth the trachea is collapsed, the ventral side being concave and the dorsal ends of each ring being in contact After respiration begins it is dilated and becomes more or less rigid. Ossification of the tracheal rings begins in the male at the age of about forty years, in the female at about sixty. The glands of the trachea represent evaginations from the epithelial linings.

==The Lungs==

As has been stated (p. 330), the caudal end of the original tube evaginates to form two hollow buds which are the beginnings. of the two lungs (Fig. 286). The evagination takes place soon after or even along with the separation of the lung groove from the gut. The right bud soon gives rise to three secondary buds, the forerunners of the three lobes of the right lung. The left bud gives rise to two secondary buds, the forerunners of the two lobes of the left lung (Fig. 287). The primary buds may be said to represent the two bronchi arising from the trachea, the five secondary buds to represent the bronchial rami which extend into the five lobes of the lungs. Successive evaginations from each of the five buds take place and form an extensive arborization for each lobe (Figs. 288 and 289).

<div id="Fig286"></div>
[[File:Bailey286.jpg|600px]]

'''Fig. 286. Transverse section of a 14 mm. pig embryo, at the level of the upper limb buds, showing especially the two bronchi.'''

The manner in which the bronchial rami branch is not definitely known. Some maintain that the branching is dichotomous, that is, each bud gives rise to two equal buds and each of these to two others, and so on. In order to assume the adult form, however, one of the buds places itself in line with the preceding bud or bronchus while the other places itself as a lateral outgrowth. Others hold that the growth is monopodial, that is, that the original bud grows in a more or less direct line and the others develop as lateral outgrowths. When the evaginations that produce the bronchial rami are completed, each terminal (respiratory) bronchus subdivides into three to six narrow tubules, the alveolar ducts. The latter again branch into several wider compartments, the atria, from which several .air sacs are given off. The walls of the air sacs are evaginated to form many closely set air cells which represent the ultimate branches of the air passages of the lungs.

<div id="Fig287"></div>
[[File:Bailey287.jpg|600px]]

'''Fig. 287. Anlage of lungs of a human embryo of 4.3 mm.''' His.

<div id="Fig288"></div>
[[File:Bailey288.jpg|600px]]

'''Fig. 288. Anlage of lungs of a human embryo of 8.5 mm.''' His.

While there is a general tendency toward bilateral symmetry in the various sets of bronchial rami, the lobes of the lungs are asymmetrical. This asymmetry is indicated in the five secondary buds that arise from the two primary, since three arise on the right side and only two on the left. The three on the right represent the upper, middle and lower lobes of the right lung (Fig. 287). The upper is known as the eparterial from the fact that its bronchus lies dorsad to the pulmonary artery. No lobe develops on the left side corresponding to the upper (eparterial) on the right. There is a possibility that it is absent in order to allow the arch of the aorta to migrate caudally as it normally does (see p. 254). One of the larger ventral bronchial rami of the left lung is absent, owing to the inclination of the heart toward the left side; but as a compensation the corresponding ramus of the right lung develops more extensively and projects into the space between the pericardium and diaphragm as the infracardiac ramus.

<div id="Fig289"></div>
[[File:Bailey289.jpg|600px]]

'''Fig. 289. Anlage of lungs of a human embryo of 10.5 mm.''' His.

From the fact that the anlage of the respiratory system is enclosed within the mesentery between the gut and the pericardial cavity, and that its caudal end becomes enclosed within the dorsal edge of the septum transversum, it is obvious that the lungs will push their way into the dorsal parietal recesses or pleural cavities (Figs. 290 and 295). The way in which the lungs and pleural cavities enlarge and separate the pericardium from the body wall on each side and from the diaphragm is described on page 346 (see Figs. 296 and 297). The mesodermal tissue that surrounds the primary lung buds is in part pushed before the numerous outgrowths and in part remains among them (Figs. 287, 288, 289). The part around the lungs, with its covering of mesothelium, comes to form the visceral layer of the pleura which closely invests the entire surface of the lungs and dips down between the lobes. At the roots of the lungs it is continuous with the parietal layer of the pleura lining the inner surface of the pleural cavities. The mesodermal tissue among the bronchi and their terminations gives rise to the connective tissue that separates the lobes and lobules and invests all the structures in the interior of the lungs. This connective tissue at first constitutes a large part of the lungs, but as development proceeds, the more rapid growth of the respiratory parts results in the relatively small amount of connective tissue characteristic of the adult lung.

Changes in the Lungs at Birth. At birth the lungs undergo rapid and remarkable changes in consequence of their assuming the respiratory function. These changes affect their size, form, position, texture, weight, etc., and furnish probably the only certain means of distinguishing between a still-born child and one that has breathed. In the foetus at term the lungs are small, possess rather sharp margins and lie in the dorsal part of the pleural cavities.

<div id="Fig290"></div>
[[File:Bailey290.jpg|600px]]

'''Fig. 290. Transverse section of a pig embryo of 35 mm., showing the developing lungs''' (bronchial rami surrounded by mesoderm). The oesophagus is seen between the two lungs; above the oesophagus is the' aorta. The dark mass in the lower part of the figure is the liver. Photograph.

After respiration they enlarge, fill practically the entire pleural cavities and naturally become more rounded at their margins. The introduction of air into the air passages converts the compact, gland-like, foetal lung into a loose, spongy tissue. The specific gravity is changed from 1.056 to 0.342. While there is a gradual increase in the weight of the lungs during development, there is a very sudden increase at birth when the blood is freely admitted to them through the pulmonary arteries. The weight of the lungs relative to that of the body changes from about i to 70 before birth, to about i to 35 or 40 after birth.

==Anomalies==

===The Larynx===

The larynx may be excessively large or unusually small. Occasionally the epiglottic cartilage consists of two pieces, indicating a failure of the two anlagen to fuse (p. 332). Similar defects may occur in the other cartilages that are derived from more than one anlage. The ventricle on either side may be abnormally large with an exaggerated appendage (laryngeal pouch) . This condition resembles that in the anthropoid apes.

===The Trachea===

The trachea is sometimes absent, in which case the bronchi arise immediately below the larynx, indicating a failure on the part of the original tube to elongate. The trachea may be abnormally short. Rarely there is a direct communication between the trachea and oesophagus, probably due to an incomplete separation of the lung groove from the gut (p. 330) . The cartilaginous rings may vary in number as a result of abnormal splittings and fusions.

===The Lungs===

Rarely the eparterial bronchial ramus on the right side arises as a branch of the trachea and not as a branch of the bronchus (p. 335). This condition is normal in certain Mammals (ox, sheep) . Rarely an eparterial bronchial ramus is present on the left side, thus producing a third lobe for the left lung. In some animals an eparterial ramus is normally present on each side, the larger bronchial rami thus being bilaterally symmetrical. Variation in size and number of lobes is not infrequent. Supernumerary or accessory lobes, formed either by evaginations from the original anlage or by independent evaginations from the gut, are met with in rare cases.

Occasionally some portion of either lung is defective. The bronchial bud that would normally give rise to the lung tissue in that region fails to develop properly, and the result is a number of rami, without the ultimate terminations, surrounded by vascular tissue. The rami may remain normal or. may become dilated and form krge bronchial cysts.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_14|Coelom, Diaphragm and Mesenteries]]

==References for Further Study==

BONNET, R.: Lehrbuch der Entwickelungsgeschichte. Berlin, 1907.

{{Ref-Flint1906}}

GOPPERT, E.: Die Entwickelung des Mundes und der Mundhohle mit Drusen uud Zunge; die Entwickelung der Schwimmblase, der Lunge und des KehlkopfesderWirbeltiere. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. II, Teil I, 1902.

HERTWIG, O.: Lehrbuch der Entwickelungsgeschichte des Menschen und der Wirbeltiere. Jena, 1906.

His, W.: Zur Bildungsgeschichte der Lungen beim menschlichen Embryo. Arch. /. Anat. u. Physiol., Anat. Abth., 1887.

KALLIUS, E.: Beitrage zur Entwickelungsgeschichte des Kehlkopfes. Anat. Hejte, Bd. IX, 1897.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

HUNTINGTON, CEO. S.: A Critique of the Theories of Pulmonary Evolution in the Mammalia. Am. Jour, of Anat., Vol. XXVII, No. 2, 1920.

{{Ref-McMurrich1914}}

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

SYMINGTON, J.: On the Relations of Larynx and Trachea to the Vertebral Column in the Foetus and Child. Journ. of Anat. and Physiol., Vol. IX.

{{Bailey_1921_Footer}}

[[Category:Respiratory]]

Book - Text-Book of Embryology 12

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{{Bailey 1921}}

=The Development of the Alimentary Tube and Appended Organs=
<div id="Fig244"></div>
[[File:Bailey244.jpg|thumb|300px|'''Fig. 244. Lateral view of human embryo with 14 pairs of primitive segments (2.5 mm).''' Kollntann. The yolk sac has been cut off. The fore-gut, mid-gut and hind-gut, as indicated in the figure, together constitute the primitive gut. Compare with Fig. 245.]]

The embryonic disk, composed of the three germ layers, primarily lies flat upon the yolk sac (see p. 107; also Fig. 75). A little later the axial portion of the embryo is indicated by the primitive streak, the neural groove (subsequently the neural tube), the notochord, and the primitive segments (Fig. 71). Then along each side of the axial portion and at the cephalic and caudal ends, the germ layers bend ventrally and medially and finally meet and fuse in the midventral line (p. 109) . The portion of the entoderm ventral to the notochord is bent into a tube which, for the most part, becomes pinched off from the parent entoderm and is suspended in the embryonic coelom by the common mesentery (Figs. 103 and 104). This entodermal tube is the primitive gut. At first it ir but slightly elongated and is closed at both ends. On the ventral side, however it opens widely into the yolk sac (Figs. 244 and 245). The primitive gut, therefore, has no communication with the exterior. It communicates at its caudal end with the central canal of the spinal cord through the neurenteric canal (Fig. 76; compare with 77).

As development proceeds, this simple tube elongates rapidly and becomes differentiated into distinct regions. The cephalic end, in connection with the branchial arches and grooves, becomes the dilated pharyngeal region. Caudal to and continuous with this, is the short, narrow cesophageal region which in turn passes over into the slightly dilated stomach region. The portion of the gut caudal to the stomach is the intestinal region. During the differential changes, the communication with the yolk sac becomes relatively smaller, forming the yolk stalk which joins the intestinal portion a short distance caudal to the stomach (Figs. 246 and 247).

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'''Fig. 245. Ventral view of human embryo of 2.4 mm.''' His, Kollmann.
: Note the opening in the ventral wall of the gut. This indicates the communication between the gut and the yolk sac. The latter has been removed. Compare with Fig. 244.

==The Mouth==

At a very early period the primary fore-brain region bends ventrally almost at a right angle to the long axis of the body to form the naso-frontal process.

As the first branchial arch develops, it grows ventrally until it meets and fuses with its fellow of the opposite side in the midventral line, thus forming the mandibular process. From the cephalic side of the first arch a secondary process maxillary process develops and fills in the space between the arch itself and the naso-frontal process. These various structures thus bound a distinct depression on the ventral side of the head. This depression is the oral pit, the forerunner of the oral and nasal cavities (Fig. 245; compare with Figs. 244 and 85). The groove in the midventral line between the mandibular processes marks the symphysis of the lower jaws. The groove on each side between the maxillary process and the mandibular process marks the angle of the mouth. The groove between the maxillary process and the naso-frontal process is the naso-optic furrow, at the dorsal end of which the eye develops. The bottom of the oral pit is formed by a portion of the ventral body wall, which separates the oral cavity from the cephalic end of the gut, and which is composed of ectoderm and entoderm, with a small amount of mesoderm between. This closing plate, the pharyngeal membrane, which is still present in I embryos of 2.15 mm., soon becomes thinner and finally breaks away, leaving I the oral pit and the gut in direct communication (Fig. 247). Since the oral pit , is lined with ectoderm, the epithelial lining of the mouth or oral cavity is largely of ectodermal origin. In the medial line of the roof of the oral cavity, near the pharyngeal membrane, the epithelium (ectoderm) evaginates to form Rathke's pocket. This comes in contact with an evagination from the floor of the brain and with it forms the pituitary body.

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'''Fig. 246. Alimentary tube of a human embryo of 4.1 mm.''' His Kollmann.

The further development of the mouth consists of an elaboration of the structures which primarily bound the oral pit and the growth of certain new structures such as the teeth and the tongue. The first branchial arch fuses with its fellow of the opposite side in the midventral line to form the symphysis of the lower jaws, giving rise also to the lower lip and chin region. As the nasofrontal process continues to grow, two depressions appear on its ventral border, one on each side, a short distance from the medial line. These depressions are the nasal pits which indicate the beginning of the external openings of the nasal passages. The part between the nasal pits is destined to give rise to the nasal septum and the medial part of the upper lip (Fig. 98). The primary oral cavity is divided into the oral cavity proper and the nasal cavity by outgrowths from the maxillary processes. From the medial side of each maxillary process a plate-like structure grows across the primary oral cavity toward the medial line (Fig. 140). These two plates, or palatine processes, meet and fuse with the lower part of the nasal septum (Fig. 248) . (For further details of this fusion, see page 121 and page 163). The palatine processes thus form the palate, or the roof of the mouth, which separates the mouth cavity from the nasal cavity. The palate does not extend far enough backward, however, to separate the posterior part of the nasal cavity from the pharynx. Thus the posterior nares and pharynx are left in communication. Externally the maxillary processes extend medially, separate the nasal pits from the oral cavity, and form the lateral portions of the upper lip (Fig. 99).

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'''Fig. 247. Sagittal section of reconstruction of a human embryo of 5 mm.''' His, Kollmann.

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'''Fig. 248. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

==The Tongue==

The {{tongue}} develops from three separate anlagen which unite secondarily. In embryos of about 3 mm a slight elevation appears on the floor of the pharynx in the region of the first branchial arch. This is the tuberculum impar, being, as the name indicates, unpaired, and is destined to give rise to the tip and body of the tongue (Fig. 249). Soon afterward two bilaterally symmetrical elevations appear on the floor of the pharynx, which are destined to give rise to the root of the tongue (Fig. 250). These paired elevations, arising in, the region of the second and third branchial arches, gradually enlarge and unite with each other and with the tuberculum impar, leaving between the latter and themselves, however, a V-shaped groove (Fig. 251). At the apex of the groove there is a depression the foramen cecum lingua which is the external opening of the thyreoglossal duct (see p. 301). The groove later disappears, but its position is indicated in the adult by the vallate papillae.

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'''Fig. 249. Floor of the pharyngeal region of a human embryo of about 3 weeks.''' {{His}}.

According to Hammar, the tuberculum impar is a transitory structure and does not give rise to the tip and body of the tongue. The tip and body are derived from a much more extensive elevation in the floor of the pharynx.

The tongue as a whole enlarges and grows from its place of origin toward the entrance to the primary oral cavity. For a time it practically fills the cavity. When the palate develops it recedes and finally comes to lie on the floor of the oral cavity proper, as in the adult. The growth of the tongue involves the epithelial lining of the pharynx and oral cavity and also the underlying mesenchymal tissue. The latter produces the connective tissue and at least a part of the intrinsic muscle fibers of the tongue. The papillae involve the epithelium and connective tissue, while the glands and taste buds are derived from the epithelium alone.

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'''Fig. 250. Floor of pharyngeal region of a human embryo of 12.5 mm.''' His.

The portion of the lingualis muscle innervated by the facial (VII) nerve is probably derived from the mesenchymal tissue in the tongue anlage. The rest of the muscle is innervated by fibers from the hypoglossal (XII) nerve, indicating a possible derivation from certain rudimentary segments in the occipital region which correspond to the three roots of the nerve. This would make it appear that during phylogenesis a part of the lingualis muscle has grown into the tongue from a region caudal to the last branchial arch.

The lingual papilla begin to develop during the third month. Their development is limited to the dorsum of the tongue and to the portion derived from the tuberculum impar. In other regions slight elevations may appear, but not in the form of distinct papillae. The fungijorm and filiform papillae appear as pointed elevations in the connective tissue, which push their way into the epithelium, the latter at the same time being raised above the surface over these points. Gradually the little masses of connective tissue assume the shapes characteristic of fungiform or filiform papillae. During the fifth month the epithelium between the papillae apparently degenerates to some extent, thus leaving them projecting still farther above the surface. The formation of papillae probably goes on for some time after birth, since at birth their form, size, number and arrangement are not the same as at later periods. It is an interesting fact that the filiform papillae lose many of their taste buds after the child is weaned.

The anlage of the vallate papillae appears as a ridge along the V-shaped line of fusion between the paired and unpaired portions of the tongue. The ridge is apparently formed by the ingrowth of a solid mass of epithelium along each side, although the connective tissue between the masses may grow toward the surface to some extent. Later the ridge is broken up into the individual papillae by the ingrowth of the epithelium at certain points. The more superficial cells of the masses then degenerate, thus leaving each papilla surrounded by a trench and wall.

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'''Fig. 251. Dorsal view of the tongue of a human embryo of 20 mm.''' His, Bonnet.

The development of the lingual glands is confined for the most part to the root and inferior surface and to the region of the vallate papillae. The glands begin to develop during the fourth month as solid ingrowths of epithelium, the mucous glands appearing first, the serous somewhat later. The epithelial masses acquire lumina and grow deeper into the tongue, where they usually branch and coil to form the secreting portions. The latter open to the surface through the original ingrowths which become the ducts. Ebner's glands develop from the bottoms of the trenches around the vallate papillae.

==The Teeth==

The development of the {{teeth}} involves the ectoderm and mesoderm, the former giving rise to the enamel, the latter to the dentine and pulp. In human embryos of 12-15 mm. (thirty-four to forty days), before the lip groove is formed, a thickening of the epithelium (ectoderm) takes place along the edges of the processes that bound the slit-like entrance to the mouth. When the lip groove appears (Fig. 140), the epithelial thickening comes to lie along the edge of the jaw, or in other words, along the edge of the gums. It then grows into the mesenchymal tissue (mesoderm) of the jaw obliquely toward the lingual surface to form the dental shelf. A little later the dental groove appears on the edge of the jaw, along the line where the ingrowth of epithelium took place.

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'''Fig. 252. Section of developing tooth from a 3 months human fetus.''' Szymonowicz.

Note the portion of the original dental shelf connecting the developing tooth with the epithelium of the mouth cavity.

The dental shelf is at first of uniform thickness, but in a short time five enlargements appear in it in each upper and lower jaw, indicating the beginnings of the milk teeth. When the embryo reaches a length of 40 mm. (an age of eleven to twelve weeks) the mesenchymal tissue on one side of these enlargements (above and to the inner side in the upper jaw, below and to the inner side in the lower jaw) becomes condensed and pushes its way into the epithelium. Each of these mesenchymal ingrowths is a dental papilla. Thus at this stage the anlage of each tooth is a mass of epithelium fitting cap-like over a mesenchymal papilla. The epithelium is the forerunner of the enamel organ; the papilla is destined to give rise to the dentine and pulp. The anlagen are connected with one another by intermediate portions of the dental shelf, and with the surface by the original ingrowth of epithelium.

===The Enamel===

The epithelial cells nearest the dental papilla become high columnar in shape, forming a single layer. Those in the interior of the mass become separated and changed into irregular, stellate, anastomosing cells, with a fluid intercellular substance, constituting the enamel pulp. Those farthest from the papilla become flattened (Fig. 252 ; compare with Fig. 253). Calcification begins in the basal ends of the columnar cells, or in the ends next the papilla, and in the intercellular substance, and gradually progresses throughout the cells, the latter at the same time becoming much more elongated. Thus the cells are transformed into enamel prisms which are held together by the calcined intercellular substance (Fig. 253).

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'''Fig. 253. Section through the border of a developing tooth of a new-born puppy.''' Bonnet.

The formation of enamel begins in the milk teeth toward the end of the fourth month and probably continues until the teeth break through the gums. The enamel organ at first surrounds the entire developing tooth except where the papilla joins he underlying mesenchymal tissue (Fig. 252). Later the deeper part of the organ disappears as such, and the enamel is formed only on that part of the tooth which eventually becomes the crown. The enamel pulp increases in amount for a time, but subsequently disappears as the tooth grows into it (Fig. 254). Its function is not fully understood. It may serve as a. line of least resistance in which the tooth grows, and it may convey nourishment to the enamel cells, the enamel organ being non-vascular.

===The Dentine and Pulp===

At first the dental papilla is simply a condensation of mesenchyme, but later it is converted into a sort of connective tissue penetrated by blood vessels and nerves (Fig. 254). The cells nearest the enamel organ become columnar and arranged in a single layer, with the nuclei toward their inner ends. The outer ends are blunt, while the inner ends are continued as slender processes that extend into the pulp and probably with other cell processes. These columnar cells are the odontoblasts, under the influence of which the lime salts of the dentine are deposited, and which are coi parable with the osteoblasts in developing bone.

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'''Fig. 254. Longitudinal section of a developing tooth of a new-born puppy.''' Bonnet.

Toward the end of the fourth month the odontoblasts form a membrane like structure, the membrana preformativa, between themselves and the enamel. This membrane is first converted into dentine by the deposition of lime salts, after which the process of calcification progresses from the enamel toward the pulp. During calcification slender processes of the odontoblasts remain in minute channels, or dentinal canals, forming the dentinal fibers which anastomose with one another (Fig. 253). In the peripheral part of the dentine certain areas apparently fail to become calcified and form the inter globular spaces. The same cells that are originally differentiated from the mesenchyme probably persist throughout development as the odontoblasts and produce the entire amount of dentine in a tooth. Even in the fully formed tooth there is a layer of odontoblasts bearing the same relation to the dentine and pulp as in the developing tooth. The chief difference between dentine formation and bone formation is that in the latter the osteoblasts become enclosed to form bone cells, while in the former the odontoblasts merely leave processes enclosed as the cell bodies recede.

The pulp of the tooth is of course derived from the mesenchymal tissue in the interior of the dental papilla (compare Figs. 252 and 254). The blood vessels and nerves grow in from the underlying connective (mesenchymal) tissue.

At an early stage the mesenchymal tissue around the anlage of the tooth, including the enamel organ, condenses to form a sort of sheath, the dental sac, which is later ruptured when the tooth breaks through the gum (Fig. 254). The cement is formed around the root of the tooth from the tissue of the dental sac in the same manner as subperiosteal bone is formed from osteogenetic tissue (p. 142). In fact, cement is true bone without Haversian systems.

The milk teeth, which are the first to develop and the first to appear above the surface, are represented by the medial incisors, lateral incisors, canines, and molars, to the number of ten in the upper and ten in the lower jaw. They may be indicated graphically thus:

Milk teeth

[[File:Baileytable04.jpg|600px]]

In describing the formation of the dental shelf, it was noted that the papillae of the milk teeth grow into corresponding thickenings of the epithelium (p. 292). The growth takes place from the side, thus leaving the edge of the shelf free to grow farther toward the lingual side of the jaw. In this free edge other tooth germs arise, which mark the beginnings of the permanent teeth (Fig. 252). In addition to the germs that correspond in position to the milk teeth, three others arise in each jaw, representing the true molars of the adult. The latter arise in a part of the dental shelf which has grown toward the articulation of the jaws without coming in contact with the surface epithelium. The first papilla of the permanent dentition to appear is that of the first molar. It appears immediately behind the second milk molar at a time when the milk teeth are well advanced (embryos of 180 mm., about seventeen weeks). The permanent incisors and canines appear about the twenty-fourth week; the premolars, which correspond to the milk molars, about the twenty-ninth week. The second molar does not appear till after birth (six months), and the third molar, or wisdom tooth, begins to develop about the fifth year.

The formation of the anlagen of the permanent teeth and the development of the enamel, dentine and pulp take place in precisely the same manner as in the milk teeth. The true molars grow out through the gums in the same way as the milk teeth. Those permanent teeth which correspond in position to milk teeth grow under the latter, exert pressure on their roots and thus loosen and finally replace them.

The two sets of teeth may be graphically represented thus:

Milk teeth

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Permanent teeth

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Normally all the epithelium of the dental shelf, except the parts directly concerned in the development of the teeth, disappears at times which vary in different individuals. Occasionally, however, remnants of this epithelium give rise to cystic structures (developmental tooth tumors) .

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'''Fig. 255. From a transverse section through the tongue and oral cavity of a mouse embryo.''' Goppert.

==The Salivary Glands==

The anlage of the submaxillary gland appears, in embryos of 10 to 12 mm., as a flange of epithelium directed ventrally from the portion of the lingual sulcus just caudal to the crossing of the lingual nerve. The flange grows into the mesenchyme of the lower jaw, and at an early period becomes triangular with its longest side free and a free vertical caudal border. Cell proliferation begins at the angle of union of the two borders and gradually progresses cephalad along the longest border, thus producing a solid ridge-like thickening of the latter.

The main portion of the gland is produced by a sprouting of the epithelium from the angle of union of the two free borders of the flange and grows deep into the mesenchyme along the mesial side of the ramus of the mandible. The sprouts branch repeatedly in the course of their development, thus laying the foundation for the division of the gland into lobes and lobules.

The distal end of the duct of the submaxillary (Wharton's) is formed from the ridge-like thickening of the free margin of the flange through a dissolution of the greater part of the flange between the lingual sulcus and the thickened margin itself, thus freeing this portion of the duct from the sulcus. By a continuation of the growth which produced the ridge along the free border of the original flange an extension of this same ridge is produced along the bottom of the lingual sulcus forward toward the chin region. This portion of the ridge is progressively constricted off from the sulcus from cehind forward, until finally the attachment of the duct reaches its definitive position at the side of the frenulum linguae.

The anlage of the Bartolinian element of the suUingual gland appears as a smaller flange attached to the lateral border of the submaxillary flange near the crossing of the lingual nerve and prolonged forward by an interrupted crest along the lingual sulcus. Its later development is similar to that of the submaxillary.

A small medial flange also on the submaxillary flange gives rise to a sprout in much the same manner as the other anlagen. While the history of this anlage is not complete in the human embryo, it probably gives rise to the anterior lingual gland (gland of Bland in and Nuhn). The alveolingual elements arise from a keel attached to the alveolingual sulcus (the groove between the floor of the mouth and the alveolar process of the lower jaw).

The parotid gland originates from the buccal sulcus in essentially the same way as the submaxillary arises from the lingual sulcus. The anlage then continues to grow through the mesenchyme of the cheek across the masseter muscle, the distal end branching freely to form the secreting portion of the gland. The outgrowths are at first solid, but later become hollow, the proximal portion of the original outgrowth forming the parotid (Steno's) duct, the more distal portions forming the smaller ducts and terminal tubules.

The histogenetic changes in the salivary glands probably continue until the child takes solid food, when the glands become of greater functional importance. In the parotid gland, which is serous in man, the original, undifferentiated epithelial cells undergo changes in form and arrangement so that by the twenty-second week the larger ducts are lined with a two-layered epithelium, the smaller ducts with a simple cuboidal epithelium, and the terminal tubules with a single layer of high columnar cells. The two-layered epithelium in the larger ducts persists. The ducts lined with the cuboidal epithelium become the socalled intermediate tubules, the cells changing to a flat type. The high columnar cells of the terminal tubules become the serous secreting cells.

Quite similar changes also occur in the submaxillary, but in foetuses of eight to nine months the crescents of Gianuzzi appear as masses of darkly staining cells forming the ends or sides of the terminal tubules. The crescents at first border on the lumina, but later, probably by a process of evagination, come to lie on the surface of the tubules.

The beginning of the secretory function may be detected by a diminution in the affinity of the cells for stains.

==The Pharynx==

The pharynx develops from the cephalic end of the primitive gut. This part of the gut is primarily of uniform diameter, is broadly attached by mesoderm to the dorsal body wall, and ends blindly (Fig. 247). When the branchial arches and grooves develop in this (the cervical) region, they affect the gut as well as the periphery of the body. The arches form ridges on the surface of the body (Fig. 85) and at the same time form ridges on the wall of the gut. The grooves form pockets which alternate with the arches (Fig. 256). The pock in the pharyngeal cavity, or inner branchial grooves, are directed outward toward corresponding outer branchial grooves (Fig. 249). The arches are covered externally with ectoderm, internally with entoderm, and are filled with mesoderm. Between the arches, or in the grooves, the ectoderm and entoden are in contact or nearly so. Thus the pharynx is not surrounded by a coelomic cavity.

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'''Fig. 256. Sagittal section through the head of a human embryo of 4.2 mm (31-34 days)'''. His

Since the branchial arches develop in such a way that they are successively smaller from the first to the fourth, the pharyngeal cavity becomes funnelshaped (Fig. 256). It also becomes somewhat flattened in the dorso-ventral direction, and in the earlier stages when the arches and grooves are fully formed, the pharynx constitutes approximately one-third the entire gut (Fig. 247). Primarily the pharyngeal cavity is separated from the oral cavity by the pharyngeal membrane (see p. 287 ; also Fig. 244). When this ruptures and disappears (during the fourth week ?) the two cavities are in open communication. What point in the adult represents the attachment of the pharyngeal membrane is not known; but the glosso- and pharyngo-palatine arches (pillars of the fauces) are usually considered as the boundary between the mouth and pharynx. The caudal limit of the pharynx is the opening of the larynx (Figs. 247 and 256).

Thus in the early stages the general adult character of the pharynx is established. While the branchial arches and grooves undergo profound changes, the pharyngeal cavity retains the same relation to the mouth and to the oesophagus and respiratory tract. The cavity becomes relatively shorter, however, and the alternating ridges and pockets in its walls are lost as the arches and grooves are transformed into other structures. The metamorphosis of the arches and grooves is considered elsewhere (p. 118).

==The Tonsils==

The tonsils arise in the region of the ventral part of the Lsecond inner branchial groove. During the third month the epithelium (entoderm) grows into the underlying connective (mesenchymal) tissue in the form of a hollow bud. From this, secondary buds develop, which are at first solid, but later (during the fourth or fifth month) become hollow by a disappearance of the central cells and open into the cavity of the primary bud, thus forming the crypts. Lymphoid cells wander from the neighboring blood vessels, or are derived directly from the' epithelium- (Retterer), and with the connective tissue form a diffuse lymphatic tissue under the epithelium (Fig. 257). By the eighth month the cells become more numerous in places, and by the third month after birth form distinct lymph follicles with germinal centers. The formation of follicles goes on slowly and is probably not complete until some time after birth.

===The Lingual Tonsils===

The lymphatic tissue of the tongue develops in relation to the lingual glands. During the eighth month lymphoid infiltration occurs around the ducts of the glands, and the connective tissue acquires the reticular character. True follicles probably do not appear until the child is at least five years old.

===The Pharyngeal Tonsils===

During the sixth month small folds appear in the mucous membrane of the roof of the pharynx and become diffusely infiltrated with lymphoid cells. This occurs first in the posterior part of the roof, but later (seventh or eighth month) it extends forward and along the sides of the nasopharygeal cavity. By the end of foetal life the ridges become quite large. Follicles may appear before birth or not until one or two years later. After puberty the ridges almost completely disappear, but the adenoid tissue remains wholly or in part.

The bursa pharyngea is an evagination from the roof of the pharynx about the upper border of the superior constrictor muscle, and is apparent in embryos of eleven weeks. It probably has no genetic relation to the hypophysis. Its significance is not known.

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'''Fig. 257. Section through the middle of the developing tonsil of a human embryo of 5 months.''' Stohr.

:6, Epithelial buds (secondary outgrowths) from the epithelium lining the primary crypt (c) ; L, lymphoid infiltration of the connective (mesodermal) tissue.

==The Branchial Epithelial Bodies==

===The Thyreoid Gland===

The {{thyreoid}} arises, after the manner of ordinary glands, as an evagination from the epithelium of the pharynx. It appears in embryos of 3 to 5 mm as a ventral outgrowth of epithelium in the floor of the pharynx, at the point where the tuberculum impar and the two paired anlagen of the tongue join (Fig. 258). This point is the foramen caecum linguae which has already been mentioned in connection with the development of the tongue (p. 290) . The evagination grows into the mesodermal tissue in the ventral wall of the neck, and forms a transverse mass of epithelium. The latter breaks up into irregular cords of cells which, by a further process of budding, grow cau dally along the ventral surface of the larynx. The cords of cells are from the first surrounded by connective tissue and later also become surrounded by networks of capillaries (Fig. 259). They ultimately break up into smaller masses which become hollow and form the alveoli. Colloid secretion begins toward the end of fcetal life or soon after birth.

As the gland grows toward its final position it becomes enlarged laterally into the two lateral lobes, which remain connected by the isthmus (Fig. 260). The Pyramidal process represents either a secondary outgrowth from the isthmus or one of the lobes, or a remnant of the original connection with the tongue, that is, of the thyreoglossal duct. The duct usually disappears for the most part, but certain structures sometimes found in the adult in the line of the duct are possibly remnants of it. They have been variously named, according to their position, accessory thyreoid , suprahyoid, and prehyoid glands (Fig. 260).

A pair of structures, appearing first in embryos of 8 to 10 mm., arise as evaginations from the ventral ends of the fourth inner branchial grooves. They grow into the mesodermal tissue and then caudally along the ventro-lateral side of the larynx, where they come into close relation with the lateral lobes of the thyreoid (Fig. 260). They have been called the lateral thyreoids, and acquire the thyreoid structure.

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'''Fig. 258. Transverse section through the region of the 3d branchial groove of an {{Echidna}} embryo.''' Maurer. i.= Pharynx, below which are the paired anlagen of the tongue.

Considerable confusion has arisen in regard to the lateral thyreoids. The earlier investigators held that they were derived from the fourth groove and united with the medial portion, which appeared at the foramen caecum, to become integral parts of the thyreoid. Further researches among the lower Vertebrates led others to deny that the thyreoid arose other than as a medial anlage, and that the so-called lateral thyreoids in the embryo were the postbranchial bodies which never assumed the thyreoid structure, but atrophied and disappeared. More recently it has been thought that, although the postbranchial bodies do not function in the lower Vertebrates, they may in the higher Mammals and man unite with the medial thyreoid and secrete colloid.

The parathyreoids or epithelial bodies also come into close relation with the thyreoid. They arise as paired evaginations from the cephalic sides of the third and fourth grooves, dorsal to the thymus and the lateral thyreoid evaginations (Figs. 258 and 261). As the thyreoid grows caudally from its point of origin, these bodies come to lie close to it or may even become embedded in it (Fig. 260). They acquire a structure which resembles that of the suprarenal gland and not that of the thyreoid. Their relation to the latter organ seems to be purely topographical.

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'''Fig. 259. Section of the right half of the thyreoid gland of a pig embryo of 22.5 mm.''' Born.

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'''Fig. 260. Branchial groove derivatives of a rabbit embryo of 16 mm.''' P.-th., parathyreoid or epithelial body. Verdun, Bonnet.

===The Thymus===

The {{thymus}} appears in embryos of about 6 mm. as an entodermal evagination from the ventral part of the third branchial groove on each side (Fig 258) . The outgrowths are at first hollow and communicate with the pharyngeal cavity; later they become solid and (in embryos of 14 mm.) lose their connection with the parent epithelium. They elongate and grow caudally in the mesodermal tissue until (in embryos of 16 mm.) their caudal ends lie ventral to the carotid arteries (Fig. 260). In embryos of 29 mm. their caudal ends rest upon the cephalic surface of the pericardium, their cephalic ends reaching to the isthmus of the thyreoid. The two parts eventually fuse to a considerable extent, but the gland as a whole always consists of two distinct lobes.

The gland continues to enlarge, at the same time becoming lobulated by the ingrowth of connective tissue, until the child is two or three years old. At this time it is situated in the anterior mediastinum, usually in the medial line. After this it begins to atrophy and becomes a mass of fibrous and fatty tissue through the growth of the interlobular septa and their encroachment upon the lobules. The classical view that the thymus begins to atrophy after the second or third year and is quite degenerated in the adult has recently been somewhat offset by the view that comparatively slight changes take place in it until puberty. According to the latter view, degeneration goes on after puberty at a rate which varies widely in different individuals, and the thymus may persist as a functional organ up to the age of sixty years.

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'''Fig. 261. Diagram of the branchial groove derivatives in man.''' Verdun.

The histogenesis of the thymus has been a subject of much study and controversy, not only in regard to its origin, but also in regard to its change from an epithelial to a lymphoid structure and the regressive changes in the latter. It has almost certainly been proven to be of entodermal origin. It is at first an epithelial mass which later becomes broken up into lobules by the ingrowth of connective tissue. In regard to the histological changes which it undergoes, the older views are in general that a " pseudomorphosis " takes place; that is, the epithelial elements are replaced by lymphoid cells which wander in from the neighboring blood vessels, Hassall's corpuscles being remnants of the epithelium. Later other investigators looked upon the changes as a "transformation," asserting that the epithelial cells were transformed into lymphoid cells in situ, and that Hassall's corpuscles were remnants of epithelium and disintegrating blood vessels. Some went even so far as to assert that the thymus was the first place of origin of the leucocytes. More recent researches furnish very strong evidence that no lymphoid cells are derived from the epithelial cells (Maximow), but that the epithelium is transformed into the reticular tissue of the thymus, in which the lymphoid cells undergo mitotic division, Hassall's corpuscles possibly representing compressed parts of the reticulum (Hammar) (Fig. 262).

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===The Glomus Caroticum===

The early formation of the glomus caroticum (carotid FIG. 262. Hassall's corpuscle from gland) has not been observed in the human ZftfO^Z** embryo. From observations on lower animals it has not been made clear whether it is derived from the entoderm of a branchial groove or from the adventitia of the carotid artery.

==The Esophagus==

When the primitive gut becomes differentiated into* distinct regions (p. 286), the cesophageal region forms a comparatively short: tube, of uniform diameter, extending from the pharynx to the stomach (Fig. 247). In embryos of about 3 to 4 mm. the anlage of the respiratory system arises from the cephalic end of the tube (see p. 330). The latter is lined with entoderm and broadly attached to the dorsal body wall by mesoderm (Fig. 247). During later stages it becomes relatively longer as the heart recedes into the 1 thorax (p. 214), but maintains its uniform diameter.

Further development produces no marked changes in the relative position; of the oesophagus. It remains broadly attached to the dorsal body wall! throughout the life of the individual. In other words, there is never a distinct! mesentery. The entoderm gives rise to the epithelial lining and the glands, the: surrounding mesoderm to the connective tissue and muscular coats.

===The Stomach===

The anlage of the {{stomach}} can be recognized in embryos of about 5 mm as a slight spindle-shaped enlargement of the primitive gut ai short distance cranial to the yolk stalk (Fig. 246). The dilatation goes on more rapidly on the dorsal than on the ventral side, thus producing the greater and^ lesser curvature respectively. The greater curvature is attached to the dorsaU body wall by the dorsal mesogastrium which is a part of the common mesentery.

The lesser curvature is connected with the ventral body wall by the ventral mesogastrium (Fig. 263).

In further development, apart from histogenesis, the greater curvature becomes much more prominent and the organ as a whole changes its position, the latter process beginning in embryos of 12 to 14 mm. The cephalic (cardiac) end moves toward the left side of the body, the pyloric end toward the right At the same time the stomach rotates, the greater curvature turning caudally from its dorsal position and the lesser curvature cranially from its ventral position. The result is that the organ comes to lie in an approximately transverse position in the body, with the cardiac end to the left, the pyloric end to the right, the greater curvature directed caudally, and the lesser curvature directed cranially (compare Figs. 247 and 263 with Figs. 276 and 304).*

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'''Fig. 263. Gastrointestinal tract and mesenteries of a human embryo of 6 weeks'''. Toldt.

* These changes may be more easily understood if the student will hold a closed book in the sagittal plane in front of him, with the back of the book toward, and the open edge away from him. The back represents the greater curvature, the open edge the lesser curvature. The upper end of the book represents the cardiac end of the stomach, the lower end the pylorus. Turn the upper (cardiac) end to the left, the lower (pyloric) end to the right, at the same time allowing the back of the book (the greater curvature) to drop downward on the side toward the body. The changes in the position of the book represent the changes in the position of the developing stomach.

It is obvious that the lower end of the oesophagus is carried toward the left side of the body with the cardiac end of the stomach, and at the same time twisted so that the side which originally faced the left comes to face ventrally. The changes in the mesentery which accompany the changes in the stomach are described elsewhere (p. 348).

The torsion of the stomach also produces an asymmetrical condition of the vagi nerves. The latter reach the stomach before it changes its position. As the changes take place, the left nerve is carried around to the left and ventrally so that in the adult it passes through the diaphragm ventral to the oesophagus and extends over the ventral surface of the stomach. The right nerve passes over the dorsal surface of the stomach.

==The Intestine==

When the primitive gut is differentiated into recognizable regions (p. 286) the intestinal region forms a simple tube, of uniform diameter, extending from the stomach to the caudal end of the embryo where it ends blindly. The yolk stalk is attached to the intestine a short distance from the stomach. Near the caudal end the allantoic duct arises (p. 582). The lumen of the yolk stalk and of the allantoic duct is continuous with that of the intestine (Fig. 247). In embryos of 2 to 3 mm. the liver anlage arises from the ventral side of the intestine near the stomach, that is, from that part of the intestine which is to become the duodenum. In embryos of 3 to 4 mm. the pancreas anlage arises in the same region, in part from the liver evagination and in part from the dorsal side of the intestine (Fig. 247).

The {{intestine}} as a whole is suspended in the abdominal cavity by the dorsal mesentery which is attached to the dorsal body wall and which is continuous with the dorsal mesogastrium. A ventral mesentery, continuous with the ventral mesogastrium, is present only at the cephalic end of the duodenum (Fig. 263).

The further development of the intestine, apart from histogenesis, consists very largely of the formation of loops and coils, due to an enormous increase in the length of the tube. The abdominal cavity at the same time enlarges to accommodate the increased bulk. As the stomach changes its position (p. 305) , the duodenum comes to lie obliquely across the body and forms a curve with the concavity directed dorsally (Fig. 263). The rest of the intestine forms a loop which extends ventrally and caudally as far as the umbilicus. The arms of the loop are almost parallel and the cephalic arm lies a little to the left of the caudal. The apex of the loop extends into the umbilical ccelom and is attached to the yolk stalk. From the dorsal end of the caudal arm the intestine extends directly to the caudal end of the body (Fig. 263).

Soon after the loop is formed a small evagination appears on its caudal arm, not far from the apex. This is the anlage of the cecum and marks the boundary between the small and large intestine (Fig. 263). At this stage, therefore, all the great divisions of the intestinal tract are distinguishable, viz. : the duodenum with the ducts of the liver and pancreas; the mesenterial small intestine with the yolk stalk; and the colon extending from the caecum to the caudal end. There are, however, practically no differences between the regions, either in structure or in size.

In further development the duodenum comes to lie more nearly transversely across the body, thus assuming its adult position. Its mesentery fuses with the peritoneum of the dorsal body wall and the duodenum thus becomes a fixed portion of the intestinal tract (p. 350; also Fig. 301). It enlarges a little more rapidly than the rest of the small intestine and acquires a greater diameter. In embryos of 12 to 13 mm. the lumen becomes obliterated by an overgrowth of the mucous membrane caudal to the ducts of the liver and pancreas. In embryos of about 15 mm., however, the lumen reappears. It seems difficult to find a cause for this peculiar growth of the mucosa.

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'''Fig. 264. Reconstruction of the liver and intestine of a human embryo of 17 mm.''' Mall. G.B., gall bladder; H. V., hepatic vein; U.V., umbilical vein; 1 -6, primary bends in the long intestinal loop; 1 represents the duodenum.

Very shortly after the formation of the long loop in the intestine, six bends become recognizable in the portion between the stomach and the apex of the loop (Fig. 264). These bends later form distinct loops which are destined to become definite parts of the small intestine. The first loop is the duodenum, the development of which has already been considered, and which maintains practically its original position. The other five loops continue to elongate and form secondary loops, all of which push their way into the umbilical coelom where they remain until the embryo reaches a length of 40 mm. (compare Figs, 265 and 266). Then they return very quickly to the abdominal cavity proper.

After their return, the primary loops, with the secondary loops derived from them, come to occupy fairly constant positions. The second and third move to the left upper part of the abdominal cavity; the fourth crosses the medial line and occupies the right upper part. The fifth crosses back and lies in the left iliac fossa; the sixth lies in the pelvis and lower part of the abdominal cavity (Fig. 267).

Certain variations may occur but are usually not considered as abnormal. The most frequent variation is one in which the fourth coil, along with the second and third, lies on the left side, its usual position on the right being occupied by the ascending colon. Not uncommonly the positions of the fourth and the second and third are reversed. Less commonly extra loops are formed.

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'''Fig. 265. Reconstruction of the stomach and intestine of a human embryo of 28 mm.''' Matt.

:The numbers are placed on the coils derived from the primary bends as shown in Fig. 302; 1 represents the duodenum.

Usually the proximal part of the yolk stalk disappears during foetal life. In a few cases, however, it persists as a blind sac of variable length, known as Meckel's diverticulum (see also p. 581).

Even before the loops return to the abdominal cavity the colon or large intestine increases in diameter more rapidly than the small intestine. After the return, the caecum is carried across to the right side and comes to lie just caudal to the liver. From the caecum the colon extends across the abdominal cavity, ventral to the duodenum, forming the transverse colon. It then descends on the left side as the descending colon which passes over into the sigmoid colon (Fig. 299). The transverse, the descending and the sigmoid portions of the colon are recognizable in the third month. Up to the time of birth the sigmoid portion is disproportionately long; after birth the other portions grow relatively faster. After the fourth month the portion to which the caecum is attached grows downward in the right side of the abdominal cavity, thus forming the ascending colon (Fig. 304).

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'''Fig. 266. Drawing from a reconstruction of a human embryo of 24 mm.''' Matt. The intestinal coils lie for the most part in the umbilical coelom. C, caecum; K, kidney; L, liven S, stomach; S. C., suprarenal gland; W, mesonephros; 12, twelfth thoracic nerve; 5, fifth lumbar nerve.

The caecum, which appears in very early stages as an evagination at the junction of the small and large intestines, for a time continues to increase uniformly in size. Then the proximal end increases more rapidly than the distal, and forms the caecum of adult anatomy. The distal end, failing to keep pace in development, remains more slender and forms the vermiform appendix (Fig. 267).

As has already been mentioned, the primitive gut ends blindly in the caudal end of the embryo (Fig. 246). The anal opening is a secondary formation, On the ventral side of the caudal end of the body there is formed a depression known as the anal pit. The mesoderm at the bottom of the pit becomes thinner until the ectoderm comes in contact with the entoderm on the ventral side of the gut, thus forming the anal membrane. The area of contact is not at the extreme end of the gut, but a short distance toward the allantoic duct. In the meantime, the urogenital ducts come to open into that portion of the gut which lies just cranial to the anal membrane. The gut enlarges in this region to i/form the cloaca. The latter becomes separated by the urorectal fold into a portion, the rectum, and a ventral portion, the urogenital sinus (Figs. 323 and 325). At about the time of separation (embryos of about 14 mm. or thirty-six to thirty-eight days) the anal membrane ruptures and the anal opening is formed. The portion of the gut caudal to the anus, known as the caudal gut, normally disappears.

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'''Fig. 267. Drawing from a model of the small intestine in the adult.''' Ventral view. Mall.

:The intestinal coils are shown in the usual relative position. The numbers indicate the coils derived from the primary bends in the foetus as shown in Figs. 264 and 265.

==Histogenesis of the Gastrointestinal Tract==

The wall of the primitive gut is composed of two layers the entoderm which lines the lumen, and the splanchnic mesoderm which borders on the ccelom or body cavity. While the germ layers are still flat, the entoderm is a single layer of flat cells with bulging nuclei, but after the closure of the gut the cells become columnar. The splanchnic mesoderm is composed of two layers the mesothelium bordering on the ccelom, the cells of which gradually change from flat to rather high, and a number of indifferent, branching mesenchymal cells lying between the mesothelium and entoderm. The entoderm is destined to give rise to the general epithelial lining of the gastrointestinal tract and to all the glands connected with it. The mesothelium around the gut forms a part of the general mesothelial lining of the ccelom, its cells apparently changing back to a flat type. The mesenchymal tissue is destined to give rise to all the connective tissue and smooth muscle of the tract. The circular layer of muscle appears first, the longitudinal next, both appearing during the third and fourth months, and last of all the muscularis mucosae (Fig. 268).

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'''Fig. 268. Transverse section of the small intestine of a pig embryo of 32 mm.''' Bonnet.

===The Mucous Membrane===

The mucous membrane is formed by the epithelium (entoderm) and the subjacent mesenchymal tissue. In its development there are two factors to be considered: (i) The formation of folds to increase the absorbing surface and (2) the formation of secreting organs or glands. As to the relation between these two factors there is a difference of opinion. Some hold that both kinds of structures are the result of the same formative process, that is, that the glands are simply the depressions or pits formed by the intersection of folds at various angles, and that the folds are produced primarily by the growth of the epithelium and mesenchymal tissue into the lumen of the gut. Others maintain that although the folds may be produced by the growth of the epithelium and mesenchymal tissue into the lumen, the glands arise as independent growths of the epithelium into the subjacent tissue. The latter view is supported by the fact that in some Amphibia the glands appear before the folds (Fig. 269). Recent work on Mammals also favors this view.

The development of the folds and glands begins in the different parts of the gastrointestinal tract at different times. It begins first in the stomach, then in the duodenum, then in the colon, and then whence it progresses slowly into the ileum. In the stomach it is uncertain whether the crypts and glands are depressions left among projections of the mucous membrane, or the glands represent evaginations of the epithelium into the underlying tissue. In the case of the large intestine the same uncertainty exists. If the so-called glands are depressions among villous projections that grow-in to the lumen of the intestine, they are not true glands from an embryological point of view.

Studies of the development of the villi in the human small intestine have led to the conclusion that they are formed primarily as growths of the mucosa into the lumen. In embryos of 19 mm. the mucosa of the cephalic end is thrown into a number of longitudinal folds (Fig. 270). These then develop progressively toward the caudal end. Beginning in embryos of 50 to 60 mm. the longitudinal folds become broken transversely into conical structures, the villi. The intestinal crypts (of Lieberkiihn) possibly represent outgrowths of the epithelium from the bottoms of the intervillous spaces.' The duodenal (B runner's) glands are possibly to be considered as a continuation of the pyloric glands of the stomach. They apparently grow as evaginations from the intervillous crypts.

The epithelial lining of the gastrointestinal tract is from the beginning a single layer of cells, although the individual cells are altered in shape and structure and acquire different functions in different regions. There is still some dispute as to whether the mucous cells are continuously being derived from the other epithelial cells or, when once formed, reproduce themselves by mitosis. As a matter of fact, mitosis has been observed in the mucous cells of the stomach.

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'''Fig. 270. From a reconstruction of the small intestine of a human embryo of 28 mm.''' Berry. Showing the longitudinal ridges which eventually become broken transversely to form the villi.

===The Lymph Follicles===

In the development of the lymph follicles in the gastrointestinal tract the same question arises as in the case of the tonsils and thymus. Are the lymphoid cells of mesodermal or of entodermal (epithelial) origin? Evidence at present favors the mesodermal origin. In the case of Peyer's patches, collections of lymphoid cells appear near the blood vessels in the stroma and neighboring parts of the submucosa. These increase in extent, the lymphoid cells dividing actively, and grow into the bases of some of the villi and deeper into the submucosa (Fig. 271). Germinal centers appear in many of the follicles, and the surrounding stroma becomes densely infiltrated with the lymphoid cells. Individual follicles may develop, in the manner described, in any part of the gastrointestinal tract. The appendix especially is the seat of extensive lymphatic tissue formation. It is stated in the section on the lymphatic system that lymph glands may arise at any time in any region as the result of unusual conditions (p. 251), and this also holds true in the case of lymph follicles in the digestive tract.

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Fig. 271. Sections through the wall of the caecum of (a) a rabbit 2.5 days and (b) 5 days after birth, showing the development of the lymph follicles. Stohr.

:Lymphoid infiltration in the stroma; r, wandering cells in the epithelium; 2, lymphoid cells in the core of a villus.

==The Development of the Liver==

The liver is the first gland of the digestive tract to appear. In embryos of about 3 mm. a longitudinal ridge-like evagination develops from the entoderm on the ventral side of the gut a short distance caudal to the stomach, that is, in the duodenal portion of the gut (Figs. 247, 272, 273). The cephalic part of the evagination is solid and, being destined to give rise to the liver proper, is called the pars hepatica. The caudal part is hollow, its cavity being continuous with the lumen of the gut, and is destined to give rise to the gall bladder, whence it is called the pars cystica. Beginning at both the cephalic and caudal ends, the evagination as a whole becomes constricted from the gut until (in embryos of about 8 mm.) its only connection with the latter is a narrow cord of cells which is the anlage of the ductus choledochus. The pars hepatica by this time has enlarged considerably and remains attached to the ductus choledochus by a short cord of cells, the anlage of the hepatic duct. The pars cystica has also become larger, its distal portion being somewhat dilated, and is connected with the ductus choledochus by the anlage of the cystic duct (Figs. 274 and 275). The pars cystica grows into the ventral mesentery and thus becomes surrounded by mesodermal tissue. The proximal portion continues to elongate to form the cystic duct and the distal portion becomes larger and more dilated to form the gall bladder.

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'''Fig. 272. Transverse section of a human embryo of 5 mm.''' Showing the liver evagination and the breaking up of the omphalomesenteric veins by the hepatic cylinders. Photograph.

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'''Fig. 273. From a model of the duodenum and the primary evaginations of the liver and pancreas in a 5 mm sheep embryo.''' Stoss.
: D.pan., Dorsal pancreas; Du., duodenum; D. ch., ductus choledochus; G. bl., gall bladder; H. du., hepatic duct.

The pars hepatica, or anlage of the liver proper, also grows into the ventral lesentery, thus becoming surrounded by mesodermal tissue. As stated in connection with the development of the diaphragm, the portion of the mesentery into which the liver grows is involved in the formation of the septum trans versum (p. 344). Thus the developing liver becomes enclosed in the septum (Fig. 292). The mesodermal tissue gives rise to the fibrous capsule of Glisson and to the small amount of connective tissue within the gland.

Although the liver develops as a series of outgrowths from the original evagination, there are certain features in its development which distinguish it from glands in general. The outgrowths come in contact with the omphalomesenteric veins which are situated in the ventral mesentery (p. 229). They push their way into and through the veins, breaking them up into smaller channels (Fig. 272). They anastomose freely with one another, and the veins send off branches which circumvent them. Thus there is formed a network of trabec ulse of liver cells, called hepatic cylinders, the meshes of which are filled with blood vessels. Therefore the liver is distinguished from other glands in general in that the hepatic cylinders, which are comparable with the smaller ducts and terminal tubules of other glands, anastomose, and in that the blood vessels are broken up by the growth of these cylinders.

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'''Fig. 274. From a reconstruction of the anlagen of the liver and pancreas and a part of the stomach and duodenum of a human embryo of 4 weeks.''' Felix.

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'''Fig. 275. From a reconstruction of the anlagen of the liver and pancreas and the stomach of a human embryo of 8 mm.''' Hammar.

:D.P., Dorsal pancreas; Du., duodenum; D. F., ductus venosus; G.B., gall bladder; R.I., right lobe of liver; S. t stomach; V. P., ventral pancreas.

This mode of development establishes what is known as a sinusoidal circulation, which differs from the ordinary capillary circulation. The sinusoids are produced by the growth of the trabeculae of the developing organ into large vessels and the breaking up of the latter into smaller vessels. It is obvious that a sinusoidal circulation is purely venous or purely arterial. Furthermore, development of this nature leaves comparatively little connective tissue within the gland, another feature characteristic of the liver.

All the blood carried to the liver by the omphalomesenteric veins must follow the tortuous course of the sinusoids before being collected again and passed on to the heart. When the umbilical veins come into connection with the liver they also join in the sinusoidal circulation. Subsequently, however, a more direct channel the ductus venosus is established and persists for a short time. This is probably due to the large volume of blood brought in by the umbilical veins. Finally the ductus venosus disappears and the sinusoidal circulation remains as the permanent form. (For the development of the veins in the liver see p. 228.)

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'''Fig. 276. Tranverse section of a 14 mm pig embryo, through the region of the stomach.''' Photograph. The arrow points into the bursa omentalis.

The lobes of the liver develop in a general way in relation to the great venous trunks which at one time or another pass into or through the gland. The anlage of the organ grows into the ventral mesentery, subsequently becoming enclosed in the septum transversum. In so doing it encounters the omphalomesenteric veins, and forms, in relation to the latter, two Incompletely separated parts which have been called the dorso-lateral lobes. When the umbilical veins enter the liver a more ventral, medial mass is formed. This becomes incompletely separated into two parts which give rise to the permanent right and left lobes. The right becomes the larger. The right umbilical vein loses its connection with the liver (p. 230). After birth the left, which lies between the right and left lobes, degenerates into the round ligament of the liver. The other lobes arise secondarily as outgrowths from the right primary dorsolateral lobe, the caudate (lobe of Spigelius) from its inner (medial) surface, the quadrate from its dorsal surface.

The liver as a whole grows rapidly and by the second month is relatively large. During the third month it fills the greater part of the abdominal cavity. After the fifth month it grows less rapidly and the other intraabdominal organs overtake it, so to speak, although at birth it forms one-eighteenth the total weight of the body. After birth it actually diminishes in size. The right lobe is from the beginning larger than the left, and after birth the predominance increases.

Histogenesis of the Liver. The hepatic part (pars hepatica) of the liver anlage is derived from the entodermal lining of the gut and constitutes a mass of cells with no lumen. From this mass, solid bud-like evaginations grow into the mesentery, break up the omphalomesenteric veins into smaller channels and form trabeculae, or hepatic cylinders (p. 316). The latter anastomose freely with one another and are composed of polyhedral, darkly staining cells with vesicular nuclei (Fig. 277, A). Lumina begin to appear in the cylinders about the fourth week as small cavities which communicate with the cavity of the gut.

The hepatic cylinders are the forerunners of the hepatic cords or cords of liver cells. There are two views as to the manner of transformation. The older view is that the cylinders gradually become stretched, the number of cells in cross-section becoming less until it is reduced to two. Between these two lies the lumen of the cord or the so-called "bile capillary" (Fig. 277, B). The other view is that branches from the sinusoids grow into the cylinders and subdivide them into hepatic cords.

As stated above, the hepatic cylinders are at first composed of darkly staining, polyhedral cells with vesicular nuclei. These are the liver cells proper. Later other small spherical cells, with dense nuclei, appear and during the fourth month become very numerous (Fig. 277, A). From this time on, they grow less in number and at birth have practically disappeared. Earlier investigators considered them as developing liver cells. Further study on the development of the blood, however, has led others to consider them as erythroblasts (p. 239). Since they are inside of the hepatic cylinders, they either wander in from the intertrabecular blood vessels or lie in intratrabecular vessels. The latter supposition accords with the view that the cylinders are broken up into hepatic cords by the ingrowth of branches from the sinusoids.

The development of the lobules of the liver, producing the peculiar relations between the parenchyma of the gland and the blood vessels, has not been clearly and completely demonstrated. In young embryos the branches of the hepatic veins are surrounded by comparatively little connective tissue. The branches of the portal vein are surrounded by a considerable amount which subdivides the liver into lobules but not in the same manner as in the adult. The trabeculae possess no radial character and there are several so-called central veins in each lobule. The changes by which these primary lobules are subdivided into the permanent ones do not take place until after birth. The branches of the portal vein, with the surrounding connective tissue, invade the primary lobules and divide them into a number of secondary lobules, corresponding to the original number of central veins. At the same time the hepatic cords (which have been formed meanwhile) become arranged radially around the central veins in the characteristic manner. The hepatic artery grows into the liver secondarily and its branches follow the course of the branches of the portal vein.

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'''Fig. 277. Sections of the liver of (^4) a human foetus of 6 months and (B) a child of 4 years.''' Toldt and Zuckerhandl. McMurrich. be, Bile "capillary"; e, erythroblast; he, hepatic cylinder (in A), cord of liver cells (in B).

Degeneration of the liver cells occurs in the region of the left triangular ligament, the gall bladder and the inferior vena cava. The bile ducts may, however, withstand the degenerative processes and persist as the vasa aberrantia of the liver. The cause of the degeneration is possibly the pressure brought to bear by other organs.

==The Development of the Pancreas==

The epithelium of the pancreas, like that of the liver, is a derivative of the entoderm. It arises from two (or three) separate anlagen, one dorsal and one (or two) ventral. The dorsal anlage appears first as a ridge-like evagination from the dorsal wall of the gut, slightly cranial to the level of the liver (Figs. 273 and 274). It appears about the same time as the liver or a little later. The mass of cells grows into the dorsal mesentery and becomes constricted from the parent epithelium except for a thin neck which becomes the duct of Santorini (Fig. 278). A little later two other diverticula appear, one from each side of the common bile duct. It is uncertain whether only one or both of these take part in the formation of the pancreas, but it seems most probable that the left one disappears entirely. The right diverticulum continues to develop and becomes constricted from the parent epithelium, leaving only a thin neck which becomes the duct of Wirsung.

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'''Figs. 278 and 279. From models of the developing liver and pancreas of rabbit embryos of 8 mm. and 10 mm''', respectively. Both seen from the right side. Hammar, Bonnet.

The smaller ventral pancreas grows to the right and then dorsally in the mesentery (Fig. 260), passing over the right surface of the portal vein, until it meets and fuses with the proximal part of the larger dorsal pancreas. The fusion takes place in the sixth week, and the two anlagen then form a single mass. A communication is established between the two ducts, and the dorsal duct (Santorini) usually disappears, leaving the ventral (Wirsung) as the permanent duct opening into the ductus choledochus. In a general way it may be said that the ventral anlage gives rise to the head, the dorsal anlage to the body and tail of the pancreas (compare Figs. 278 and 279).

As the pancreas grows into the dorsal mesentery it comes to lie in the dorsal mesogastrium between the greater curvature of the stomach and the vertebral column, and since the dorsal mesogastrium at first lies in the medial sagittal plane, the pancreas is similarly situated. After the sixth week, however, as the stomach changes its position (p. 305) , the pancreas is carried along with the mesogastrium and comes to lie in a transverse plane, with its head to the right and embedded in the bend of the duodenum, and its tail reaching to the spleen on the left. The organ as a whole is at first movable along with the mesentery, but when it assumes its transverse position it lies close to the dorsal abdominal wall. The mesentery then fuses with the adjacent peritoneum (see p. 350), and the pancreas is firmly fixed.

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'''Fig. 280. From a transverse section through the region of the duodenum of a pig embryo of 14 mm.''' Photograph.

The connective tissue of the pancreas is derived from the mesodermal tissue of the mesentery. As the processes or buds which form the ducts and terminal tubules grow out from the primary masses, they penetrate the mesodermal tissue and are surrounded by it. Groups of tubules form lobes and lobules, and the entire gland is surrounded by a capsule of connective tissue.

Histogenesis of the Pancreas. The masses of entodermal cells forming the anlagen of the pancreas develop further by a process of budding, which goes on until finally a compound tubular gland is produced. According to some investigators the primary evaginations are hollow, their lumina beinj continuous with the lumen of the gut. According to others they are solid al first and acquire their lumina secondarily. The same uncertainty exists regard to the later outgrowths or buds.

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'''Fig. 281. Sections of the developing pancreas of a guinea-pig embryo of 12 mm.''' (a); of 33 mm. (&) ; of Torpedo marmorata (c) . Hetty.

:c t Capillaries; Dg, ducts; Gz, duct cells; Lz, Langhans' cells. The cells in c show distinct zymogen granules

The early entodermal cells proliferate, and the resulting cells change according to their position in the gland. Those lining the larger ducts become high columnar, with more or less homogeneous cytoplasm; those lining the intermediate (intercalated) ducts become low; those lining the terminal secreting tubules become pyramidal and more highly specialized, and also acquire certain constituents the zymogen granules (Fig. 281, c) which vary with the functional activities of the gland. The centro-tubular cells in the terminal tubules are probably to be explained on a developmental basis. While a few maintain that they are "wandering" cells, it is quite generally accepted that they are simply continuations of the flat cells lining the intermediate ducts, the result being that the cells of the terminal tubules seem to spread out over the ends of the intermediate ducts in the form of cap-like structures.

It was once thought that the islands of Langerhans were derived from the mesodermal tissue. Recently it has been pretty clearly demonstrated that they are derived from entoderm. In guinea-pig embryos of 5 to 6 mm., at a time when the dorsal pancreas has merely begun its constriction from the gut, certain cells in the mass appear darker and slightly larger than the others. They show darker areas of cytoplasm around the nuclei, and later the darker areas extend throughout the cells and the nuclei become larger and more vesicular. When lumina appear in the outgrowths or buds, these cells occupy a position on or near the surface of the buds (Fig. 281, a). In further development they tend to separate themselves from the buds and collect in clumps (Fig. 281, b). Capillaries then penetrate the clumps and break them up into the trabeculae of cells characteristic of the islands of Langerhans (Fig. 281, c). Studies on the development of the islands in the human pancreas indicate a similar origin and mode of development.

==Anomalies==

One of the most striking anomalies of the organs of alimentation is found in connection with a more general anomalous condition known as transposition of the viscera (situs viscerum inversus) . The transposition may be so complete that the minor asymmetries normally present on the two sides are all repeated in reverse order, the functions of the organs being unimpaired. As regards the alimentary tract, this means that the position of the stomach is reversed in the abdominal cavity; that the duodenum crosses from left to right; that the various coils of the jejunum and ileum occupy positions opposite to the normal; that the caecum and ascending colon are situated on the left side and the descending colon on the right; and that the larger lobe of the liver lies on the left side. The other visceral organs are transposed accordingly, the heart being inclined toward the right side, the left lung consisting of three lobes and the right of two, the left kidney being lower than the right, etc. Such cases are not uncommon, two hundred being on record.

Various theories as to the causes of transposition of the organs have been advanced. In the most plausible of these the anomalous condition is considered as due to the influence of the large veins in the embryo. It seems best, therefore, to consider first the transposition of the heart (dextrocardia, referred to on page 255).

After the tvvo anlagen unite in the midventral line, the heart constitutes a simple straight tube which lies in a longitudinal direction in the primitive pericardial cavity, and which is joined caudally by the two omphalomesenteric veins and cranially by the ventral aortic trunk (p. 197) . Normally the left omphalomesenteric vein is the*larger and pours a greater quantity of blood into the heart tube than the right. This condition is regarded as the primary factor in the deflection of the tube toward the right side (p. 199; also Fig. 158). If the conditions were reversed, that is, if the right omphalomesenteric vein were the larger and poured the greater quantity of blood into the heart tube, the primary bend of the latter would be toward the left side. Consequently the heart would continue to develop in the transposed position and eventually come to lie on the side opposite to the normal.

Although dextrocardia is very frequently associated with transposition of the abdominal organs, it is not necessarily so, for there are cases of the latter in which the heart occupies the normal position. Consequently it seems that further influences must be present to account for transposition of the abdominal organs when the thoracic organs are normal. A number of investigators have emphasized the importance of the influence of the large venous trunks in the abdominal region, especially on the position of 'the liver and stomach.

Primarily the omphalomesenteric veins pass cranially through the mesentery. Later they form two loops or rings around the duodenum. Then the left half of the upper ring and the right half of the lower disappear, the common venous trunk thus following a spiral course around the duodenum (p. 231 ; also Fig. 201). This primary relation of the omphalomesenteric vein is retained in the relation of the portal vein to the duodenum. The stomach lies to the left of the portal vein. After the allantoic (placental) circulation is established the umbilical veins pass cranially in the lateral body walls. After the veins come into connection with the liver, the right atrophies and the left increases in size and becomes the single large umbilical vein of later stages (p. 230; also Fig. 202). The right lobe of the liver becomes the larger.

If, as is maintained by some investigators, the usual position of the stomach and liver is due to the persistence of the left venous trunks, a persistence of the right venous trunks would afford a plausible explanation of the transposition of these organs. It is not unreasonable to attribute also the transposition of the other abdominal organs directly or indirectly to the persistence of the right venous trunks. Certainly a reversal in the position of the stomach would cause a reversal in the position of the duodenum.

If these conditions are the real ones, the fact that the thoracic organs can be transposed without a transposition of the abdominal organs, or vice versa, is accounted for. The primary bend of the heart tube occurs at a very early period, before the changes in the vessels in the region of the liver. Consequently a reversal of the conditions of the omphalomesenteric at a very early stage only would be likely to affect the heart. The principal changes in size of the venous trunks in the abdominal region take place after their channels have been broken up in the liver. In other words, the modifications in the veins in the liver occur after the definite relations of the heart have been established. Therefore the transposition of the abdominal organs may take place after the heart has begun to develop normally.

===The Mouth===

Anomalies in the mouth region, due to defective fusion of the processes that bound it, have been considered elsewhere (p. 180).

Anomalies of the tongue sometimes arise as the result of imperfect development of one or more of its anlagen. Imperfect development of the tuberculum impar results in total or partial lack of the anterior part. Defects in the root are probably due to imperfect development of one or both of the paired anlagen (p. 289). Malformations of the lower jaw (micrognathus, agnathus) are usually accompanied by malformations of the tongue, both structures being derived largely from the first pair of branchial arches.

===The Pharynx===

The pharynx is the seat of cysts, fistulae and diverticula which have been considered in connection with the anomalies in the region of the branchial arches and grooves (Chap. XX).

The thyreoid gland is not infrequently the seat of certain anomalies that arise as the result of abnormal development. Persistent portions of the thyreoglossal duct, the upper end of which is indicated by the foramen caecum linguae, may give rise to cystic structures extending to the region of the hyoid bone. Persistent portions of the duct may even give rise to accessory thyreoid (suprahyoid, prehyoid) glands (p. 301; also Fig. 260). Considerable variation also exists in the isthmus and lateral lobes of the thyreoid, due to variation in the manner of development of the medial anlage.

Impaired development of the thymus gland sometimes leads to cysts which come to lie in the anterior mediastinum.

===The Oesophagus===

Very rarely the oesophagus is entirely lacking, being represented by a mere cord of tissue. More frequently it is defective in certain parts. Tne atresia may begin just below the pharynx or just above the stomach, the intermediate portion being composed of a cord of fibrous tissue. Occasionally the non-atretic portion opens into the trachea. Possibly this represents an imperfect separation between the primitive gut and the anlage of the respiratory system (p. 330).

===The Stomach===

Occasionally the stomach is smaller than the normal. It may even be a narrow tube resembling the other portions of the gut, owing to lack of dilatation. Other congenital malformations, apart from transposition (p. 323), are very rare.

===The Intestines===

One of the most common anomalies is the persistence of the proximal end of the yolk stalk, forming MeckeVs diverticulum (see p. 581). This usually is attached to the ileum about three feet from the caecum. In exceptional cases it retains its lumen and, when the stump of the umbilical cord disappears, forms a congenital umbilical fistula. Usually, however, the diverticulum is shorter and ends blindly. Occasionally it becomes constricted from the intestine and forms a cystic structure. (See also Chap. XX.)

Congenital stenosis and atresia may occur in different regions of the intestine, the duodenum being the most common site. Normally the lumen of the duodenum becomes closed for a brief period during development (p. 307) , and congenital closure of the lumen may represent a persistence of the early embryonic condition.

A conspicuous malformation is the persistence of the cloaca. The septum which normally separates the latter structure into rectum and urogenital sinus fails to develop, thus leaving a common cavity (see Figs. 323 and 324). In addition to this the cloacal membrane may fail to rupture and the cloaca become much distended. More often the septum develops in part, leaving only a small opening between the rectum and urogenital sinus. After the latter undergoes further development, the rectum comes to open into the urethra or bladder, or into the vagina or uterus.

Atresia of the anus is not infrequently met with. The cloacal (or anal) membrane fails to rupture and the rectum ends blindly. In other cases the rectum opens into the urogenital sinus, as described in the preceding paragraph. Occasionally the lumen of the rectum is closed atresia recti and the gut ends blindly some distance from the surface, being connected with the anal region by a cord of fibrous tissue.

Variations in the position of the intestinal loops, apart from transposition (p. 323), are of frequent occurrence. It is not customary to include these variations among malformations (see p. 308) . The caecum (and appendix) and colon present some striking variations. The caecum may be situated high up in the abdominal cavity, the ascending colon being absent. Or it may be situated at any intermediate point between that and its usual position in the right iliac fossa. These variations are due to different degrees of development of the ascending colon (p. 309).

===The Liver===

Congenital malformations of the liver are rare. The most frequent, apart from transposition, include anomalies in the size and number of lobes. Accessory lobes may occur within the falciform ligament. One case of lack of development of the gall bladder has been observed. Stenosis of the bile passages is occasionally met with.

===The Pancreas===

Occasionally accessory glands are found in the intestinal or gastric wall. These probably represent aberrant portions of the main gland, and may give rise to cystic structures. Very recently, however, a number of intestinal diverticula have been observed in certain mammalian embryos and also in human embryos. Although the history of these unusual diverticula has not been traced, their presence may offer a clue to the origin of accessory pancreatic structures. The ducts of the pancreas are subject to distinct variations, which, however, are not usually considered as anomalies. Not infrequently the duct of the dorsal anlage (duct of Santorini) persists and opens directly into the duodenum. It may persist along with the duct of the ventral anlage (duct of Wirsung), or the latter may disappear (p. 321; compare Figs. 2 78 and 279).

:'''Next:''' [[Book_-_Text-Book_of_Embryology_13|Respiratory]]

==References for Further Study==

BADERTSCHER, J. A. : The Development of the Thymus in the Pig. I, Morphogenesis. II, Histogenesis. Am. Jour, of Anat., Vol. XVII, 1915.

{{Ref-Bardeen1914}}

{{Ref-Bell1905}}

BERRY, J. M.: On the Development of the Villi of the Human Intestine. Anat. Anz., Bd. XVI, 1900.

BONNET, R.: Lehrbuch der Entwickelungsgeschichte. Berlin, 1907.

BORN, G.: Ueber die Derivate der embryonalen Schlundbogen und Schlundspalten bei Saugetiere. Arch.}, mik. Anat., Bd. XXII, 1883.

BRACKET, A. : Die Entwickelung und Histogenese der Leber und des Pancreas. Ergebnisse der Anat. u. Entwick., Bd. VI, 1897.

CHIEVITZ, J. C.: Beitrage zur Entwickelungsgeschichte der Speicheldriisen. Arch. f. Anat. u. Physiol., Anat. Abth., 1885.

CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.

Fox, H.: The Pharyngeal Pouches and their Derivatives in the Mammalia. Am. Jour, of Anat., Vol. VIII, No. 3, 1908.

FUSARI, R.: Sur les phenomenes, que Ton observe dans la muqueuse du canal digestif durant le developement du fcetus humain. Arch. ital. Biol., T. XLII, 1904.

GOPPERT, E.: Die Entwickelung des Mundes und der Mundhohle mit Driisen und Zunge; die Entwickelung der Schwimmblase, der Lunge und des Kehlkopfes der Wirbeltiere. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere. Bd. II, Teil I, 1902.

HAMMAR, J. A.: Einige Plattenmodelle zur Beleuchtung der friiheren embryonalen Leberentwickelung. Arch.f. Anat. u. Physiol., Anat. Abth., 1893.

HAMMAR, J. A.: Allgemeine Morphologic der Schlundspalten beim Menschen. Entwickelung des Mittelohrraumes und des ausseren Gehorganges. Arch. f. mik. Anat., Bd. LIX, 1902.

HAMMAR, J. A. : Das Schicksal der zweiten Schlundspalte. Zur vergleichenden Embryologie und Morphologic der Tonsille. Arch.f. mik. Anat., Bd. LXI, 1903.

HELLY, K.: Studien iiber Langerhanssche Inseln. Arch. f. mik. Anat., Bd. LXVII, 1907.

HERTWIG, O. : Lehrbuch der Entwickehmgsgeschichte der Wirbeltiere und des Menschen. Jena, 1906.

HENDRICKSON, W. F.: The Development of the Bile Capillaries as Revealed by Golgi's Method. Johns Hopkins Hosp. Bull., 1898.

His, W.: Anatomic menschlicher Embryonen. Leipzig, 1880-1885.

His, W.: Die Entwickelung der menschlichen und tierischen Physiognomien. Arch, f. Anat. u. Physiol., Anat. Abth., 1892.

JACKSON, C, M.: On the Development and Topography of the Thoracic and Abdominal Viscera. Anat. Record, Vol. Ill, 1909.

{{Ref-Johnson1910}}

JOHNSON, F. P.: The Development of the Mucous Membrane of the Large Intestine and Vermiform Appendix in the Human Embryo. Am. Jour. of. Anat., Vol. XIV, 1903

JOHNSON, F. P. : The Development of the Rectum in the Human Embryo. Am. Jour. of Anat., Vol. XVI, 1914.

KINGSBURY, B. F.: The Development of the Human Pharynx. I, The Pharyngeal Derivatives. Am. Jour, of Anat., Vol. XVIII, 1918.

KOHN, A.: Die Epithelkorperchen. Ergebnisse der Anat. u. Entwick., Bd. IX, 1899.

KOLLMANN, J.: Die Entwickelung der Lymphknotchen in dem Blinddarm und in dem Processus vermiformis. Die Entwickelung der Tonsillen und die Entwickelung der Milz. Arch.f. Anat. u. Physiol., Anat. Abth., 1900.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

MALL, F. P.: Ueber die Entwickelung des menschlichen Darmes und seiner Lage beim Erwachsenen Arch.f. Anat. u. Physiol., Anat. Abth. Suppl., 1897.

MAURER, F.: Die Entwickelung des Darmsystems. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere., Bd. II, Teil I, 1902.

McMuRRiCH, J. P. : The Development of the Human Body. Third Ed. Philadelphia, 1907.

MUMMERY, J. H.: The Microscopic Anatomy of the Teeth, 1919.

{{Ref-Norris1918}}

{{Ref-Pearce1903}}

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

POLZL, A.: Zur Entwickelungsgeschichte des menschlichen Gaumens. Anat. Hefte, 1905

ROSE, C.: Ueber die Entwickelung der Zahne des Menschen. Arch. f. mik. Anat., Bd. XXXVIII, 1891.

STEIDA, A.: Ueber Atresia ani congenita und die damit verbundenen Missbildungen. Arch.], klin. Chir., Bd. LXX, 1903.

STOHR, P.: Ueber die Entwickelung der Darmlymphknotchen und iiber die Riickbildung von Darmdriisen. Arch. f. Anat. u. Physiol., AnaL Abth., 1898.

TANDLER, J.: Zur Entwickelungsgeschichte des menschlichen Duodenum in friihen Embryonalstadien. Morph. Jahrb., Bd. XXIX, 1900.

TOLDT und ZUCKERHANDL Ueber die Form und Texturveranderungen der menschlichen Leber wahrend Wachsthums. Sitzungsber. d. kaiser. Akad. d. Wissensch., Wien. Math.-Naturwiss. Klasse., Bd. LXXII, 1875.

TOURNEUX ET VERDUN: Sur les premiers developpements de la Thyroide, du Thymus et des glandes parathyroidiennes chez I'homme. Jour. de. I' Anat. et. de la Physiol., T. XXXIII, 1897

{{Bailey_1921_Footer}}

[[Category:Gastrointestinal Tract]] [[Category:Tooth]]

Book - Text-Book of Embryology 12

2024-01-25T00:56:16Z

Z8600021:

{{Bailey 1921}}

=The Development of the Alimentary Tube and Appended Organs=
<div id="Fig244"></div>
[[File:Bailey244.jpg|thumb|300px|'''Fig. 244. Lateral view of human embryo with 14 pairs of primitive segments (2.5 mm).''' Kollntann. The yolk sac has been cut off. The fore-gut, mid-gut and hind-gut, as indicated in the figure, together constitute the primitive gut. Compare with Fig. 245.]]

The embryonic disk, composed of the three germ layers, primarily lies flat upon the yolk sac (see p. 107; also Fig. 75). A little later the axial portion of the embryo is indicated by the primitive streak, the neural groove (subsequently the neural tube), the notochord, and the primitive segments (Fig. 71). Then along each side of the axial portion and at the cephalic and caudal ends, the germ layers bend ventrally and medially and finally meet and fuse in the midventral line (p. 109) . The portion of the entoderm ventral to the notochord is bent into a tube which, for the most part, becomes pinched off from the parent entoderm and is suspended in the embryonic coelom by the common mesentery (Figs. 103 and 104). This entodermal tube is the primitive gut. At first it ir but slightly elongated and is closed at both ends. On the ventral side, however it opens widely into the yolk sac (Figs. 244 and 245). The primitive gut, therefore, has no communication with the exterior. It communicates at its caudal end with the central canal of the spinal cord through the neurenteric canal (Fig. 76; compare with 77).

As development proceeds, this simple tube elongates rapidly and becomes differentiated into distinct regions. The cephalic end, in connection with the branchial arches and grooves, becomes the dilated pharyngeal region. Caudal to and continuous with this, is the short, narrow cesophageal region which in turn passes over into the slightly dilated stomach region. The portion of the gut caudal to the stomach is the intestinal region. During the differential changes, the communication with the yolk sac becomes relatively smaller, forming the yolk stalk which joins the intestinal portion a short distance caudal to the stomach (Figs. 246 and 247).

<div id="Fig245"></div>
[[File:Bailey245.jpg|600px]]

'''Fig. 245. Ventral view of human embryo of 2.4 mm.''' His, Kollmann.
: Note the opening in the ventral wall of the gut. This indicates the communication between the gut and the yolk sac. The latter has been removed. Compare with Fig. 244.

==The Mouth==

At a very early period the primary fore-brain region bends ventrally almost at a right angle to the long axis of the body to form the naso-frontal process.

As the first branchial arch develops, it grows ventrally until it meets and fuses with its fellow of the opposite side in the midventral line, thus forming the mandibular process. From the cephalic side of the first arch a secondary process maxillary process develops and fills in the space between the arch itself and the naso-frontal process. These various structures thus bound a distinct depression on the ventral side of the head. This depression is the oral pit, the forerunner of the oral and nasal cavities (Fig. 245; compare with Figs. 244 and 85). The groove in the midventral line between the mandibular processes marks the symphysis of the lower jaws. The groove on each side between the maxillary process and the mandibular process marks the angle of the mouth. The groove between the maxillary process and the naso-frontal process is the naso-optic furrow, at the dorsal end of which the eye develops. The bottom of the oral pit is formed by a portion of the ventral body wall, which separates the oral cavity from the cephalic end of the gut, and which is composed of ectoderm and entoderm, with a small amount of mesoderm between. This closing plate, the pharyngeal membrane, which is still present in I embryos of 2.15 mm., soon becomes thinner and finally breaks away, leaving I the oral pit and the gut in direct communication (Fig. 247). Since the oral pit , is lined with ectoderm, the epithelial lining of the mouth or oral cavity is largely of ectodermal origin. In the medial line of the roof of the oral cavity, near the pharyngeal membrane, the epithelium (ectoderm) evaginates to form Rathke's pocket. This comes in contact with an evagination from the floor of the brain and with it forms the pituitary body.

<div id="Fig246"></div>
[[File:Bailey246.jpg|600px]]

'''Fig. 246. Alimentary tube of a human embryo of 4.1 mm.''' His Kollmann.

The further development of the mouth consists of an elaboration of the structures which primarily bound the oral pit and the growth of certain new structures such as the teeth and the tongue. The first branchial arch fuses with its fellow of the opposite side in the midventral line to form the symphysis of the lower jaws, giving rise also to the lower lip and chin region. As the nasofrontal process continues to grow, two depressions appear on its ventral border, one on each side, a short distance from the medial line. These depressions are the nasal pits which indicate the beginning of the external openings of the nasal passages. The part between the nasal pits is destined to give rise to the nasal septum and the medial part of the upper lip (Fig. 98). The primary oral cavity is divided into the oral cavity proper and the nasal cavity by outgrowths from the maxillary processes. From the medial side of each maxillary process a plate-like structure grows across the primary oral cavity toward the medial line (Fig. 140). These two plates, or palatine processes, meet and fuse with the lower part of the nasal septum (Fig. 248) . (For further details of this fusion, see page 121 and page 163). The palatine processes thus form the palate, or the roof of the mouth, which separates the mouth cavity from the nasal cavity. The palate does not extend far enough backward, however, to separate the posterior part of the nasal cavity from the pharynx. Thus the posterior nares and pharynx are left in communication. Externally the maxillary processes extend medially, separate the nasal pits from the oral cavity, and form the lateral portions of the upper lip (Fig. 99).

<div id="Fig247"></div>
[[File:Bailey247.jpg|600px]]

'''Fig. 247. Sagittal section of reconstruction of a human embryo of 5 mm.''' His, Kollmann.

<div id="Fig248"></div>
[[File:Bailey248.jpg|600px]]

'''Fig. 248. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

==The Tongue==

The {{tongue}} develops from three separate anlagen which unite secondarily. In embryos of about 3 mm a slight elevation appears on the floor of the pharynx in the region of the first branchial arch. This is the tuberculum impar, being, as the name indicates, unpaired, and is destined to give rise to the tip and body of the tongue (Fig. 249). Soon afterward two bilaterally symmetrical elevations appear on the floor of the pharynx, which are destined to give rise to the root of the tongue (Fig. 250). These paired elevations, arising in, the region of the second and third branchial arches, gradually enlarge and unite with each other and with the tuberculum impar, leaving between the latter and themselves, however, a V-shaped groove (Fig. 251). At the apex of the groove there is a depression the foramen cecum lingua which is the external opening of the thyreoglossal duct (see p. 301). The groove later disappears, but its position is indicated in the adult by the vallate papillae.

<div id="Fig249"></div>
[[File:Bailey249.jpg|600px]]

'''Fig. 249. Floor of the pharyngeal region of a human embryo of about 3 weeks.''' {{His}}.

According to Hammar, the tuberculum impar is a transitory structure and does not give rise to the tip and body of the tongue. The tip and body are derived from a much more extensive elevation in the floor of the pharynx.

The tongue as a whole enlarges and grows from its place of origin toward the entrance to the primary oral cavity. For a time it practically fills the cavity. When the palate develops it recedes and finally comes to lie on the floor of the oral cavity proper, as in the adult. The growth of the tongue involves the epithelial lining of the pharynx and oral cavity and also the underlying mesenchymal tissue. The latter produces the connective tissue and at least a part of the intrinsic muscle fibers of the tongue. The papillae involve the epithelium and connective tissue, while the glands and taste buds are derived from the epithelium alone.

<div id="Fig250"></div>
[[File:Bailey250.jpg|600px]]

'''Fig. 250. Floor of pharyngeal region of a human embryo of 12.5 mm.''' His.

The portion of the lingualis muscle innervated by the facial (VII) nerve is probably derived from the mesenchymal tissue in the tongue anlage. The rest of the muscle is innervated by fibers from the hypoglossal (XII) nerve, indicating a possible derivation from certain rudimentary segments in the occipital region which correspond to the three roots of the nerve. This would make it appear that during phylogenesis a part of the lingualis muscle has grown into the tongue from a region caudal to the last branchial arch.

The lingual papilla begin to develop during the third month. Their development is limited to the dorsum of the tongue and to the portion derived from the tuberculum impar. In other regions slight elevations may appear, but not in the form of distinct papillae. The fungijorm and filiform papillae appear as pointed elevations in the connective tissue, which push their way into the epithelium, the latter at the same time being raised above the surface over these points. Gradually the little masses of connective tissue assume the shapes characteristic of fungiform or filiform papillae. During the fifth month the epithelium between the papillae apparently degenerates to some extent, thus leaving them projecting still farther above the surface. The formation of papillae probably goes on for some time after birth, since at birth their form, size, number and arrangement are not the same as at later periods. It is an interesting fact that the filiform papillae lose many of their taste buds after the child is weaned.

The anlage of the vallate papillae appears as a ridge along the V-shaped line of fusion between the paired and unpaired portions of the tongue. The ridge is apparently formed by the ingrowth of a solid mass of epithelium along each side, although the connective tissue between the masses may grow toward the surface to some extent. Later the ridge is broken up into the individual papillae by the ingrowth of the epithelium at certain points. The more superficial cells of the masses then degenerate, thus leaving each papilla surrounded by a trench and wall.

<div id="Fig251"></div>
[[File:Bailey251.jpg|600px]]

'''Fig. 251. Dorsal view of the tongue of a human embryo of 20 mm.''' His, Bonnet.

The development of the lingual glands is confined for the most part to the root and inferior surface and to the region of the vallate papillae. The glands begin to develop during the fourth month as solid ingrowths of epithelium, the mucous glands appearing first, the serous somewhat later. The epithelial masses acquire lumina and grow deeper into the tongue, where they usually branch and coil to form the secreting portions. The latter open to the surface through the original ingrowths which become the ducts. Ebner's glands develop from the bottoms of the trenches around the vallate papillae.

==The Teeth==

The development of the {{teeth}} involves the ectoderm and mesoderm, the former giving rise to the enamel, the latter to the dentine and pulp. In human embryos of 12-15 mm. (thirty-four to forty days), before the lip groove is formed, a thickening of the epithelium (ectoderm) takes place along the edges of the processes that bound the slit-like entrance to the mouth. When the lip groove appears (Fig. 140), the epithelial thickening comes to lie along the edge of the jaw, or in other words, along the edge of the gums. It then grows into the mesenchymal tissue (mesoderm) of the jaw obliquely toward the lingual surface to form the dental shelf. A little later the dental groove appears on the edge of the jaw, along the line where the ingrowth of epithelium took place.

<div id="Fig252"></div>
[[File:Bailey252.jpg|600px]]

'''Fig. 252. Section of developing tooth from a 3 months human fetus.''' Szymonowicz.

Note the portion of the original dental shelf connecting the developing tooth with the epithelium of the mouth cavity.

The dental shelf is at first of uniform thickness, but in a short time five enlargements appear in it in each upper and lower jaw, indicating the beginnings of the milk teeth. When the embryo reaches a length of 40 mm. (an age of eleven to twelve weeks) the mesenchymal tissue on one side of these enlargements (above and to the inner side in the upper jaw, below and to the inner side in the lower jaw) becomes condensed and pushes its way into the epithelium. Each of these mesenchymal ingrowths is a dental papilla. Thus at this stage the anlage of each tooth is a mass of epithelium fitting cap-like over a mesenchymal papilla. The epithelium is the forerunner of the enamel organ; the papilla is destined to give rise to the dentine and pulp. The anlagen are connected with one another by intermediate portions of the dental shelf, and with the surface by the original ingrowth of epithelium.

===The Enamel===

The epithelial cells nearest the dental papilla become high columnar in shape, forming a single layer. Those in the interior of the mass become separated and changed into irregular, stellate, anastomosing cells, with a fluid intercellular substance, constituting the enamel pulp. Those farthest from the papilla become flattened (Fig. 252 ; compare with Fig. 253). Calcification begins in the basal ends of the columnar cells, or in the ends next the papilla, and in the intercellular substance, and gradually progresses throughout the cells, the latter at the same time becoming much more elongated. Thus the cells are transformed into enamel prisms which are held together by the calcined intercellular substance (Fig. 253).

<div id="Fig253"></div>
[[File:Bailey253.jpg|600px]]

'''Fig. 253. Section through the border of a developing tooth of a new-born puppy.''' Bonnet.

The formation of enamel begins in the milk teeth toward the end of the fourth month and probably continues until the teeth break through the gums. The enamel organ at first surrounds the entire developing tooth except where the papilla joins he underlying mesenchymal tissue (Fig. 252). Later the deeper part of the organ disappears as such, and the enamel is formed only on that part of the tooth which eventually becomes the crown. The enamel pulp increases in amount for a time, but subsequently disappears as the tooth grows into it (Fig. 254). Its function is not fully understood. It may serve as a. line of least resistance in which the tooth grows, and it may convey nourishment to the enamel cells, the enamel organ being non-vascular.

===The Dentine and Pulp===

At first the dental papilla is simply a condensation of mesenchyme, but later it is converted into a sort of connective tissue penetrated by blood vessels and nerves (Fig. 254). The cells nearest the enamel organ become columnar and arranged in a single layer, with the nuclei toward their inner ends. The outer ends are blunt, while the inner ends are continued as slender processes that extend into the pulp and probably with other cell processes. These columnar cells are the odontoblasts, under the influence of which the lime salts of the dentine are deposited, and which are coi parable with the osteoblasts in developing bone.

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'''Fig. 254. Longitudinal section of a developing tooth of a new-born puppy.''' Bonnet.

Toward the end of the fourth month the odontoblasts form a membrane like structure, the membrana preformativa, between themselves and the enamel. This membrane is first converted into dentine by the deposition of lime salts, after which the process of calcification progresses from the enamel toward the pulp. During calcification slender processes of the odontoblasts remain in minute channels, or dentinal canals, forming the dentinal fibers which anastomose with one another (Fig. 253). In the peripheral part of the dentine certain areas apparently fail to become calcified and form the inter globular spaces. The same cells that are originally differentiated from the mesenchyme probably persist throughout development as the odontoblasts and produce the entire amount of dentine in a tooth. Even in the fully formed tooth there is a layer of odontoblasts bearing the same relation to the dentine and pulp as in the developing tooth. The chief difference between dentine formation and bone formation is that in the latter the osteoblasts become enclosed to form bone cells, while in the former the odontoblasts merely leave processes enclosed as the cell bodies recede.

The pulp of the tooth is of course derived from the mesenchymal tissue in the interior of the dental papilla (compare Figs. 252 and 254). The blood vessels and nerves grow in from the underlying connective (mesenchymal) tissue.

At an early stage the mesenchymal tissue around the anlage of the tooth, including the enamel organ, condenses to form a sort of sheath, the dental sac, which is later ruptured when the tooth breaks through the gum (Fig. 254). The cement is formed around the root of the tooth from the tissue of the dental sac in the same manner as subperiosteal bone is formed from osteogenetic tissue (p. 142). In fact, cement is true bone without Haversian systems.

The milk teeth, which are the first to develop and the first to appear above the surface, are represented by the medial incisors, lateral incisors, canines, and molars, to the number of ten in the upper and ten in the lower jaw. They may be indicated graphically thus:

Milk teeth

[[File:Baileytable04.jpg|600px]]

In describing the formation of the dental shelf, it was noted that the papillae of the milk teeth grow into corresponding thickenings of the epithelium (p. 292). The growth takes place from the side, thus leaving the edge of the shelf free to grow farther toward the lingual side of the jaw. In this free edge other tooth germs arise, which mark the beginnings of the permanent teeth (Fig. 252). In addition to the germs that correspond in position to the milk teeth, three others arise in each jaw, representing the true molars of the adult. The latter arise in a part of the dental shelf which has grown toward the articulation of the jaws without coming in contact with the surface epithelium. The first papilla of the permanent dentition to appear is that of the first molar. It appears immediately behind the second milk molar at a time when the milk teeth are well advanced (embryos of 180 mm., about seventeen weeks). The permanent incisors and canines appear about the twenty-fourth week; the premolars, which correspond to the milk molars, about the twenty-ninth week. The second molar does not appear till after birth (six months), and the third molar, or wisdom tooth, begins to develop about the fifth year.

The formation of the anlagen of the permanent teeth and the development of the enamel, dentine and pulp take place in precisely the same manner as in the milk teeth. The true molars grow out through the gums in the same way as the milk teeth. Those permanent teeth which correspond in position to milk teeth grow under the latter, exert pressure on their roots and thus loosen and finally replace them.

The two sets of teeth may be graphically represented thus:

Milk teeth

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Permanent teeth

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Normally all the epithelium of the dental shelf, except the parts directly concerned in the development of the teeth, disappears at times which vary in different individuals. Occasionally, however, remnants of this epithelium give rise to cystic structures (developmental tooth tumors) .

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'''Fig. 255. From a transverse section through the tongue and oral cavity of a mouse embryo.''' Goppert.

==The Salivary Glands==

The anlage of the submaxillary gland appears, in embryos of 10 to 12 mm., as a flange of epithelium directed ventrally from the portion of the lingual sulcus just caudal to the crossing of the lingual nerve. The flange grows into the mesenchyme of the lower jaw, and at an early period becomes triangular with its longest side free and a free vertical caudal border. Cell proliferation begins at the angle of union of the two borders and gradually progresses cephalad along the longest border, thus producing a solid ridge-like thickening of the latter.

The main portion of the gland is produced by a sprouting of the epithelium from the angle of union of the two free borders of the flange and grows deep into the mesenchyme along the mesial side of the ramus of the mandible. The sprouts branch repeatedly in the course of their development, thus laying the foundation for the division of the gland into lobes and lobules.

The distal end of the duct of the submaxillary (Wharton's) is formed from the ridge-like thickening of the free margin of the flange through a dissolution of the greater part of the flange between the lingual sulcus and the thickened margin itself, thus freeing this portion of the duct from the sulcus. By a continuation of the growth which produced the ridge along the free border of the original flange an extension of this same ridge is produced along the bottom of the lingual sulcus forward toward the chin region. This portion of the ridge is progressively constricted off from the sulcus from cehind forward, until finally the attachment of the duct reaches its definitive position at the side of the frenulum linguae.

The anlage of the Bartolinian element of the suUingual gland appears as a smaller flange attached to the lateral border of the submaxillary flange near the crossing of the lingual nerve and prolonged forward by an interrupted crest along the lingual sulcus. Its later development is similar to that of the submaxillary.

A small medial flange also on the submaxillary flange gives rise to a sprout in much the same manner as the other anlagen. While the history of this anlage is not complete in the human embryo, it probably gives rise to the anterior lingual gland (gland of Bland in and Nuhn). The alveolingual elements arise from a keel attached to the alveolingual sulcus (the groove between the floor of the mouth and the alveolar process of the lower jaw).

The parotid gland originates from the buccal sulcus in essentially the same way as the submaxillary arises from the lingual sulcus. The anlage then continues to grow through the mesenchyme of the cheek across the masseter muscle, the distal end branching freely to form the secreting portion of the gland. The outgrowths are at first solid, but later become hollow, the proximal portion of the original outgrowth forming the parotid (Steno's) duct, the more distal portions forming the smaller ducts and terminal tubules.

The histogenetic changes in the salivary glands probably continue until the child takes solid food, when the glands become of greater functional importance. In the parotid gland, which is serous in man, the original, undifferentiated epithelial cells undergo changes in form and arrangement so that by the twenty-second week the larger ducts are lined with a two-layered epithelium, the smaller ducts with a simple cuboidal epithelium, and the terminal tubules with a single layer of high columnar cells. The two-layered epithelium in the larger ducts persists. The ducts lined with the cuboidal epithelium become the socalled intermediate tubules, the cells changing to a flat type. The high columnar cells of the terminal tubules become the serous secreting cells.

Quite similar changes also occur in the submaxillary, but in foetuses of eight to nine months the crescents of Gianuzzi appear as masses of darkly staining cells forming the ends or sides of the terminal tubules. The crescents at first border on the lumina, but later, probably by a process of evagination, come to lie on the surface of the tubules.

The beginning of the secretory function may be detected by a diminution in the affinity of the cells for stains.

==The Pharynx==

The pharynx develops from the cephalic end of the primitive gut. This part of the gut is primarily of uniform diameter, is broadly attached by mesoderm to the dorsal body wall, and ends blindly (Fig. 247). When the branchial arches and grooves develop in this (the cervical) region, they affect the gut as well as the periphery of the body. The arches form ridges on the surface of the body (Fig. 85) and at the same time form ridges on the wall of the gut. The grooves form pockets which alternate with the arches (Fig. 256). The pock in the pharyngeal cavity, or inner branchial grooves, are directed outward toward corresponding outer branchial grooves (Fig. 249). The arches are covered externally with ectoderm, internally with entoderm, and are filled with mesoderm. Between the arches, or in the grooves, the ectoderm and entoden are in contact or nearly so. Thus the pharynx is not surrounded by a coelomic cavity.

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'''Fig. 256. Sagittal section through the head of a human embryo of 4.2 mm (31-34 days)'''. His

Since the branchial arches develop in such a way that they are successively smaller from the first to the fourth, the pharyngeal cavity becomes funnelshaped (Fig. 256). It also becomes somewhat flattened in the dorso-ventral direction, and in the earlier stages when the arches and grooves are fully formed, the pharynx constitutes approximately one-third the entire gut (Fig. 247). Primarily the pharyngeal cavity is separated from the oral cavity by the pharyngeal membrane (see p. 287 ; also Fig. 244). When this ruptures and disappears (during the fourth week ?) the two cavities are in open communication. What point in the adult represents the attachment of the pharyngeal membrane is not known; but the glosso- and pharyngo-palatine arches (pillars of the fauces) are usually considered as the boundary between the mouth and pharynx. The caudal limit of the pharynx is the opening of the larynx (Figs. 247 and 256).

Thus in the early stages the general adult character of the pharynx is established. While the branchial arches and grooves undergo profound changes, the pharyngeal cavity retains the same relation to the mouth and to the oesophagus and respiratory tract. The cavity becomes relatively shorter, however, and the alternating ridges and pockets in its walls are lost as the arches and grooves are transformed into other structures. The metamorphosis of the arches and grooves is considered elsewhere (p. 118).

==The Tonsils==

The tonsils arise in the region of the ventral part of the Lsecond inner branchial groove. During the third month the epithelium (entoderm) grows into the underlying connective (mesenchymal) tissue in the form of a hollow bud. From this, secondary buds develop, which are at first solid, but later (during the fourth or fifth month) become hollow by a disappearance of the central cells and open into the cavity of the primary bud, thus forming the crypts. Lymphoid cells wander from the neighboring blood vessels, or are derived directly from the' epithelium- (Retterer), and with the connective tissue form a diffuse lymphatic tissue under the epithelium (Fig. 257). By the eighth month the cells become more numerous in places, and by the third month after birth form distinct lymph follicles with germinal centers. The formation of follicles goes on slowly and is probably not complete until some time after birth.

===The Lingual Tonsils===

The lymphatic tissue of the tongue develops in relation to the lingual glands. During the eighth month lymphoid infiltration occurs around the ducts of the glands, and the connective tissue acquires the reticular character. True follicles probably do not appear until the child is at least five years old.

===The Pharyngeal Tonsils===

During the sixth month small folds appear in the mucous membrane of the roof of the pharynx and become diffusely infiltrated with lymphoid cells. This occurs first in the posterior part of the roof, but later (seventh or eighth month) it extends forward and along the sides of the nasopharygeal cavity. By the end of foetal life the ridges become quite large. Follicles may appear before birth or not until one or two years later. After puberty the ridges almost completely disappear, but the adenoid tissue remains wholly or in part.

The bursa pharyngea is an evagination from the roof of the pharynx about the upper border of the superior constrictor muscle, and is apparent in embryos of eleven weeks. It probably has no genetic relation to the hypophysis. Its significance is not known.

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'''Fig. 257. Section through the middle of the developing tonsil of a human embryo of 5 months.''' Stohr.

:6, Epithelial buds (secondary outgrowths) from the epithelium lining the primary crypt (c) ; L, lymphoid infiltration of the connective (mesodermal) tissue.

==The Branchial Epithelial Bodies==

===The Thyreoid Gland===

The {{thyreoid}} {{thyroid}} arises, after the manner of ordinary glands, as an evagination from the epithelium of the pharynx. It appears in embryos of 3 to 5 mm. as a ventral outgrowth of epithelium in the floor of the pharynx, at the point where the tuberculum impar and the two paired anlagen of the tongue join (Fig. 258). This point is the foramen caecum linguae which has already been mentioned in connection with the development of the tongue (p. 290) . The evagination grows into the mesodermal tissue in the ventral wall of the neck, and forms a transverse mass of epithelium. The latter breaks up into irregular cords of cells which, by a further process of budding, grow cau dally along the ventral surface of the larynx. The cords of cells are from the first surrounded by connective tissue and later also become surrounded by networks of capillaries (Fig. 259). They ultimately break up into smaller masses which become hollow and form the alveoli. Colloid secretion begins toward the end of fcetal life or soon after birth.

As the gland grows toward its final position it becomes enlarged laterally into the two lateral lobes, which remain connected by the isthmus (Fig. 260). The Pyramidal process represents either a secondary outgrowth from the isthmus or one of the lobes, or a remnant of the original connection with the tongue, that is, of the thyreoglossal duct. The duct usually disappears for the most part, but certain structures sometimes found in the adult in the line of the duct are possibly remnants of it. They have been variously named, according to their position, accessory thyreoid , suprahyoid, and prehyoid glands (Fig. 260).

A pair of structures, appearing first in embryos of 8 to 10 mm., arise as evaginations from the ventral ends of the fourth inner branchial grooves. They grow into the mesodermal tissue and then caudally along the ventro-lateral side of the larynx, where they come into close relation with the lateral lobes of the thyreoid (Fig. 260). They have been called the lateral thyreoids, and acquire the thyreoid structure.

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'''Fig. 258. Transverse section through the region of the 3d branchial groove of an Echidna embryo.''' Maurer. i.= Pharynx, below which are the paired anlagen of the tongue.

Considerable confusion has arisen in regard to the lateral thyreoids. The earlier investigators held that they were derived from the fourth groove and united with the medial portion, which appeared at the foramen caecum, to become integral parts of the thyreoid. Further researches among the lower Vertebrates led others to deny that the thyreoid arose other than as a medial anlage, and that the so-called lateral thyreoids in the embryo were the postbranchial bodies which never assumed the thyreoid structure, but atrophied and disappeared. More recently it has been thought that, although the postbranchial bodies do not function in the lower Vertebrates, they may in the higher Mammals and man unite with the medial thyreoid and secrete colloid.

The parathyreoids or epithelial bodies also come into close relation with the thyreoid. They arise as paired evaginations from the cephalic sides of the third and fourth grooves, dorsal to the thymus and the lateral thyreoid evaginations (Figs. 258 and 261). As the thyreoid grows caudally from its point of origin, these bodies come to lie close to it or may even become embedded in it (Fig. 260). They acquire a structure which resembles that of the suprarenal gland and not that of the thyreoid. Their relation to the latter organ seems to be purely topographical.

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'''Fig. 259. Section of the right half of the thyreoid gland of a pig embryo of 22.5 mm.''' Born.

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'''Fig. 260. Branchial groove derivatives of a rabbit embryo of 16 mm.''' P.-th., parathyreoid or epithelial body. Verdun, Bonnet.

===The Thymus===

The thymus appears in embryos of about 6 mm. as an entodermal evagination from the ventral part of the third branchial groove on each side (Fig 258) . The outgrowths are at first hollow and communicate with the pharyngeal cavity; later they become solid and (in embryos of 14 mm.) lose their connection with the parent epithelium. They elongate and grow caudally in the mesodermal tissue until (in embryos of 16 mm.) their caudal ends lie ventral to the carotid arteries (Fig. 260). In embryos of 29 mm. their caudal ends rest upon the cephalic surface of the pericardium, their cephalic ends reaching to the isthmus of the thyreoid. The two parts eventually fuse to a considerable extent, but the gland as a whole always consists of two distinct lobes.

The gland continues to enlarge, at the same time becoming lobulated by the ingrowth of connective tissue, until the child is two or three years old. At this time it is situated in the anterior mediastinum, usually in the medial line. After this it begins to atrophy and becomes a mass of fibrous and fatty tissue through the growth of the interlobular septa and their encroachment upon the lobules. The classical view that the thymus begins to atrophy after the second or third year and is quite degenerated in the adult has recently been somewhat offset by the view that comparatively slight changes take place in it until puberty. According to the latter view, degeneration goes on after puberty at a rate which varies widely in different individuals, and the thymus may persist as a functional organ up to the age of sixty years.

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'''Fig. 261. Diagram of the branchial groove derivatives in man.''' Verdun.

The histogenesis of the thymus has been a subject of much study and controversy, not only in regard to its origin, but also in regard to its change from an epithelial to a lymphoid structure and the regressive changes in the latter. It has almost certainly been proven to be of entodermal origin. It is at first an epithelial mass which later becomes broken up into lobules by the ingrowth of connective tissue. In regard to the histological changes which it undergoes, the older views are in general that a " pseudomorphosis " takes place; that is, the epithelial elements are replaced by lymphoid cells which wander in from the neighboring blood vessels, Hassall's corpuscles being remnants of the epithelium. Later other investigators looked upon the changes as a "transformation," asserting that the epithelial cells were transformed into lymphoid cells in situ, and that Hassall's corpuscles were remnants of epithelium and disintegrating blood vessels. Some went even so far as to assert that the thymus was the first place of origin of the leucocytes. More recent researches furnish very strong evidence that no lymphoid cells are derived from the epithelial cells (Maximow), but that the epithelium is transformed into the reticular tissue of the thymus, in which the lymphoid cells undergo mitotic division, Hassall's corpuscles possibly representing compressed parts of the reticulum (Hammar) (Fig. 262).

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===The Glomus Caroticum===

The early formation of the glomus caroticum (carotid FIG. 262. Hassall's corpuscle from gland) has not been observed in the human ZftfO^Z** embryo. From observations on lower animals it has not been made clear whether it is derived from the entoderm of a branchial groove or from the adventitia of the carotid artery.

==The Esophagus==

When the primitive gut becomes differentiated into* distinct regions (p. 286), the cesophageal region forms a comparatively short: tube, of uniform diameter, extending from the pharynx to the stomach (Fig. 247). In embryos of about 3 to 4 mm. the anlage of the respiratory system arises from the cephalic end of the tube (see p. 330). The latter is lined with entoderm and broadly attached to the dorsal body wall by mesoderm (Fig. 247). During later stages it becomes relatively longer as the heart recedes into the 1 thorax (p. 214), but maintains its uniform diameter.

Further development produces no marked changes in the relative position; of the oesophagus. It remains broadly attached to the dorsal body wall! throughout the life of the individual. In other words, there is never a distinct! mesentery. The entoderm gives rise to the epithelial lining and the glands, the: surrounding mesoderm to the connective tissue and muscular coats.

===The Stomach===

The anlage of the stomach can br recognized in embryos of about 5 mm. as a slight spindle-shaped enlargement of the primitive gut ai short distance cranial to the yolk stalk (Fig. 246). The dilatation goes on more rapidly on the dorsal than on the ventral side, thus producing the greater and^ lesser curvature respectively. The greater curvature is attached to the dorsaU body wall by the dorsal mesogastrium which is a part of the common mesentery.

The lesser curvature is connected with the ventral body wall by the ventral mesogastrium (Fig. 263).

In further development, apart from histogenesis, the greater curvature becomes much more prominent and the organ as a whole changes its position, the latter process beginning in embryos of 12 to 14 mm. The cephalic (cardiac) end moves toward the left side of the body, the pyloric end toward the right At the same time the stomach rotates, the greater curvature turning caudally from its dorsal position and the lesser curvature cranially from its ventral position. The result is that the organ comes to lie in an approximately transverse position in the body, with the cardiac end to the left, the pyloric end to the right, the greater curvature directed caudally, and the lesser curvature directed cranially (compare Figs. 247 and 263 with Figs. 276 and 304).*

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'''Fig. 263. Gastrointestinal tract and mesenteries of a human embryo of 6 weeks'''. Toldt.

* These changes may be more easily understood if the student will hold a closed book in the sagittal plane in front of him, with the back of the book toward, and the open edge away from him. The back represents the greater curvature, the open edge the lesser curvature. The upper end of the book represents the cardiac end of the stomach, the lower end the pylorus. Turn the upper (cardiac) end to the left, the lower (pyloric) end to the right, at the same time allowing the back of the book (the greater curvature) to drop downward on the side toward the body. The changes in the position of the book represent the changes in the position of the developing stomach.

It is obvious that the lower end of the oesophagus is carried toward the left side of the body with the cardiac end of the stomach, and at the same time twisted so that the side which originally faced the left comes to face ventrally. The changes in the mesentery which accompany the changes in the stomach are described elsewhere (p. 348) .

The torsion of the stomach also produces an asymmetrical condition of the vagi nerves. The latter reach the stomach before it changes its position. As the changes take place, the left nerve is carried around to the left and ventrally so that in the adult it passes through the diaphragm ventral to the oesophagus and extends over the ventral surface of the stomach. The right nerve passes over the dorsal surface of the stomach.

==The Intestine==

When the primitive gut is differentiated into recognizable regions (p. 286) the intestinal region forms a simple tube, of uniform diameter, extending from the stomach to the caudal end of the embryo where it ends blindly. The yolk stalk is attached to the intestine a short distance from the stomach. Near the caudal end the allantoic duct arises (p. 582). The lumen of the yolk stalk and of the allantoic duct is continuous with that of the intestine (Fig. 247). In embryos of 2 to 3 mm. the liver anlage arises from the ventral side of the intestine near the stomach, that is, from that part of the intestine which is to become the duodenum. In embryos of 3 to 4 mm. the pancreas anlage arises in the same region, in part from the liver evagination and in part from the dorsal side of the intestine (Fig. 247).

The intestine as a whole is suspended in the abdominal cavity by the dorsal mesentery which is attached to the dorsal body wall and which is continuous with the dorsal mesogastrium. A ventral mesentery, continuous with the ventral mesogastrium, is present only at the cephalic end of the duodenum (Fig. 263).

The further development of the intestine, apart from histogenesis, consists very largely of the formation of loops and coils, due to an enormous increase in the length of the tube. The abdominal cavity at the same time enlarges to accommodate the increased bulk. As the stomach changes its position (p. 305) , the duodenum comes to lie obliquely across the body and forms a curve with the concavity directed dorsally (Fig. 263). The rest of the intestine forms a loop which extends ventrally and caudally as far as the umbilicus. The arms of the loop are almost parallel and the cephalic arm lies a little to the left of the caudal. The apex of the loop extends into the umbilical ccelom and is attached to the yolk stalk. From the dorsal end of the caudal arm the intestine extends directly to the caudal end of the body (Fig. 263).

Soon after the loop is formed a small evagination appears on its caudal arm, not far from the apex. This is the anlage of the cecum and marks the boundary between the small and large intestine (Fig. 263). At this stage, therefore, all the great divisions of the intestinal tract are distinguishable, viz. : the duodenum with the ducts of the liver and pancreas; the mesenterial small intestine with the yolk stalk; and the colon extending from the caecum to the caudal end. There are, however, practically no differences between the regions, either in structure or in size.

In further development the duodenum comes to lie more nearly transversely across the body, thus assuming its adult position. Its mesentery fuses with the peritoneum of the dorsal body wall and the duodenum thus becomes a fixed portion of the intestinal tract (p. 350; also Fig. 301). It enlarges a little more rapidly than the rest of the small intestine and acquires a greater diameter. In embryos of 12 to 13 mm. the lumen becomes obliterated by an overgrowth of the mucous membrane caudal to the ducts of the liver and pancreas. In embryos of about 15 mm., however, the lumen reappears. It seems difficult to find a cause for this peculiar growth of the mucosa.

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'''Fig. 264. Reconstruction of the liver and intestine of a human embryo of 17 mm.''' Mall. G.B., gall bladder; H. V., hepatic vein; U.V., umbilical vein; 1 -6, primary bends in the long intestinal loop; 1 represents the duodenum.

Very shortly after the formation of the long loop in the intestine, six bends become recognizable in the portion between the stomach and the apex of the loop (Fig. 264). These bends later form distinct loops which are destined to become definite parts of the small intestine. The first loop is the duodenum, the development of which has already been considered, and which maintains practically its original position. The other five loops continue to elongate and form secondary loops, all of which push their way into the umbilical coelom where they remain until the embryo reaches a length of 40 mm. (compare Figs, 265 and 266). Then they return very quickly to the abdominal cavity proper.

After their return, the primary loops, with the secondary loops derived from them, come to occupy fairly constant positions. The second and third move to the left upper part of the abdominal cavity; the fourth crosses the medial line and occupies the right upper part. The fifth crosses back and lies in the left iliac fossa; the sixth lies in the pelvis and lower part of the abdominal cavity (Fig. 267).

Certain variations may occur but are usually not considered as abnormal. The most frequent variation is one in which the fourth coil, along with the second and third, lies on the left side, its usual position on the right being occupied by the ascending colon. Not uncommonly the positions of the fourth and the second and third are reversed. Less commonly extra loops are formed.

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'''Fig. 265. Reconstruction of the stomach and intestine of a human embryo of 28 mm.''' Matt.

:The numbers are placed on the coils derived from the primary bends as shown in Fig. 302; 1 represents the duodenum.

Usually the proximal part of the yolk stalk disappears during foetal life. In a few cases, however, it persists as a blind sac of variable length, known as Meckel's diverticulum (see also p. 581).

Even before the loops return to the abdominal cavity the colon or large intestine increases in diameter more rapidly than the small intestine. After the return, the caecum is carried across to the right side and comes to lie just caudal to the liver. From the caecum the colon extends across the abdominal cavity, ventral to the duodenum, forming the transverse colon. It then descends on the left side as the descending colon which passes over into the sigmoid colon (Fig. 299). The transverse, the descending and the sigmoid portions of the colon are recognizable in the third month. Up to the time of birth the sigmoid portion is disproportionately long; after birth the other portions grow relatively faster. After the fourth month the portion to which the caecum is attached grows downward in the right side of the abdominal cavity, thus forming the ascending colon (Fig. 304).

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'''Fig. 266. Drawing from a reconstruction of a human embryo of 24 mm.''' Matt. The intestinal coils lie for the most part in the umbilical coelom. C, caecum; K, kidney; L, liven S, stomach; S. C., suprarenal gland; W, mesonephros; 12, twelfth thoracic nerve; 5, fifth lumbar nerve.

The caecum, which appears in very early stages as an evagination at the junction of the small and large intestines, for a time continues to increase uniformly in size. Then the proximal end increases more rapidly than the distal, and forms the caecum of adult anatomy. The distal end, failing to keep pace in development, remains more slender and forms the vermiform appendix (Fig. 267).

As has already been mentioned, the primitive gut ends blindly in the caudal end of the embryo (Fig. 246). The anal opening is a secondary formation, On the ventral side of the caudal end of the body there is formed a depression known as the anal pit. The mesoderm at the bottom of the pit becomes thinner until the ectoderm comes in contact with the entoderm on the ventral side of the gut, thus forming the anal membrane. The area of contact is not at the extreme end of the gut, but a short distance toward the allantoic duct. In the meantime, the urogenital ducts come to open into that portion of the gut which lies just cranial to the anal membrane. The gut enlarges in this region to i/form the cloaca. The latter becomes separated by the urorectal fold into a portion, the rectum, and a ventral portion, the urogenital sinus (Figs. 323 and 325). At about the time of separation (embryos of about 14 mm. or thirty-six to thirty-eight days) the anal membrane ruptures and the anal opening is formed. The portion of the gut caudal to the anus, known as the caudal gut, normally disappears.

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'''Fig. 267. Drawing from a model of the small intestine in the adult.''' Ventral view. Mall.

:The intestinal coils are shown in the usual relative position. The numbers indicate the coils derived from the primary bends in the foetus as shown in Figs. 264 and 265.

==Histogenesis of the Gastrointestinal Tract==

The wall of the primitive gut is composed of two layers the entoderm which lines the lumen, and the splanchnic mesoderm which borders on the ccelom or body cavity. While the germ layers are still flat, the entoderm is a single layer of flat cells with bulging nuclei, but after the closure of the gut the cells become columnar. The splanchnic mesoderm is composed of two layers the mesothelium bordering on the ccelom, the cells of which gradually change from flat to rather high, and a number of indifferent, branching mesenchymal cells lying between the mesothelium and entoderm. The entoderm is destined to give rise to the general epithelial lining of the gastrointestinal tract and to all the glands connected with it. The mesothelium around the gut forms a part of the general mesothelial lining of the ccelom, its cells apparently changing back to a flat type. The mesenchymal tissue is destined to give rise to all the connective tissue and smooth muscle of the tract. The circular layer of muscle appears first, the longitudinal next, both appearing during the third and fourth months, and last of all the muscularis mucosae (Fig. 268).

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'''Fig. 268. Transverse section of the small intestine of a pig embryo of 32 mm.''' Bonnet.

===The Mucous Membrane===

The mucous membrane is formed by the epithelium (entoderm) and the subjacent mesenchymal tissue. In its development there are two factors to be considered: (i) The formation of folds to increase the absorbing surface and (2) the formation of secreting organs or glands. As to the relation between these two factors there is a difference of opinion. Some hold that both kinds of structures are the result of the same formative process, that is, that the glands are simply the depressions or pits formed by the intersection of folds at various angles, and that the folds are produced primarily by the growth of the epithelium and mesenchymal tissue into the lumen of the gut. Others maintain that although the folds may be produced by the growth of the epithelium and mesenchymal tissue into the lumen, the glands arise as independent growths of the epithelium into the subjacent tissue. The latter view is supported by the fact that in some Amphibia the glands appear before the folds (Fig. 269). Recent work on Mammals also favors this view.

The development of the folds and glands begins in the different parts of the gastrointestinal tract at different times. It begins first in the stomach, then in the duodenum, then in the colon, and then whence it progresses slowly into the ileum. In the stomach it is uncertain whether the crypts and glands are depressions left among projections of the mucous membrane, or the glands represent evaginations of the epithelium into the underlying tissue. In the case of the large intestine the same uncertainty exists. If the so-called glands are depressions among villous projections that grow-in to the lumen of the intestine, they are not true glands from an embryological point of view.

Studies of the development of the villi in the human small intestine have led to the conclusion that they are formed primarily as growths of the mucosa into the lumen. In embryos of 19 mm. the mucosa of the cephalic end is thrown into a number of longitudinal folds (Fig. 270). These then develop progressively toward the caudal end. Beginning in embryos of 50 to 60 mm. the longitudinal folds become broken transversely into conical structures, the villi. The intestinal crypts (of Lieberkiihn) possibly represent outgrowths of the epithelium from the bottoms of the intervillous spaces.' The duodenal (B runner's) glands are possibly to be considered as a continuation of the pyloric glands of the stomach. They apparently grow as evaginations from the intervillous crypts.

The epithelial lining of the gastrointestinal tract is from the beginning a single layer of cells, although the individual cells are altered in shape and structure and acquire different functions in different regions. There is still some dispute as to whether the mucous cells are continuously being derived from the other epithelial cells or, when once formed, reproduce themselves by mitosis. As a matter of fact, mitosis has been observed in the mucous cells of the stomach.

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'''Fig. 270. From a reconstruction of the small intestine of a human embryo of 28 mm.''' Berry. Showing the longitudinal ridges which eventually become broken transversely to form the villi.

===The Lymph Follicles===

In the development of the lymph follicles in the gastrointestinal tract the same question arises as in the case of the tonsils and thymus. Are the lymphoid cells of mesodermal or of entodermal (epithelial) origin? Evidence at present favors the mesodermal origin. In the case of Peyer's patches, collections of lymphoid cells appear near the blood vessels in the stroma and neighboring parts of the submucosa. These increase in extent, the lymphoid cells dividing actively, and grow into the bases of some of the villi and deeper into the submucosa (Fig. 271). Germinal centers appear in many of the follicles, and the surrounding stroma becomes densely infiltrated with the lymphoid cells. Individual follicles may develop, in the manner described, in any part of the gastrointestinal tract. The appendix especially is the seat of extensive lymphatic tissue formation. It is stated in the section on the lymphatic system that lymph glands may arise at any time in any region as the result of unusual conditions (p. 251), and this also holds true in the case of lymph follicles in the digestive tract.

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Fig. 271. Sections through the wall of the caecum of (a) a rabbit 2.5 days and (b) 5 days after birth, showing the development of the lymph follicles. Stohr.

:Lymphoid infiltration in the stroma; r, wandering cells in the epithelium; 2, lymphoid cells in the core of a villus.

==The Development of the Liver==

The liver is the first gland of the digestive tract to appear. In embryos of about 3 mm. a longitudinal ridge-like evagination develops from the entoderm on the ventral side of the gut a short distance caudal to the stomach, that is, in the duodenal portion of the gut (Figs. 247, 272, 273). The cephalic part of the evagination is solid and, being destined to give rise to the liver proper, is called the pars hepatica. The caudal part is hollow, its cavity being continuous with the lumen of the gut, and is destined to give rise to the gall bladder, whence it is called the pars cystica. Beginning at both the cephalic and caudal ends, the evagination as a whole becomes constricted from the gut until (in embryos of about 8 mm.) its only connection with the latter is a narrow cord of cells which is the anlage of the ductus choledochus. The pars hepatica by this time has enlarged considerably and remains attached to the ductus choledochus by a short cord of cells, the anlage of the hepatic duct. The pars cystica has also become larger, its distal portion being somewhat dilated, and is connected with the ductus choledochus by the anlage of the cystic duct (Figs. 274 and 275). The pars cystica grows into the ventral mesentery and thus becomes surrounded by mesodermal tissue. The proximal portion continues to elongate to form the cystic duct and the distal portion becomes larger and more dilated to form the gall bladder.

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'''Fig. 272. Transverse section of a human embryo of 5 mm.''' Showing the liver evagination and the breaking up of the omphalomesenteric veins by the hepatic cylinders. Photograph.

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'''Fig. 273. From a model of the duodenum and the primary evaginations of the liver and pancreas in a 5 mm sheep embryo.''' Stoss.
: D.pan., Dorsal pancreas; Du., duodenum; D. ch., ductus choledochus; G. bl., gall bladder; H. du., hepatic duct.

The pars hepatica, or anlage of the liver proper, also grows into the ventral lesentery, thus becoming surrounded by mesodermal tissue. As stated in connection with the development of the diaphragm, the portion of the mesentery into which the liver grows is involved in the formation of the septum trans versum (p. 344). Thus the developing liver becomes enclosed in the septum (Fig. 292). The mesodermal tissue gives rise to the fibrous capsule of Glisson and to the small amount of connective tissue within the gland.

Although the liver develops as a series of outgrowths from the original evagination, there are certain features in its development which distinguish it from glands in general. The outgrowths come in contact with the omphalomesenteric veins which are situated in the ventral mesentery (p. 229). They push their way into and through the veins, breaking them up into smaller channels (Fig. 272). They anastomose freely with one another, and the veins send off branches which circumvent them. Thus there is formed a network of trabec ulse of liver cells, called hepatic cylinders, the meshes of which are filled with blood vessels. Therefore the liver is distinguished from other glands in general in that the hepatic cylinders, which are comparable with the smaller ducts and terminal tubules of other glands, anastomose, and in that the blood vessels are broken up by the growth of these cylinders.

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'''Fig. 274. From a reconstruction of the anlagen of the liver and pancreas and a part of the stomach and duodenum of a human embryo of 4 weeks.''' Felix.

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'''Fig. 275. From a reconstruction of the anlagen of the liver and pancreas and the stomach of a human embryo of 8 mm.''' Hammar.

:D.P., Dorsal pancreas; Du., duodenum; D. F., ductus venosus; G.B., gall bladder; R.I., right lobe of liver; S. t stomach; V. P., ventral pancreas.

This mode of development establishes what is known as a sinusoidal circulation, which differs from the ordinary capillary circulation. The sinusoids are produced by the growth of the trabeculae of the developing organ into large vessels and the breaking up of the latter into smaller vessels. It is obvious that a sinusoidal circulation is purely venous or purely arterial. Furthermore, development of this nature leaves comparatively little connective tissue within the gland, another feature characteristic of the liver.

All the blood carried to the liver by the omphalomesenteric veins must follow the tortuous course of the sinusoids before being collected again and passed on to the heart. When the umbilical veins come into connection with the liver they also join in the sinusoidal circulation. Subsequently, however, a more direct channel the ductus venosus is established and persists for a short time. This is probably due to the large volume of blood brought in by the umbilical veins. Finally the ductus venosus disappears and the sinusoidal circulation remains as the permanent form. (For the development of the veins in the liver see p. 228.)

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'''Fig. 276. Tranverse section of a 14 mm pig embryo, through the region of the stomach.''' Photograph. The arrow points into the bursa omentalis.

The lobes of the liver develop in a general way in relation to the great venous trunks which at one time or another pass into or through the gland. The anlage of the organ grows into the ventral mesentery, subsequently becoming enclosed in the septum transversum. In so doing it encounters the omphalomesenteric veins, and forms, in relation to the latter, two Incompletely separated parts which have been called the dorso-lateral lobes. When the umbilical veins enter the liver a more ventral, medial mass is formed. This becomes incompletely separated into two parts which give rise to the permanent right and left lobes. The right becomes the larger. The right umbilical vein loses its connection with the liver (p. 230). After birth the left, which lies between the right and left lobes, degenerates into the round ligament of the liver. The other lobes arise secondarily as outgrowths from the right primary dorsolateral lobe, the caudate (lobe of Spigelius) from its inner (medial) surface, the quadrate from its dorsal surface.

The liver as a whole grows rapidly and by the second month is relatively large. During the third month it fills the greater part of the abdominal cavity. After the fifth month it grows less rapidly and the other intraabdominal organs overtake it, so to speak, although at birth it forms one-eighteenth the total weight of the body. After birth it actually diminishes in size. The right lobe is from the beginning larger than the left, and after birth the predominance increases.

Histogenesis of the Liver. The hepatic part (pars hepatica) of the liver anlage is derived from the entodermal lining of the gut and constitutes a mass of cells with no lumen. From this mass, solid bud-like evaginations grow into the mesentery, break up the omphalomesenteric veins into smaller channels and form trabeculae, or hepatic cylinders (p. 316). The latter anastomose freely with one another and are composed of polyhedral, darkly staining cells with vesicular nuclei (Fig. 277, A). Lumina begin to appear in the cylinders about the fourth week as small cavities which communicate with the cavity of the gut.

The hepatic cylinders are the forerunners of the hepatic cords or cords of liver cells. There are two views as to the manner of transformation. The older view is that the cylinders gradually become stretched, the number of cells in cross-section becoming less until it is reduced to two. Between these two lies the lumen of the cord or the so-called "bile capillary" (Fig. 277, B). The other view is that branches from the sinusoids grow into the cylinders and subdivide them into hepatic cords.

As stated above, the hepatic cylinders are at first composed of darkly staining, polyhedral cells with vesicular nuclei. These are the liver cells proper. Later other small spherical cells, with dense nuclei, appear and during the fourth month become very numerous (Fig. 277, A). From this time on, they grow less in number and at birth have practically disappeared. Earlier investigators considered them as developing liver cells. Further study on the development of the blood, however, has led others to consider them as erythroblasts (p. 239). Since they are inside of the hepatic cylinders, they either wander in from the intertrabecular blood vessels or lie in intratrabecular vessels. The latter supposition accords with the view that the cylinders are broken up into hepatic cords by the ingrowth of branches from the sinusoids.

The development of the lobules of the liver, producing the peculiar relations between the parenchyma of the gland and the blood vessels, has not been clearly and completely demonstrated. In young embryos the branches of the hepatic veins are surrounded by comparatively little connective tissue. The branches of the portal vein are surrounded by a considerable amount which subdivides the liver into lobules but not in the same manner as in the adult. The trabeculae possess no radial character and there are several so-called central veins in each lobule. The changes by which these primary lobules are subdivided into the permanent ones do not take place until after birth. The branches of the portal vein, with the surrounding connective tissue, invade the primary lobules and divide them into a number of secondary lobules, corresponding to the original number of central veins. At the same time the hepatic cords (which have been formed meanwhile) become arranged radially around the central veins in the characteristic manner. The hepatic artery grows into the liver secondarily and its branches follow the course of the branches of the portal vein.

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'''Fig. 277. Sections of the liver of (^4) a human foetus of 6 months and (B) a child of 4 years.''' Toldt and Zuckerhandl. McMurrich. be, Bile "capillary"; e, erythroblast; he, hepatic cylinder (in A), cord of liver cells (in B).

Degeneration of the liver cells occurs in the region of the left triangular ligament, the gall bladder and the inferior vena cava. The bile ducts may, however, withstand the degenerative processes and persist as the vasa aberrantia of the liver. The cause of the degeneration is possibly the pressure brought to bear by other organs.

==The Development of the Pancreas==

The epithelium of the pancreas, like that of the liver, is a derivative of the entoderm. It arises from two (or three) separate anlagen, one dorsal and one (or two) ventral. The dorsal anlage appears first as a ridge-like evagination from the dorsal wall of the gut, slightly cranial to the level of the liver (Figs. 273 and 274). It appears about the same time as the liver or a little later. The mass of cells grows into the dorsal mesentery and becomes constricted from the parent epithelium except for a thin neck which becomes the duct of Santorini (Fig. 278). A little later two other diverticula appear, one from each side of the common bile duct. It is uncertain whether only one or both of these take part in the formation of the pancreas, but it seems most probable that the left one disappears entirely. The right diverticulum continues to develop and becomes constricted from the parent epithelium, leaving only a thin neck which becomes the duct of Wirsung.

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'''Figs. 278 and 279. From models of the developing liver and pancreas of rabbit embryos of 8 mm. and 10 mm''', respectively. Both seen from the right side. Hammar, Bonnet.

The smaller ventral pancreas grows to the right and then dorsally in the mesentery (Fig. 260), passing over the right surface of the portal vein, until it meets and fuses with the proximal part of the larger dorsal pancreas. The fusion takes place in the sixth week, and the two anlagen then form a single mass. A communication is established between the two ducts, and the dorsal duct (Santorini) usually disappears, leaving the ventral (Wirsung) as the permanent duct opening into the ductus choledochus. In a general way it may be said that the ventral anlage gives rise to the head, the dorsal anlage to the body and tail of the pancreas (compare Figs. 278 and 279).

As the pancreas grows into the dorsal mesentery it comes to lie in the dorsal mesogastrium between the greater curvature of the stomach and the vertebral column, and since the dorsal mesogastrium at first lies in the medial sagittal plane, the pancreas is similarly situated. After the sixth week, however, as the stomach changes its position (p. 305) , the pancreas is carried along with the mesogastrium and comes to lie in a transverse plane, with its head to the right and embedded in the bend of the duodenum, and its tail reaching to the spleen on the left. The organ as a whole is at first movable along with the mesentery, but when it assumes its transverse position it lies close to the dorsal abdominal wall. The mesentery then fuses with the adjacent peritoneum (see p. 350), and the pancreas is firmly fixed.

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'''Fig. 280. From a transverse section through the region of the duodenum of a pig embryo of 14 mm.''' Photograph.

The connective tissue of the pancreas is derived from the mesodermal tissue of the mesentery. As the processes or buds which form the ducts and terminal tubules grow out from the primary masses, they penetrate the mesodermal tissue and are surrounded by it. Groups of tubules form lobes and lobules, and the entire gland is surrounded by a capsule of connective tissue.

Histogenesis of the Pancreas. The masses of entodermal cells forming the anlagen of the pancreas develop further by a process of budding, which goes on until finally a compound tubular gland is produced. According to some investigators the primary evaginations are hollow, their lumina beinj continuous with the lumen of the gut. According to others they are solid al first and acquire their lumina secondarily. The same uncertainty exists regard to the later outgrowths or buds.

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'''Fig. 281. Sections of the developing pancreas of a guinea-pig embryo of 12 mm.''' (a); of 33 mm. (&) ; of Torpedo marmorata (c) . Hetty.

:c t Capillaries; Dg, ducts; Gz, duct cells; Lz, Langhans' cells. The cells in c show distinct zymogen granules

The early entodermal cells proliferate, and the resulting cells change according to their position in the gland. Those lining the larger ducts become high columnar, with more or less homogeneous cytoplasm; those lining the intermediate (intercalated) ducts become low; those lining the terminal secreting tubules become pyramidal and more highly specialized, and also acquire certain constituents the zymogen granules (Fig. 281, c) which vary with the functional activities of the gland. The centro-tubular cells in the terminal tubules are probably to be explained on a developmental basis. While a few maintain that they are "wandering" cells, it is quite generally accepted that they are simply continuations of the flat cells lining the intermediate ducts, the result being that the cells of the terminal tubules seem to spread out over the ends of the intermediate ducts in the form of cap-like structures.

It was once thought that the islands of Langerhans were derived from the mesodermal tissue. Recently it has been pretty clearly demonstrated that they are derived from entoderm. In guinea-pig embryos of 5 to 6 mm., at a time when the dorsal pancreas has merely begun its constriction from the gut, certain cells in the mass appear darker and slightly larger than the others. They show darker areas of cytoplasm around the nuclei, and later the darker areas extend throughout the cells and the nuclei become larger and more vesicular. When lumina appear in the outgrowths or buds, these cells occupy a position on or near the surface of the buds (Fig. 281, a). In further development they tend to separate themselves from the buds and collect in clumps (Fig. 281, b). Capillaries then penetrate the clumps and break them up into the trabeculae of cells characteristic of the islands of Langerhans (Fig. 281, c). Studies on the development of the islands in the human pancreas indicate a similar origin and mode of development.

==Anomalies==

One of the most striking anomalies of the organs of alimentation is found in connection with a more general anomalous condition known as transposition of the viscera (situs viscerum inversus) . The transposition may be so complete that the minor asymmetries normally present on the two sides are all repeated in reverse order, the functions of the organs being unimpaired. As regards the alimentary tract, this means that the position of the stomach is reversed in the abdominal cavity; that the duodenum crosses from left to right; that the various coils of the jejunum and ileum occupy positions opposite to the normal; that the caecum and ascending colon are situated on the left side and the descending colon on the right; and that the larger lobe of the liver lies on the left side. The other visceral organs are transposed accordingly, the heart being inclined toward the right side, the left lung consisting of three lobes and the right of two, the left kidney being lower than the right, etc. Such cases are not uncommon, two hundred being on record.

Various theories as to the causes of transposition of the organs have been advanced. In the most plausible of these the anomalous condition is considered as due to the influence of the large veins in the embryo. It seems best, therefore, to consider first the transposition of the heart (dextrocardia, referred to on page 255).

After the tvvo anlagen unite in the midventral line, the heart constitutes a simple straight tube which lies in a longitudinal direction in the primitive pericardial cavity, and which is joined caudally by the two omphalomesenteric veins and cranially by the ventral aortic trunk (p. 197) . Normally the left omphalomesenteric vein is the*larger and pours a greater quantity of blood into the heart tube than the right. This condition is regarded as the primary factor in the deflection of the tube toward the right side (p. 199; also Fig. 158). If the conditions were reversed, that is, if the right omphalomesenteric vein were the larger and poured the greater quantity of blood into the heart tube, the primary bend of the latter would be toward the left side. Consequently the heart would continue to develop in the transposed position and eventually come to lie on the side opposite to the normal.

Although dextrocardia is very frequently associated with transposition of the abdominal organs, it is not necessarily so, for there are cases of the latter in which the heart occupies the normal position. Consequently it seems that further influences must be present to account for transposition of the abdominal organs when the thoracic organs are normal. A number of investigators have emphasized the importance of the influence of the large venous trunks in the abdominal region, especially on the position of 'the liver and stomach.

Primarily the omphalomesenteric veins pass cranially through the mesentery. Later they form two loops or rings around the duodenum. Then the left half of the upper ring and the right half of the lower disappear, the common venous trunk thus following a spiral course around the duodenum (p. 231 ; also Fig. 201). This primary relation of the omphalomesenteric vein is retained in the relation of the portal vein to the duodenum. The stomach lies to the left of the portal vein. After the allantoic (placental) circulation is established the umbilical veins pass cranially in the lateral body walls. After the veins come into connection with the liver, the right atrophies and the left increases in size and becomes the single large umbilical vein of later stages (p. 230; also Fig. 202). The right lobe of the liver becomes the larger.

If, as is maintained by some investigators, the usual position of the stomach and liver is due to the persistence of the left venous trunks, a persistence of the right venous trunks would afford a plausible explanation of the transposition of these organs. It is not unreasonable to attribute also the transposition of the other abdominal organs directly or indirectly to the persistence of the right venous trunks. Certainly a reversal in the position of the stomach would cause a reversal in the position of the duodenum.

If these conditions are the real ones, the fact that the thoracic organs can be transposed without a transposition of the abdominal organs, or vice versa, is accounted for. The primary bend of the heart tube occurs at a very early period, before the changes in the vessels in the region of the liver. Consequently a reversal of the conditions of the omphalomesenteric at a very early stage only would be likely to affect the heart. The principal changes in size of the venous trunks in the abdominal region take place after their channels have been broken up in the liver. In other words, the modifications in the veins in the liver occur after the definite relations of the heart have been established. Therefore the transposition of the abdominal organs may take place after the heart has begun to develop normally.

===The Mouth===

Anomalies in the mouth region, due to defective fusion of the processes that bound it, have been considered elsewhere (p. 180).

Anomalies of the tongue sometimes arise as the result of imperfect development of one or more of its anlagen. Imperfect development of the tuberculum impar results in total or partial lack of the anterior part. Defects in the root are probably due to imperfect development of one or both of the paired anlagen (p. 289). Malformations of the lower jaw (micrognathus, agnathus) are usually accompanied by malformations of the tongue, both structures being derived largely from the first pair of branchial arches.

===The Pharynx===

The pharynx is the seat of cysts, fistulae and diverticula which have been considered in connection with the anomalies in the region of the branchial arches and grooves (Chap. XX).

The thyreoid gland is not infrequently the seat of certain anomalies that arise as the result of abnormal development. Persistent portions of the thyreoglossal duct, the upper end of which is indicated by the foramen caecum linguae, may give rise to cystic structures extending to the region of the hyoid bone. Persistent portions of the duct may even give rise to accessory thyreoid (suprahyoid, prehyoid) glands (p. 301; also Fig. 260). Considerable variation also exists in the isthmus and lateral lobes of the thyreoid, due to variation in the manner of development of the medial anlage.

Impaired development of the thymus gland sometimes leads to cysts which come to lie in the anterior mediastinum.

===The Oesophagus===

Very rarely the oesophagus is entirely lacking, being represented by a mere cord of tissue. More frequently it is defective in certain parts. Tne atresia may begin just below the pharynx or just above the stomach, the intermediate portion being composed of a cord of fibrous tissue. Occasionally the non-atretic portion opens into the trachea. Possibly this represents an imperfect separation between the primitive gut and the anlage of the respiratory system (p. 330).

===The Stomach===

Occasionally the stomach is smaller than the normal. It may even be a narrow tube resembling the other portions of the gut, owing to lack of dilatation. Other congenital malformations, apart from transposition (p. 323), are very rare.

===The Intestines===

One of the most common anomalies is the persistence of the proximal end of the yolk stalk, forming MeckeVs diverticulum (see p. 581). This usually is attached to the ileum about three feet from the caecum. In exceptional cases it retains its lumen and, when the stump of the umbilical cord disappears, forms a congenital umbilical fistula. Usually, however, the diverticulum is shorter and ends blindly. Occasionally it becomes constricted from the intestine and forms a cystic structure. (See also Chap. XX.)

Congenital stenosis and atresia may occur in different regions of the intestine, the duodenum being the most common site. Normally the lumen of the duodenum becomes closed for a brief period during development (p. 307) , and congenital closure of the lumen may represent a persistence of the early embryonic condition.

A conspicuous malformation is the persistence of the cloaca. The septum which normally separates the latter structure into rectum and urogenital sinus fails to develop, thus leaving a common cavity (see Figs. 323 and 324). In addition to this the cloacal membrane may fail to rupture and the cloaca become much distended. More often the septum develops in part, leaving only a small opening between the rectum and urogenital sinus. After the latter undergoes further development, the rectum comes to open into the urethra or bladder, or into the vagina or uterus.

Atresia of the anus is not infrequently met with. The cloacal (or anal) membrane fails to rupture and the rectum ends blindly. In other cases the rectum opens into the urogenital sinus, as described in the preceding paragraph. Occasionally the lumen of the rectum is closed atresia recti and the gut ends blindly some distance from the surface, being connected with the anal region by a cord of fibrous tissue.

Variations in the position of the intestinal loops, apart from transposition (p. 323), are of frequent occurrence. It is not customary to include these variations among malformations (see p. 308) . The caecum (and appendix) and colon present some striking variations. The caecum may be situated high up in the abdominal cavity, the ascending colon being absent. Or it may be situated at any intermediate point between that and its usual position in the right iliac fossa. These variations are due to different degrees of development of the ascending colon (p. 309).

===The Liver===

Congenital malformations of the liver are rare. The most frequent, apart from transposition, include anomalies in the size and number of lobes. Accessory lobes may occur within the falciform ligament. One case of lack of development of the gall bladder has been observed. Stenosis of the bile passages is occasionally met with.

===The Pancreas===

Occasionally accessory glands are found in the intestinal or gastric wall. These probably represent aberrant portions of the main gland, and may give rise to cystic structures. Very recently, however, a number of intestinal diverticula have been observed in certain mammalian embryos and also in human embryos. Although the history of these unusual diverticula has not been traced, their presence may offer a clue to the origin of accessory pancreatic structures. The ducts of the pancreas are subject to distinct variations, which, however, are not usually considered as anomalies. Not infrequently the duct of the dorsal anlage (duct of Santorini) persists and opens directly into the duodenum. It may persist along with the duct of the ventral anlage (duct of Wirsung), or the latter may disappear (p. 321; compare Figs. 2 78 and 279).

:'''Next:''' [[Book_-_Text-Book_of_Embryology_13|Respiratory]]

==References for Further Study==

BADERTSCHER, J. A. : The Development of the Thymus in the Pig. I, Morphogenesis. II, Histogenesis. Am. Jour, of Anat., Vol. XVII, 1915.

{{Ref-Bardeen1914}}

{{Ref-Bell1905}}

BERRY, J. M.: On the Development of the Villi of the Human Intestine. Anat. Anz., Bd. XVI, 1900.

BONNET, R.: Lehrbuch der Entwickelungsgeschichte. Berlin, 1907.

BORN, G.: Ueber die Derivate der embryonalen Schlundbogen und Schlundspalten bei Saugetiere. Arch.}, mik. Anat., Bd. XXII, 1883.

BRACKET, A. : Die Entwickelung und Histogenese der Leber und des Pancreas. Ergebnisse der Anat. u. Entwick., Bd. VI, 1897.

CHIEVITZ, J. C.: Beitrage zur Entwickelungsgeschichte der Speicheldriisen. Arch. f. Anat. u. Physiol., Anat. Abth., 1885.

CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.

Fox, H.: The Pharyngeal Pouches and their Derivatives in the Mammalia. Am. Jour, of Anat., Vol. VIII, No. 3, 1908.

FUSARI, R.: Sur les phenomenes, que Ton observe dans la muqueuse du canal digestif durant le developement du fcetus humain. Arch. ital. Biol., T. XLII, 1904.

GOPPERT, E.: Die Entwickelung des Mundes und der Mundhohle mit Driisen und Zunge; die Entwickelung der Schwimmblase, der Lunge und des Kehlkopfes der Wirbeltiere. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere. Bd. II, Teil I, 1902.

HAMMAR, J. A.: Einige Plattenmodelle zur Beleuchtung der friiheren embryonalen Leberentwickelung. Arch.f. Anat. u. Physiol., Anat. Abth., 1893.

HAMMAR, J. A.: Allgemeine Morphologic der Schlundspalten beim Menschen. Entwickelung des Mittelohrraumes und des ausseren Gehorganges. Arch. f. mik. Anat., Bd. LIX, 1902.

HAMMAR, J. A. : Das Schicksal der zweiten Schlundspalte. Zur vergleichenden Embryologie und Morphologic der Tonsille. Arch.f. mik. Anat., Bd. LXI, 1903.

HELLY, K.: Studien iiber Langerhanssche Inseln. Arch. f. mik. Anat., Bd. LXVII, 1907.

HERTWIG, O. : Lehrbuch der Entwickehmgsgeschichte der Wirbeltiere und des Menschen. Jena, 1906.

HENDRICKSON, W. F.: The Development of the Bile Capillaries as Revealed by Golgi's Method. Johns Hopkins Hosp. Bull., 1898.

His, W.: Anatomic menschlicher Embryonen. Leipzig, 1880-1885.

His, W.: Die Entwickelung der menschlichen und tierischen Physiognomien. Arch, f. Anat. u. Physiol., Anat. Abth., 1892.

JACKSON, C, M.: On the Development and Topography of the Thoracic and Abdominal Viscera. Anat. Record, Vol. Ill, 1909.

{{Ref-Johnson1910}}

JOHNSON, F. P.: The Development of the Mucous Membrane of the Large Intestine and Vermiform Appendix in the Human Embryo. Am. Jour. of. Anat., Vol. XIV, 1903

JOHNSON, F. P. : The Development of the Rectum in the Human Embryo. Am. Jour. of Anat., Vol. XVI, 1914.

KINGSBURY, B. F.: The Development of the Human Pharynx. I, The Pharyngeal Derivatives. Am. Jour, of Anat., Vol. XVIII, 1918.

KOHN, A.: Die Epithelkorperchen. Ergebnisse der Anat. u. Entwick., Bd. IX, 1899.

KOLLMANN, J.: Die Entwickelung der Lymphknotchen in dem Blinddarm und in dem Processus vermiformis. Die Entwickelung der Tonsillen und die Entwickelung der Milz. Arch.f. Anat. u. Physiol., Anat. Abth., 1900.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

MALL, F. P.: Ueber die Entwickelung des menschlichen Darmes und seiner Lage beim Erwachsenen Arch.f. Anat. u. Physiol., Anat. Abth. Suppl., 1897.

MAURER, F.: Die Entwickelung des Darmsystems. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere., Bd. II, Teil I, 1902.

McMuRRiCH, J. P. : The Development of the Human Body. Third Ed. Philadelphia, 1907.

MUMMERY, J. H.: The Microscopic Anatomy of the Teeth, 1919.

{{Ref-Norris1918}}

{{Ref-Pearce1903}}

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

POLZL, A.: Zur Entwickelungsgeschichte des menschlichen Gaumens. Anat. Hefte, 1905

ROSE, C.: Ueber die Entwickelung der Zahne des Menschen. Arch. f. mik. Anat., Bd. XXXVIII, 1891.

STEIDA, A.: Ueber Atresia ani congenita und die damit verbundenen Missbildungen. Arch.], klin. Chir., Bd. LXX, 1903.

STOHR, P.: Ueber die Entwickelung der Darmlymphknotchen und iiber die Riickbildung von Darmdriisen. Arch. f. Anat. u. Physiol., AnaL Abth., 1898.

TANDLER, J.: Zur Entwickelungsgeschichte des menschlichen Duodenum in friihen Embryonalstadien. Morph. Jahrb., Bd. XXIX, 1900.

TOLDT und ZUCKERHANDL Ueber die Form und Texturveranderungen der menschlichen Leber wahrend Wachsthums. Sitzungsber. d. kaiser. Akad. d. Wissensch., Wien. Math.-Naturwiss. Klasse., Bd. LXXII, 1875.

TOURNEUX ET VERDUN: Sur les premiers developpements de la Thyroide, du Thymus et des glandes parathyroidiennes chez I'homme. Jour. de. I' Anat. et. de la Physiol., T. XXXIII, 1897

{{Bailey_1921_Footer}}

[[Category:Gastrointestinal Tract]] [[Category:Tooth]]

Book - Text-Book of Embryology 12

2024-01-25T00:53:28Z

Z8600021:

{{Bailey 1921}}

=The Development of the Alimentary Tube and Appended Organs=
<div id="Fig244"></div>
[[File:Bailey244.jpg|thumb|300px|'''Fig. 244. Lateral view of human embryo with 14 pairs of primitive segments (2.5 mm).''' Kollntann. The yolk sac has been cut off. The fore-gut, mid-gut and hind-gut, as indicated in the figure, together constitute the primitive gut. Compare with Fig. 245.]]

The embryonic disk, composed of the three germ layers, primarily lies flat upon the yolk sac (see p. 107; also Fig. 75). A little later the axial portion of the embryo is indicated by the primitive streak, the neural groove (subsequently the neural tube), the notochord, and the primitive segments (Fig. 71). Then along each side of the axial portion and at the cephalic and caudal ends, the germ layers bend ventrally and medially and finally meet and fuse in the midventral line (p. 109) . The portion of the entoderm ventral to the notochord is bent into a tube which, for the most part, becomes pinched off from the parent entoderm and is suspended in the embryonic coelom by the common mesentery (Figs. 103 and 104). This entodermal tube is the primitive gut. At first it ir but slightly elongated and is closed at both ends. On the ventral side, however it opens widely into the yolk sac (Figs. 244 and 245). The primitive gut, therefore, has no communication with the exterior. It communicates at its caudal end with the central canal of the spinal cord through the neurenteric canal (Fig. 76; compare with 77).

As development proceeds, this simple tube elongates rapidly and becomes differentiated into distinct regions. The cephalic end, in connection with the branchial arches and grooves, becomes the dilated pharyngeal region. Caudal to and continuous with this, is the short, narrow cesophageal region which in turn passes over into the slightly dilated stomach region. The portion of the gut caudal to the stomach is the intestinal region. During the differential changes, the communication with the yolk sac becomes relatively smaller, forming the yolk stalk which joins the intestinal portion a short distance caudal to the stomach (Figs. 246 and 247).

<div id="Fig245"></div>
[[File:Bailey245.jpg|600px]]

'''Fig. 245. Ventral view of human embryo of 2.4 mm.''' His, Kollmann.
: Note the opening in the ventral wall of the gut. This indicates the communication between the gut and the yolk sac. The latter has been removed. Compare with Fig. 244.

==The Mouth==

At a very early period the primary fore-brain region bends ventrally almost at a right angle to the long axis of the body to form the naso-frontal process.

As the first branchial arch develops, it grows ventrally until it meets and fuses with its fellow of the opposite side in the midventral line, thus forming the mandibular process. From the cephalic side of the first arch a secondary process maxillary process develops and fills in the space between the arch itself and the naso-frontal process. These various structures thus bound a distinct depression on the ventral side of the head. This depression is the oral pit, the forerunner of the oral and nasal cavities (Fig. 245; compare with Figs. 244 and 85). The groove in the midventral line between the mandibular processes marks the symphysis of the lower jaws. The groove on each side between the maxillary process and the mandibular process marks the angle of the mouth. The groove between the maxillary process and the naso-frontal process is the naso-optic furrow, at the dorsal end of which the eye develops. The bottom of the oral pit is formed by a portion of the ventral body wall, which separates the oral cavity from the cephalic end of the gut, and which is composed of ectoderm and entoderm, with a small amount of mesoderm between. This closing plate, the pharyngeal membrane, which is still present in I embryos of 2.15 mm., soon becomes thinner and finally breaks away, leaving I the oral pit and the gut in direct communication (Fig. 247). Since the oral pit , is lined with ectoderm, the epithelial lining of the mouth or oral cavity is largely of ectodermal origin. In the medial line of the roof of the oral cavity, near the pharyngeal membrane, the epithelium (ectoderm) evaginates to form Rathke's pocket. This comes in contact with an evagination from the floor of the brain and with it forms the pituitary body.

<div id="Fig246"></div>
[[File:Bailey246.jpg|600px]]

'''Fig. 246. Alimentary tube of a human embryo of 4.1 mm.''' His Kollmann.

The further development of the mouth consists of an elaboration of the structures which primarily bound the oral pit and the growth of certain new structures such as the teeth and the tongue. The first branchial arch fuses with its fellow of the opposite side in the midventral line to form the symphysis of the lower jaws, giving rise also to the lower lip and chin region. As the nasofrontal process continues to grow, two depressions appear on its ventral border, one on each side, a short distance from the medial line. These depressions are the nasal pits which indicate the beginning of the external openings of the nasal passages. The part between the nasal pits is destined to give rise to the nasal septum and the medial part of the upper lip (Fig. 98). The primary oral cavity is divided into the oral cavity proper and the nasal cavity by outgrowths from the maxillary processes. From the medial side of each maxillary process a plate-like structure grows across the primary oral cavity toward the medial line (Fig. 140). These two plates, or palatine processes, meet and fuse with the lower part of the nasal septum (Fig. 248) . (For further details of this fusion, see page 121 and page 163). The palatine processes thus form the palate, or the roof of the mouth, which separates the mouth cavity from the nasal cavity. The palate does not extend far enough backward, however, to separate the posterior part of the nasal cavity from the pharynx. Thus the posterior nares and pharynx are left in communication. Externally the maxillary processes extend medially, separate the nasal pits from the oral cavity, and form the lateral portions of the upper lip (Fig. 99).

<div id="Fig247"></div>
[[File:Bailey247.jpg|600px]]

'''Fig. 247. Sagittal section of reconstruction of a human embryo of 5 mm.''' His, Kollmann.

<div id="Fig248"></div>
[[File:Bailey248.jpg|600px]]

'''Fig. 248. From a section through the head of a human embryo of 28 mm.''' Showing the nasal septum, the nasal cavities, the oral cavity, and the palatine processes. Peter.

==The Tongue==

The tongue develops from three separate anlagen which unite secondarily. In embryos of about 3 mm. a slight elevation appears on the floor of the pharynx in the region of the first branchial arch. This is the tuberculum impar, being, as the name indicates, unpaired, and is destined to give rise to the tip and body of the tongue (Fig. 249) . Soon afterward two bilaterally symmetrical elevations appear on the floor of the pharynx, which are destined to give rise to the root of the tongue (Fig. 250). These paired elevations, arising in, the region of the second and third branchial arches, gradually enlarge and unite with each other and with the tuberculum impar, leaving between the latter and themselves, however, a V-shaped groove (Fig. 251). At the apex of the groove there is a depression the foramen cecum lingua which is the external opening of the thyreoglossal duct (see p. 301). The groove later disappears, but its position is indicated in the adult by the vallate papillae.

<div id="Fig249"></div>
[[File:Bailey249.jpg|600px]]

'''Fig. 249. Floor of the pharyngeal region of a human embryo of about 3 weeks.''' His.

According to Hammar, the tuberculum impar is a transitory structure and does not give rise to the tip and body of the tongue. The tip and body are derived from a much more extensive elevation in the floor of the pharynx.

The tongue as a whole enlarges and grows from its place of origin toward the entrance to the primary oral cavity. For a time it practically fills the cavity. When the palate develops it recedes and finally comes to lie on the floor of the oral cavity proper, as in the adult. The growth of the tongue involves the epithelial lining of the pharynx and oral cavity and also the underlying mesenchymal tissue. The latter produces the connective tissue and at least a part of the intrinsic muscle fibers of the tongue. The papillae involve the epithelium and connective tissue, while the glands and taste buds are derived from the epithelium alone.

<div id="Fig250"></div>
[[File:Bailey250.jpg|600px]]

'''Fig. 250. Floor of pharyngeal region of a human embryo of 12.5 mm.''' His.

The portion of the lingualis muscle innervated by the facial (VII) nerve is probably derived from the mesenchymal tissue in the tongue anlage. The rest of the muscle is innervated by fibers from the hypoglossal (XII) nerve, indicating a possible derivation from certain rudimentary segments in the occipital region which correspond to the three roots of the nerve. This would make it appear that during phylogenesis a part of the lingualis muscle has grown into the tongue from a region caudal to the last branchial arch.

The lingual papilla begin to develop during the third month. Their development is limited to the dorsum of the tongue and to the portion derived from the tuberculum impar. In other regions slight elevations may appear, but not in the form of distinct papillae. The fungijorm and filiform papillae appear as pointed elevations in the connective tissue, which push their way into the epithelium, the latter at the same time being raised above the surface over these points. Gradually the little masses of connective tissue assume the shapes characteristic of fungiform or filiform papillae. During the fifth month the epithelium between the papillae apparently degenerates to some extent, thus leaving them projecting still farther above the surface. The formation of papillae probably goes on for some time after birth, since at birth their form, size, number and arrangement are not the same as at later periods. It is an interesting fact that the filiform papillae lose many of their taste buds after the child is weaned.

The anlage of the vallate papillae appears as a ridge along the V-shaped line of fusion between the paired and unpaired portions of the tongue. The ridge is apparently formed by the ingrowth of a solid mass of epithelium along each side, although the connective tissue between the masses may grow toward the surface to some extent. Later the ridge is broken up into the individual papillae by the ingrowth of the epithelium at certain points. The more superficial cells of the masses then degenerate, thus leaving each papilla surrounded by a trench and wall.

<div id="Fig251"></div>
[[File:Bailey251.jpg|600px]]

'''Fig. 251. Dorsal view of the tongue of a human embryo of 20 mm.''' His, Bonnet.

The development of the lingual glands is confined for the most part to the root and inferior surface and to the region of the vallate papillae. The glands begin to develop during the fourth month as solid ingrowths of epithelium, the mucous glands appearing first, the serous somewhat later. The epithelial masses acquire lumina and grow deeper into the tongue, where they usually branch and coil to form the secreting portions. The latter open to the surface through the original ingrowths which become the ducts. Ebner's glands develop from the bottoms of the trenches around the vallate papillae.

==The Teeth==

The development of the teeth involves the ectoderm and mesoderm, the former giving rise to the enamel, the latter to the dentine and pulp. In human embryos of 12-15 mm. (thirty-four to forty days), before the lip groove is formed, a thickening of the epithelium (ectoderm) takes place along the edges of the processes that bound the slit-like entrance to the mouth. When the lip groove appears (Fig. 140), the epithelial thickening comes to lie along the edge of the jaw, or in other words, along the edge of the gums. It then grows into the mesenchymal tissue (mesoderm) of the jaw obliquely toward the lingual surface to form the dental shelf. A little later the dental groove appears on the edge of the jaw, along the line where the ingrowth of epithelium took place.

<div id="Fig252"></div>
[[File:Bailey252.jpg|600px]]

'''Fig. 252. Section of developing tooth from a 3 months human fetus.''' Szymonowicz.

Note the portion of the original dental shelf connecting the developing tooth with the epithelium of the mouth cavity.

The dental shelf is at first of uniform thickness, but in a short time five enlargements appear in it in each upper and lower jaw, indicating the beginnings of the milk teeth. When the embryo reaches a length of 40 mm. (an age of eleven to twelve weeks) the mesenchymal tissue on one side of these enlargements (above and to the inner side in the upper jaw, below and to the inner side in the lower jaw) becomes condensed and pushes its way into the epithelium. Each of these mesenchymal ingrowths is a dental papilla. Thus at this stage the anlage of each tooth is a mass of epithelium fitting cap-like over a mesenchymal papilla. The epithelium is the forerunner of the enamel organ; the papilla is destined to give rise to the dentine and pulp. The anlagen are connected with one another by intermediate portions of the dental shelf, and with the surface by the original ingrowth of epithelium.

===The Enamel===

The epithelial cells nearest the dental papilla become high columnar in shape, forming a single layer. Those in the interior of the mass become separated and changed into irregular, stellate, anastomosing cells, with a fluid intercellular substance, constituting the enamel pulp. Those farthest from the papilla become flattened (Fig. 252 ; compare with Fig. 253). Calcification begins in the basal ends of the columnar cells, or in the ends next the papilla, and in the intercellular substance, and gradually progresses throughout the cells, the latter at the same time becoming much more elongated. Thus the cells are transformed into enamel prisms which are held together by the calcined intercellular substance (Fig. 253).

<div id="Fig253"></div>
[[File:Bailey253.jpg|600px]]

'''Fig. 253. Section through the border of a developing tooth of a new-born puppy.''' Bonnet.

The formation of enamel begins in the milk teeth toward the end of the fourth month and probably continues until the teeth break through the gums. The enamel organ at first surrounds the entire developing tooth except where the papilla joins he underlying mesenchymal tissue (Fig. 252). Later the deeper part of the organ disappears as such, and the enamel is formed only on that part of the tooth which eventually becomes the crown. The enamel pulp increases in amount for a time, but subsequently disappears as the tooth grows into it (Fig. 254). Its function is not fully understood. It may serve as a. line of least resistance in which the tooth grows, and it may convey nourishment to the enamel cells, the enamel organ being non-vascular.

===The Dentine and Pulp===

At first the dental papilla is simply a condensation of mesenchyme, but later it is converted into a sort of connective tissue penetrated by blood vessels and nerves (Fig. 254). The cells nearest the enamel organ become columnar and arranged in a single layer, with the nuclei toward their inner ends. The outer ends are blunt, while the inner ends are continued as slender processes that extend into the pulp and probably with other cell processes. These columnar cells are the odontoblasts , under tl influence of which the lime salts of the dentine are deposited, and which are coi parable with the osteoblasts in developing bone.

<div id="Fig254"></div>
[[File:Bailey254.jpg|600px]]

'''Fig. 254. Longitudinal section of a developing tooth of a new-born puppy.''' Bonnet.

Toward the end of the fourth month the odontoblasts form a membrane like structure, the membrana preformativa, between themselves and the enamel. This membrane is first converted into dentine by the deposition of lime salts, after which the process of calcification progresses from the enamel toward the pulp. During calcification slender processes of the odontoblasts remain in minute channels, or dentinal canals, forming the dentinal fibers which anastomose with one another (Fig. 253). In the peripheral part of the dentine certain areas apparently fail to become calcified and form the inter globular spaces. The same cells that are originally differentiated from the mesenchyme probably persist throughout development as the odontoblasts and produce the entire amount of dentine in a tooth. Even in the fully formed tooth there is a layer of odontoblasts bearing the same relation to the dentine and pulp as in the developing tooth. The chief difference between dentine formation and bone formation is that in the latter the osteoblasts become enclosed to form bone cells, while in the former the odontoblasts merely leave processes enclosed as the cell bodies recede.

The pulp of the tooth is of course derived from the mesenchymal tissue in the interior of the dental papilla (compare Figs. 252 and 254). The blood vessels and nerves grow in from the underlying connective (mesenchymal) tissue.

At an early stage the mesenchymal tissue around the anlage of the tooth, including the enamel organ, condenses to form a sort of sheath, the dental sac, which is later ruptured when the tooth breaks through the gum (Fig. 254). The cement is formed around the root of the tooth from the tissue of the dental sac in the same manner as subperiosteal bone is formed from osteogenetic tissue (p. 142). In fact, cement is true bone without Haversian systems.

The milk teeth, which are the first to develop and the first to appear above the surface, are represented by the medial incisors, lateral incisors, canines, and molars, to the number of ten in the upper and ten in the lower jaw. They may be indicated graphically thus:

Milk teeth

[[File:Baileytable04.jpg|600px]]

In describing the formation of the dental shelf, it was noted that the papillae of the milk teeth grow into corresponding thickenings of the epithelium (p. 292). The growth takes place from the side, thus leaving the edge of the shelf free to grow farther toward the lingual side of the jaw. In this free edge other tooth germs arise, which mark the beginnings of the permanent teeth (Fig. 252). In addition to the germs that correspond in position to the milk teeth, three others arise in each jaw, representing the true molars of the adult. The latter arise in a part of the dental shelf which has grown toward the articulation of the jaws without coming in contact with the surface epithelium. The first papilla of the permanent dentition to appear is that of the first molar. It appears immediately behind the second milk molar at a time when the milk teeth are well advanced (embryos of 180 mm., about seventeen weeks). The permanent incisors and canines appear about the twenty-fourth week; the premolars, which correspond to the milk molars, about the twenty-ninth week. The second molar does not appear till after birth (six months), and the third molar, or wisdom tooth, begins to develop about the fifth year.

The formation of the anlagen of the permanent teeth and the development of the enamel, dentine and pulp take place in precisely the same manner as in the milk teeth. The true molars grow out through the gums in the same way as the milk teeth. Those permanent teeth which correspond in position to milk teeth grow under the latter, exert pressure on their roots and thus loosen and finally replace them.

The two sets of teeth may be graphically represented thus:

Milk teeth

<div id="Baileytable04"></div>
[[File:Baileytable04.jpg|600px]]

Permanent teeth

<div id="Baileytable05"></div>
[[File:Baileytable05.jpg|600px]]

Normally all the epithelium of the dental shelf, except the parts directly concerned in the development of the teeth, disappears at times which vary in different individuals. Occasionally, however, remnants of this epithelium give rise to cystic structures (developmental tooth tumors) .

<div id="Fig255"></div>
[[File:Bailey255.jpg|600px]]

'''Fig. 255. From a transverse section through the tongue and oral cavity of a mouse embryo.''' Goppert.

==The Salivary Glands==

The anlage of the submaxillary gland appears, in embryos of 10 to 12 mm., as a flange of epithelium directed ventrally from the portion of the lingual sulcus just caudal to the crossing of the lingual nerve. The flange grows into the mesenchyme of the lower jaw, and at an early period becomes triangular with its longest side free and a free vertical caudal border. Cell proliferation begins at the angle of union of the two borders and gradually progresses cephalad along the longest border, thus producing a solid ridge-like thickening of the latter.

The main portion of the gland is produced by a sprouting of the epithelium from the angle of union of the two free borders of the flange and grows deep into the mesenchyme along the mesial side of the ramus of the mandible. The sprouts branch repeatedly in the course of their development, thus laying the foundation for the division of the gland into lobes and lobules.

The distal end of the duct of the submaxillary (Wharton's) is formed from the ridge-like thickening of the free margin of the flange through a dissolution of the greater part of the flange between the lingual sulcus and the thickened margin itself, thus freeing this portion of the duct from the sulcus. By a continuation of the growth which produced the ridge along the free border of the original flange an extension of this same ridge is produced along the bottom of the lingual sulcus forward toward the chin region. This portion of the ridge is progressively constricted off from the sulcus from cehind forward, until finally the attachment of the duct reaches its definitive position at the side of the frenulum linguae.

The anlage of the Bartolinian element of the suUingual gland appears as a smaller flange attached to the lateral border of the submaxillary flange near the crossing of the lingual nerve and prolonged forward by an interrupted crest along the lingual sulcus. Its later development is similar to that of the submaxillary.

A small medial flange also on the submaxillary flange gives rise to a sprout in much the same manner as the other anlagen. While the history of this anlage is not complete in the human embryo, it probably gives rise to the anterior lingual gland (gland of Bland in and Nuhn). The alveolingual elements arise from a keel attached to the alveolingual sulcus (the groove between the floor of the mouth and the alveolar process of the lower jaw).

The parotid gland originates from the buccal sulcus in essentially the same way as the submaxillary arises from the lingual sulcus. The anlage then continues to grow through the mesenchyme of the cheek across the masseter muscle, the distal end branching freely to form the secreting portion of the gland. The outgrowths are at first solid, but later become hollow, the proximal portion of the original outgrowth forming the parotid (Steno's) duct, the more distal portions forming the smaller ducts and terminal tubules.

The histogenetic changes in the salivary glands probably continue until the child takes solid food, when the glands become of greater functional importance. In the parotid gland, which is serous in man, the original, undifferentiated epithelial cells undergo changes in form and arrangement so that by the twenty-second week the larger ducts are lined with a two-layered epithelium, the smaller ducts with a simple cuboidal epithelium, and the terminal tubules with a single layer of high columnar cells. The two-layered epithelium in the larger ducts persists. The ducts lined with the cuboidal epithelium become the socalled intermediate tubules, the cells changing to a flat type. The high columnar cells of the terminal tubules become the serous secreting cells.

Quite similar changes also occur in the submaxillary, but in foetuses of eight to nine months the crescents of Gianuzzi appear as masses of darkly staining cells forming the ends or sides of the terminal tubules. The crescents at first border on the lumina, but later, probably by a process of evagination, come to lie on the surface of the tubules.

The beginning of the secretory function may be detected by a diminution in the affinity of the cells for stains.

==The Pharynx==

The pharynx develops from the cephalic end of the primitive gut. This part of the gut is primarily of uniform diameter, is broadly attached by mesoderm to the dorsal body wall, and ends blindly (Fig. 247). When the branchial arches and grooves develop in this (the cervical) region, they affect the gut as well as the periphery of the body. The arches form ridges on the surface of the body (Fig. 85) and at the same time form ridges on the wall of the gut. The grooves form pockets which alternate with the arches (Fig. 256). The pock in the pharyngeal cavity, or inner branchial grooves, are directed outward toward corresponding outer branchial grooves (Fig. 249). The arches are covered externally with ectoderm, internally with entoderm, and are filled with mesoderm. Between the arches, or in the grooves, the ectoderm and entoden are in contact or nearly so. Thus the pharynx is not surrounded by a coelomic cavity.

<div id="Fig256"></div>
[[File:Bailey256.jpg|600px]]

'''Fig. 256. Sagittal section through the head of a human embryo of 4.2 mm (31-34 days)'''. His

Since the branchial arches develop in such a way that they are successively smaller from the first to the fourth, the pharyngeal cavity becomes funnelshaped (Fig. 256). It also becomes somewhat flattened in the dorso-ventral direction, and in the earlier stages when the arches and grooves are fully formed, the pharynx constitutes approximately one-third the entire gut (Fig. 247). Primarily the pharyngeal cavity is separated from the oral cavity by the pharyngeal membrane (see p. 287 ; also Fig. 244). When this ruptures and disappears (during the fourth week ?) the two cavities are in open communication. What point in the adult represents the attachment of the pharyngeal membrane is not known; but the glosso- and pharyngo-palatine arches (pillars of the fauces) are usually considered as the boundary between the mouth and pharynx. The caudal limit of the pharynx is the opening of the larynx (Figs. 247 and 256).

Thus in the early stages the general adult character of the pharynx is established. While the branchial arches and grooves undergo profound changes, the pharyngeal cavity retains the same relation to the mouth and to the oesophagus and respiratory tract. The cavity becomes relatively shorter, however, and the alternating ridges and pockets in its walls are lost as the arches and grooves are transformed into other structures. The metamorphosis of the arches and grooves is considered elsewhere (p. 118).

==The Tonsils==

The tonsils arise in the region of the ventral part of the Lsecond inner branchial groove. During the third month the epithelium (entoderm) grows into the underlying connective (mesenchymal) tissue in the form of a hollow bud. From this, secondary buds develop, which are at first solid, but later (during the fourth or fifth month) become hollow by a disappearance of the central cells and open into the cavity of the primary bud, thus forming the crypts. Lymphoid cells wander from the neighboring blood vessels, or are derived directly from the' epithelium- (Retterer), and with the connective tissue form a diffuse lymphatic tissue under the epithelium (Fig. 257). By the eighth month the cells become more numerous in places, and by the third month after birth form distinct lymph follicles with germinal centers. The formation of follicles goes on slowly and is probably not complete until some time after birth.

===The Lingual Tonsils===

The lymphatic tissue of the tongue develops in relation to the lingual glands. During the eighth month lymphoid infiltration occurs around the ducts of the glands, and the connective tissue acquires the reticular character. True follicles probably do not appear until the child is at least five years old.

===The Pharyngeal Tonsils===

During the sixth month small folds appear in the mucous membrane of the roof of the pharynx and become diffusely infiltrated with lymphoid cells. This occurs first in the posterior part of the roof, but later (seventh or eighth month) it extends forward and along the sides of the nasopharygeal cavity. By the end of foetal life the ridges become quite large. Follicles may appear before birth or not until one or two years later. After puberty the ridges almost completely disappear, but the adenoid tissue remains wholly or in part.

The bursa pharyngea is an evagination from the roof of the pharynx about the upper border of the superior constrictor muscle, and is apparent in embryos of eleven weeks. It probably has no genetic relation to the hypophysis. Its significance is not known.

<div id="Fig257"></div>
[[File:Bailey257.jpg|600px]]

'''Fig. 257. Section through the middle of the developing tonsil of a human embryo of 5 months.''' Stohr.

:6, Epithelial buds (secondary outgrowths) from the epithelium lining the primary crypt (c) ; L, lymphoid infiltration of the connective (mesodermal) tissue.

==The Branchial Epithelial Bodies==

===The Thyreoid Gland===

The thyreoid arises, after the manner of ordinary glands, as an evagination from the epithelium of the pharynx. It appears in embryos of 3 to 5 mm. as a ventral outgrowth of epithelium in the floor of the pharynx, at the point where the tuberculum impar and the two paired anlagen of the tongue join (Fig. 258). This point is the foramen caecum linguae which has already been mentioned in connection with the development of the tongue (p. 290) . The evagination grows into the mesodermal tissue in the ventral wall of the neck, and forms a transverse mass of epithelium. The latter breaks up into irregular cords of cells which, by a further process of budding, grow cau dally along the ventral surface of the larynx. The cords of cells are from the first surrounded by connective tissue and later also become surrounded by networks of capillaries (Fig. 259). They ultimately break up into smaller masses which become hollow and form the alveoli. Colloid secretion begins toward the end of fcetal life or soon after birth.

As the gland grows toward its final position it becomes enlarged laterally into the two lateral lobes, which remain connected by the isthmus (Fig. 260). The Pyramidal process represents either a secondary outgrowth from the isthmus or one of the lobes, or a remnant of the original connection with the tongue, that is, of the thyreoglossal duct. The duct usually disappears for the most part, but certain structures sometimes found in the adult in the line of the duct are possibly remnants of it. They have been variously named, according to their position, accessory thyreoid , suprahyoid, and prehyoid glands (Fig. 260).

A pair of structures, appearing first in embryos of 8 to 10 mm., arise as evaginations from the ventral ends of the fourth inner branchial grooves. They grow into the mesodermal tissue and then caudally along the ventro-lateral side of the larynx, where they come into close relation with the lateral lobes of the thyreoid (Fig. 260). They have been called the lateral thyreoids, and acquire the thyreoid structure.

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'''Fig. 258. Transverse section through the region of the 3d branchial groove of an Echidna embryo.''' Maurer. i.= Pharynx, below which are the paired anlagen of the tongue.

Considerable confusion has arisen in regard to the lateral thyreoids. The earlier investigators held that they were derived from the fourth groove and united with the medial portion, which appeared at the foramen caecum, to become integral parts of the thyreoid. Further researches among the lower Vertebrates led others to deny that the thyreoid arose other than as a medial anlage, and that the so-called lateral thyreoids in the embryo were the postbranchial bodies which never assumed the thyreoid structure, but atrophied and disappeared. More recently it has been thought that, although the postbranchial bodies do not function in the lower Vertebrates, they may in the higher Mammals and man unite with the medial thyreoid and secrete colloid.

The parathyreoids or epithelial bodies also come into close relation with the thyreoid. They arise as paired evaginations from the cephalic sides of the third and fourth grooves, dorsal to the thymus and the lateral thyreoid evaginations (Figs. 258 and 261). As the thyreoid grows caudally from its point of origin, these bodies come to lie close to it or may even become embedded in it (Fig. 260). They acquire a structure which resembles that of the suprarenal gland and not that of the thyreoid. Their relation to the latter organ seems to be purely topographical.

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'''Fig. 259. Section of the right half of the thyreoid gland of a pig embryo of 22.5 mm.''' Born.

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'''Fig. 260. Branchial groove derivatives of a rabbit embryo of 16 mm.''' P.-th., parathyreoid or epithelial body. Verdun, Bonnet.

===The Thymus===

The thymus appears in embryos of about 6 mm. as an entodermal evagination from the ventral part of the third branchial groove on each side (Fig 258) . The outgrowths are at first hollow and communicate with the pharyngeal cavity; later they become solid and (in embryos of 14 mm.) lose their connection with the parent epithelium. They elongate and grow caudally in the mesodermal tissue until (in embryos of 16 mm.) their caudal ends lie ventral to the carotid arteries (Fig. 260). In embryos of 29 mm. their caudal ends rest upon the cephalic surface of the pericardium, their cephalic ends reaching to the isthmus of the thyreoid. The two parts eventually fuse to a considerable extent, but the gland as a whole always consists of two distinct lobes.

The gland continues to enlarge, at the same time becoming lobulated by the ingrowth of connective tissue, until the child is two or three years old. At this time it is situated in the anterior mediastinum, usually in the medial line. After this it begins to atrophy and becomes a mass of fibrous and fatty tissue through the growth of the interlobular septa and their encroachment upon the lobules. The classical view that the thymus begins to atrophy after the second or third year and is quite degenerated in the adult has recently been somewhat offset by the view that comparatively slight changes take place in it until puberty. According to the latter view, degeneration goes on after puberty at a rate which varies widely in different individuals, and the thymus may persist as a functional organ up to the age of sixty years.

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'''Fig. 261. Diagram of the branchial groove derivatives in man.''' Verdun.

The histogenesis of the thymus has been a subject of much study and controversy, not only in regard to its origin, but also in regard to its change from an epithelial to a lymphoid structure and the regressive changes in the latter. It has almost certainly been proven to be of entodermal origin. It is at first an epithelial mass which later becomes broken up into lobules by the ingrowth of connective tissue. In regard to the histological changes which it undergoes, the older views are in general that a " pseudomorphosis " takes place; that is, the epithelial elements are replaced by lymphoid cells which wander in from the neighboring blood vessels, Hassall's corpuscles being remnants of the epithelium. Later other investigators looked upon the changes as a "transformation," asserting that the epithelial cells were transformed into lymphoid cells in situ, and that Hassall's corpuscles were remnants of epithelium and disintegrating blood vessels. Some went even so far as to assert that the thymus was the first place of origin of the leucocytes. More recent researches furnish very strong evidence that no lymphoid cells are derived from the epithelial cells (Maximow), but that the epithelium is transformed into the reticular tissue of the thymus, in which the lymphoid cells undergo mitotic division, Hassall's corpuscles possibly representing compressed parts of the reticulum (Hammar) (Fig. 262).

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===The Glomus Caroticum===

The early formation of the glomus caroticum (carotid FIG. 262. Hassall's corpuscle from gland) has not been observed in the human ZftfO^Z** embryo. From observations on lower animals it has not been made clear whether it is derived from the entoderm of a branchial groove or from the adventitia of the carotid artery.

==The Esophagus==

When the primitive gut becomes differentiated into* distinct regions (p. 286), the cesophageal region forms a comparatively short: tube, of uniform diameter, extending from the pharynx to the stomach (Fig. 247). In embryos of about 3 to 4 mm. the anlage of the respiratory system arises from the cephalic end of the tube (see p. 330). The latter is lined with entoderm and broadly attached to the dorsal body wall by mesoderm (Fig. 247). During later stages it becomes relatively longer as the heart recedes into the 1 thorax (p. 214), but maintains its uniform diameter.

Further development produces no marked changes in the relative position; of the oesophagus. It remains broadly attached to the dorsal body wall! throughout the life of the individual. In other words, there is never a distinct! mesentery. The entoderm gives rise to the epithelial lining and the glands, the: surrounding mesoderm to the connective tissue and muscular coats.

===The Stomach===

The anlage of the stomach can br recognized in embryos of about 5 mm. as a slight spindle-shaped enlargement of the primitive gut ai short distance cranial to the yolk stalk (Fig. 246). The dilatation goes on more rapidly on the dorsal than on the ventral side, thus producing the greater and^ lesser curvature respectively. The greater curvature is attached to the dorsaU body wall by the dorsal mesogastrium which is a part of the common mesentery.

The lesser curvature is connected with the ventral body wall by the ventral mesogastrium (Fig. 263).

In further development, apart from histogenesis, the greater curvature becomes much more prominent and the organ as a whole changes its position, the latter process beginning in embryos of 12 to 14 mm. The cephalic (cardiac) end moves toward the left side of the body, the pyloric end toward the right At the same time the stomach rotates, the greater curvature turning caudally from its dorsal position and the lesser curvature cranially from its ventral position. The result is that the organ comes to lie in an approximately transverse position in the body, with the cardiac end to the left, the pyloric end to the right, the greater curvature directed caudally, and the lesser curvature directed cranially (compare Figs. 247 and 263 with Figs. 276 and 304).*

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'''Fig. 263. Gastrointestinal tract and mesenteries of a human embryo of 6 weeks'''. Toldt.

* These changes may be more easily understood if the student will hold a closed book in the sagittal plane in front of him, with the back of the book toward, and the open edge away from him. The back represents the greater curvature, the open edge the lesser curvature. The upper end of the book represents the cardiac end of the stomach, the lower end the pylorus. Turn the upper (cardiac) end to the left, the lower (pyloric) end to the right, at the same time allowing the back of the book (the greater curvature) to drop downward on the side toward the body. The changes in the position of the book represent the changes in the position of the developing stomach.

It is obvious that the lower end of the oesophagus is carried toward the left side of the body with the cardiac end of the stomach, and at the same time twisted so that the side which originally faced the left comes to face ventrally. The changes in the mesentery which accompany the changes in the stomach are described elsewhere (p. 348) .

The torsion of the stomach also produces an asymmetrical condition of the vagi nerves. The latter reach the stomach before it changes its position. As the changes take place, the left nerve is carried around to the left and ventrally so that in the adult it passes through the diaphragm ventral to the oesophagus and extends over the ventral surface of the stomach. The right nerve passes over the dorsal surface of the stomach.

==The Intestine==

When the primitive gut is differentiated into recognizable regions (p. 286) the intestinal region forms a simple tube, of uniform diameter, extending from the stomach to the caudal end of the embryo where it ends blindly. The yolk stalk is attached to the intestine a short distance from the stomach. Near the caudal end the allantoic duct arises (p. 582). The lumen of the yolk stalk and of the allantoic duct is continuous with that of the intestine (Fig. 247). In embryos of 2 to 3 mm. the liver anlage arises from the ventral side of the intestine near the stomach, that is, from that part of the intestine which is to become the duodenum. In embryos of 3 to 4 mm. the pancreas anlage arises in the same region, in part from the liver evagination and in part from the dorsal side of the intestine (Fig. 247).

The intestine as a whole is suspended in the abdominal cavity by the dorsal mesentery which is attached to the dorsal body wall and which is continuous with the dorsal mesogastrium. A ventral mesentery, continuous with the ventral mesogastrium, is present only at the cephalic end of the duodenum (Fig. 263).

The further development of the intestine, apart from histogenesis, consists very largely of the formation of loops and coils, due to an enormous increase in the length of the tube. The abdominal cavity at the same time enlarges to accommodate the increased bulk. As the stomach changes its position (p. 305) , the duodenum comes to lie obliquely across the body and forms a curve with the concavity directed dorsally (Fig. 263). The rest of the intestine forms a loop which extends ventrally and caudally as far as the umbilicus. The arms of the loop are almost parallel and the cephalic arm lies a little to the left of the caudal. The apex of the loop extends into the umbilical ccelom and is attached to the yolk stalk. From the dorsal end of the caudal arm the intestine extends directly to the caudal end of the body (Fig. 263).

Soon after the loop is formed a small evagination appears on its caudal arm, not far from the apex. This is the anlage of the cecum and marks the boundary between the small and large intestine (Fig. 263). At this stage, therefore, all the great divisions of the intestinal tract are distinguishable, viz. : the duodenum with the ducts of the liver and pancreas; the mesenterial small intestine with the yolk stalk; and the colon extending from the caecum to the caudal end. There are, however, practically no differences between the regions, either in structure or in size.

In further development the duodenum comes to lie more nearly transversely across the body, thus assuming its adult position. Its mesentery fuses with the peritoneum of the dorsal body wall and the duodenum thus becomes a fixed portion of the intestinal tract (p. 350; also Fig. 301). It enlarges a little more rapidly than the rest of the small intestine and acquires a greater diameter. In embryos of 12 to 13 mm. the lumen becomes obliterated by an overgrowth of the mucous membrane caudal to the ducts of the liver and pancreas. In embryos of about 15 mm., however, the lumen reappears. It seems difficult to find a cause for this peculiar growth of the mucosa.

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'''Fig. 264. Reconstruction of the liver and intestine of a human embryo of 17 mm.''' Mall. G.B., gall bladder; H. V., hepatic vein; U.V., umbilical vein; 1 -6, primary bends in the long intestinal loop; 1 represents the duodenum.

Very shortly after the formation of the long loop in the intestine, six bends become recognizable in the portion between the stomach and the apex of the loop (Fig. 264). These bends later form distinct loops which are destined to become definite parts of the small intestine. The first loop is the duodenum, the development of which has already been considered, and which maintains practically its original position. The other five loops continue to elongate and form secondary loops, all of which push their way into the umbilical coelom where they remain until the embryo reaches a length of 40 mm. (compare Figs, 265 and 266). Then they return very quickly to the abdominal cavity proper.

After their return, the primary loops, with the secondary loops derived from them, come to occupy fairly constant positions. The second and third move to the left upper part of the abdominal cavity; the fourth crosses the medial line and occupies the right upper part. The fifth crosses back and lies in the left iliac fossa; the sixth lies in the pelvis and lower part of the abdominal cavity (Fig. 267).

Certain variations may occur but are usually not considered as abnormal. The most frequent variation is one in which the fourth coil, along with the second and third, lies on the left side, its usual position on the right being occupied by the ascending colon. Not uncommonly the positions of the fourth and the second and third are reversed. Less commonly extra loops are formed.

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'''Fig. 265. Reconstruction of the stomach and intestine of a human embryo of 28 mm.''' Matt.

:The numbers are placed on the coils derived from the primary bends as shown in Fig. 302; 1 represents the duodenum.

Usually the proximal part of the yolk stalk disappears during foetal life. In a few cases, however, it persists as a blind sac of variable length, known as Meckel's diverticulum (see also p. 581).

Even before the loops return to the abdominal cavity the colon or large intestine increases in diameter more rapidly than the small intestine. After the return, the caecum is carried across to the right side and comes to lie just caudal to the liver. From the caecum the colon extends across the abdominal cavity, ventral to the duodenum, forming the transverse colon. It then descends on the left side as the descending colon which passes over into the sigmoid colon (Fig. 299). The transverse, the descending and the sigmoid portions of the colon are recognizable in the third month. Up to the time of birth the sigmoid portion is disproportionately long; after birth the other portions grow relatively faster. After the fourth month the portion to which the caecum is attached grows downward in the right side of the abdominal cavity, thus forming the ascending colon (Fig. 304).

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'''Fig. 266. Drawing from a reconstruction of a human embryo of 24 mm.''' Matt. The intestinal coils lie for the most part in the umbilical coelom. C, caecum; K, kidney; L, liven S, stomach; S. C., suprarenal gland; W, mesonephros; 12, twelfth thoracic nerve; 5, fifth lumbar nerve.

The caecum, which appears in very early stages as an evagination at the junction of the small and large intestines, for a time continues to increase uniformly in size. Then the proximal end increases more rapidly than the distal, and forms the caecum of adult anatomy. The distal end, failing to keep pace in development, remains more slender and forms the vermiform appendix (Fig. 267).

As has already been mentioned, the primitive gut ends blindly in the caudal end of the embryo (Fig. 246). The anal opening is a secondary formation, On the ventral side of the caudal end of the body there is formed a depression known as the anal pit. The mesoderm at the bottom of the pit becomes thinner until the ectoderm comes in contact with the entoderm on the ventral side of the gut, thus forming the anal membrane. The area of contact is not at the extreme end of the gut, but a short distance toward the allantoic duct. In the meantime, the urogenital ducts come to open into that portion of the gut which lies just cranial to the anal membrane. The gut enlarges in this region to i/form the cloaca. The latter becomes separated by the urorectal fold into a portion, the rectum, and a ventral portion, the urogenital sinus (Figs. 323 and 325). At about the time of separation (embryos of about 14 mm. or thirty-six to thirty-eight days) the anal membrane ruptures and the anal opening is formed. The portion of the gut caudal to the anus, known as the caudal gut, normally disappears.

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'''Fig. 267. Drawing from a model of the small intestine in the adult.''' Ventral view. Mall.

:The intestinal coils are shown in the usual relative position. The numbers indicate the coils derived from the primary bends in the foetus as shown in Figs. 264 and 265.

==Histogenesis of the Gastrointestinal Tract==

The wall of the primitive gut is composed of two layers the entoderm which lines the lumen, and the splanchnic mesoderm which borders on the ccelom or body cavity. While the germ layers are still flat, the entoderm is a single layer of flat cells with bulging nuclei, but after the closure of the gut the cells become columnar. The splanchnic mesoderm is composed of two layers the mesothelium bordering on the ccelom, the cells of which gradually change from flat to rather high, and a number of indifferent, branching mesenchymal cells lying between the mesothelium and entoderm. The entoderm is destined to give rise to the general epithelial lining of the gastrointestinal tract and to all the glands connected with it. The mesothelium around the gut forms a part of the general mesothelial lining of the ccelom, its cells apparently changing back to a flat type. The mesenchymal tissue is destined to give rise to all the connective tissue and smooth muscle of the tract. The circular layer of muscle appears first, the longitudinal next, both appearing during the third and fourth months, and last of all the muscularis mucosae (Fig. 268).

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'''Fig. 268. Transverse section of the small intestine of a pig embryo of 32 mm.''' Bonnet.

===The Mucous Membrane===

The mucous membrane is formed by the epithelium (entoderm) and the subjacent mesenchymal tissue. In its development there are two factors to be considered: (i) The formation of folds to increase the absorbing surface and (2) the formation of secreting organs or glands. As to the relation between these two factors there is a difference of opinion. Some hold that both kinds of structures are the result of the same formative process, that is, that the glands are simply the depressions or pits formed by the intersection of folds at various angles, and that the folds are produced primarily by the growth of the epithelium and mesenchymal tissue into the lumen of the gut. Others maintain that although the folds may be produced by the growth of the epithelium and mesenchymal tissue into the lumen, the glands arise as independent growths of the epithelium into the subjacent tissue. The latter view is supported by the fact that in some Amphibia the glands appear before the folds (Fig. 269). Recent work on Mammals also favors this view.

The development of the folds and glands begins in the different parts of the gastrointestinal tract at different times. It begins first in the stomach, then in the duodenum, then in the colon, and then whence it progresses slowly into the ileum. In the stomach it is uncertain whether the crypts and glands are depressions left among projections of the mucous membrane, or the glands represent evaginations of the epithelium into the underlying tissue. In the case of the large intestine the same uncertainty exists. If the so-called glands are depressions among villous projections that grow-in to the lumen of the intestine, they are not true glands from an embryological point of view.

Studies of the development of the villi in the human small intestine have led to the conclusion that they are formed primarily as growths of the mucosa into the lumen. In embryos of 19 mm. the mucosa of the cephalic end is thrown into a number of longitudinal folds (Fig. 270). These then develop progressively toward the caudal end. Beginning in embryos of 50 to 60 mm. the longitudinal folds become broken transversely into conical structures, the villi. The intestinal crypts (of Lieberkiihn) possibly represent outgrowths of the epithelium from the bottoms of the intervillous spaces.' The duodenal (B runner's) glands are possibly to be considered as a continuation of the pyloric glands of the stomach. They apparently grow as evaginations from the intervillous crypts.

The epithelial lining of the gastrointestinal tract is from the beginning a single layer of cells, although the individual cells are altered in shape and structure and acquire different functions in different regions. There is still some dispute as to whether the mucous cells are continuously being derived from the other epithelial cells or, when once formed, reproduce themselves by mitosis. As a matter of fact, mitosis has been observed in the mucous cells of the stomach.

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'''Fig. 270. From a reconstruction of the small intestine of a human embryo of 28 mm.''' Berry. Showing the longitudinal ridges which eventually become broken transversely to form the villi.

===The Lymph Follicles===

In the development of the lymph follicles in the gastrointestinal tract the same question arises as in the case of the tonsils and thymus. Are the lymphoid cells of mesodermal or of entodermal (epithelial) origin? Evidence at present favors the mesodermal origin. In the case of Peyer's patches, collections of lymphoid cells appear near the blood vessels in the stroma and neighboring parts of the submucosa. These increase in extent, the lymphoid cells dividing actively, and grow into the bases of some of the villi and deeper into the submucosa (Fig. 271). Germinal centers appear in many of the follicles, and the surrounding stroma becomes densely infiltrated with the lymphoid cells. Individual follicles may develop, in the manner described, in any part of the gastrointestinal tract. The appendix especially is the seat of extensive lymphatic tissue formation. It is stated in the section on the lymphatic system that lymph glands may arise at any time in any region as the result of unusual conditions (p. 251), and this also holds true in the case of lymph follicles in the digestive tract.

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Fig. 271. Sections through the wall of the caecum of (a) a rabbit 2.5 days and (b) 5 days after birth, showing the development of the lymph follicles. Stohr.

:Lymphoid infiltration in the stroma; r, wandering cells in the epithelium; 2, lymphoid cells in the core of a villus.

==The Development of the Liver==

The liver is the first gland of the digestive tract to appear. In embryos of about 3 mm. a longitudinal ridge-like evagination develops from the entoderm on the ventral side of the gut a short distance caudal to the stomach, that is, in the duodenal portion of the gut (Figs. 247, 272, 273). The cephalic part of the evagination is solid and, being destined to give rise to the liver proper, is called the pars hepatica. The caudal part is hollow, its cavity being continuous with the lumen of the gut, and is destined to give rise to the gall bladder, whence it is called the pars cystica. Beginning at both the cephalic and caudal ends, the evagination as a whole becomes constricted from the gut until (in embryos of about 8 mm.) its only connection with the latter is a narrow cord of cells which is the anlage of the ductus choledochus. The pars hepatica by this time has enlarged considerably and remains attached to the ductus choledochus by a short cord of cells, the anlage of the hepatic duct. The pars cystica has also become larger, its distal portion being somewhat dilated, and is connected with the ductus choledochus by the anlage of the cystic duct (Figs. 274 and 275). The pars cystica grows into the ventral mesentery and thus becomes surrounded by mesodermal tissue. The proximal portion continues to elongate to form the cystic duct and the distal portion becomes larger and more dilated to form the gall bladder.

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'''Fig. 272. Transverse section of a human embryo of 5 mm.''' Showing the liver evagination and the breaking up of the omphalomesenteric veins by the hepatic cylinders. Photograph.

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'''Fig. 273. From a model of the duodenum and the primary evaginations of the liver and pancreas in a 5 mm sheep embryo.''' Stoss.
: D.pan., Dorsal pancreas; Du., duodenum; D. ch., ductus choledochus; G. bl., gall bladder; H. du., hepatic duct.

The pars hepatica, or anlage of the liver proper, also grows into the ventral lesentery, thus becoming surrounded by mesodermal tissue. As stated in connection with the development of the diaphragm, the portion of the mesentery into which the liver grows is involved in the formation of the septum trans versum (p. 344). Thus the developing liver becomes enclosed in the septum (Fig. 292). The mesodermal tissue gives rise to the fibrous capsule of Glisson and to the small amount of connective tissue within the gland.

Although the liver develops as a series of outgrowths from the original evagination, there are certain features in its development which distinguish it from glands in general. The outgrowths come in contact with the omphalomesenteric veins which are situated in the ventral mesentery (p. 229). They push their way into and through the veins, breaking them up into smaller channels (Fig. 272). They anastomose freely with one another, and the veins send off branches which circumvent them. Thus there is formed a network of trabec ulse of liver cells, called hepatic cylinders, the meshes of which are filled with blood vessels. Therefore the liver is distinguished from other glands in general in that the hepatic cylinders, which are comparable with the smaller ducts and terminal tubules of other glands, anastomose, and in that the blood vessels are broken up by the growth of these cylinders.

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'''Fig. 274. From a reconstruction of the anlagen of the liver and pancreas and a part of the stomach and duodenum of a human embryo of 4 weeks.''' Felix.

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'''Fig. 275. From a reconstruction of the anlagen of the liver and pancreas and the stomach of a human embryo of 8 mm.''' Hammar.

:D.P., Dorsal pancreas; Du., duodenum; D. F., ductus venosus; G.B., gall bladder; R.I., right lobe of liver; S. t stomach; V. P., ventral pancreas.

This mode of development establishes what is known as a sinusoidal circulation, which differs from the ordinary capillary circulation. The sinusoids are produced by the growth of the trabeculae of the developing organ into large vessels and the breaking up of the latter into smaller vessels. It is obvious that a sinusoidal circulation is purely venous or purely arterial. Furthermore, development of this nature leaves comparatively little connective tissue within the gland, another feature characteristic of the liver.

All the blood carried to the liver by the omphalomesenteric veins must follow the tortuous course of the sinusoids before being collected again and passed on to the heart. When the umbilical veins come into connection with the liver they also join in the sinusoidal circulation. Subsequently, however, a more direct channel the ductus venosus is established and persists for a short time. This is probably due to the large volume of blood brought in by the umbilical veins. Finally the ductus venosus disappears and the sinusoidal circulation remains as the permanent form. (For the development of the veins in the liver see p. 228.)

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'''Fig. 276. Tranverse section of a 14 mm pig embryo, through the region of the stomach.''' Photograph. The arrow points into the bursa omentalis.

The lobes of the liver develop in a general way in relation to the great venous trunks which at one time or another pass into or through the gland. The anlage of the organ grows into the ventral mesentery, subsequently becoming enclosed in the septum transversum. In so doing it encounters the omphalomesenteric veins, and forms, in relation to the latter, two Incompletely separated parts which have been called the dorso-lateral lobes. When the umbilical veins enter the liver a more ventral, medial mass is formed. This becomes incompletely separated into two parts which give rise to the permanent right and left lobes. The right becomes the larger. The right umbilical vein loses its connection with the liver (p. 230). After birth the left, which lies between the right and left lobes, degenerates into the round ligament of the liver. The other lobes arise secondarily as outgrowths from the right primary dorsolateral lobe, the caudate (lobe of Spigelius) from its inner (medial) surface, the quadrate from its dorsal surface.

The liver as a whole grows rapidly and by the second month is relatively large. During the third month it fills the greater part of the abdominal cavity. After the fifth month it grows less rapidly and the other intraabdominal organs overtake it, so to speak, although at birth it forms one-eighteenth the total weight of the body. After birth it actually diminishes in size. The right lobe is from the beginning larger than the left, and after birth the predominance increases.

Histogenesis of the Liver. The hepatic part (pars hepatica) of the liver anlage is derived from the entodermal lining of the gut and constitutes a mass of cells with no lumen. From this mass, solid bud-like evaginations grow into the mesentery, break up the omphalomesenteric veins into smaller channels and form trabeculae, or hepatic cylinders (p. 316). The latter anastomose freely with one another and are composed of polyhedral, darkly staining cells with vesicular nuclei (Fig. 277, A). Lumina begin to appear in the cylinders about the fourth week as small cavities which communicate with the cavity of the gut.

The hepatic cylinders are the forerunners of the hepatic cords or cords of liver cells. There are two views as to the manner of transformation. The older view is that the cylinders gradually become stretched, the number of cells in cross-section becoming less until it is reduced to two. Between these two lies the lumen of the cord or the so-called "bile capillary" (Fig. 277, B). The other view is that branches from the sinusoids grow into the cylinders and subdivide them into hepatic cords.

As stated above, the hepatic cylinders are at first composed of darkly staining, polyhedral cells with vesicular nuclei. These are the liver cells proper. Later other small spherical cells, with dense nuclei, appear and during the fourth month become very numerous (Fig. 277, A). From this time on, they grow less in number and at birth have practically disappeared. Earlier investigators considered them as developing liver cells. Further study on the development of the blood, however, has led others to consider them as erythroblasts (p. 239). Since they are inside of the hepatic cylinders, they either wander in from the intertrabecular blood vessels or lie in intratrabecular vessels. The latter supposition accords with the view that the cylinders are broken up into hepatic cords by the ingrowth of branches from the sinusoids.

The development of the lobules of the liver, producing the peculiar relations between the parenchyma of the gland and the blood vessels, has not been clearly and completely demonstrated. In young embryos the branches of the hepatic veins are surrounded by comparatively little connective tissue. The branches of the portal vein are surrounded by a considerable amount which subdivides the liver into lobules but not in the same manner as in the adult. The trabeculae possess no radial character and there are several so-called central veins in each lobule. The changes by which these primary lobules are subdivided into the permanent ones do not take place until after birth. The branches of the portal vein, with the surrounding connective tissue, invade the primary lobules and divide them into a number of secondary lobules, corresponding to the original number of central veins. At the same time the hepatic cords (which have been formed meanwhile) become arranged radially around the central veins in the characteristic manner. The hepatic artery grows into the liver secondarily and its branches follow the course of the branches of the portal vein.

<div id="Fig277"></div>
[[File:Bailey277.jpg|600px]]

'''Fig. 277. Sections of the liver of (^4) a human foetus of 6 months and (B) a child of 4 years.''' Toldt and Zuckerhandl. McMurrich. be, Bile "capillary"; e, erythroblast; he, hepatic cylinder (in A), cord of liver cells (in B).

Degeneration of the liver cells occurs in the region of the left triangular ligament, the gall bladder and the inferior vena cava. The bile ducts may, however, withstand the degenerative processes and persist as the vasa aberrantia of the liver. The cause of the degeneration is possibly the pressure brought to bear by other organs.

==The Development of the Pancreas==

The epithelium of the pancreas, like that of the liver, is a derivative of the entoderm. It arises from two (or three) separate anlagen, one dorsal and one (or two) ventral. The dorsal anlage appears first as a ridge-like evagination from the dorsal wall of the gut, slightly cranial to the level of the liver (Figs. 273 and 274). It appears about the same time as the liver or a little later. The mass of cells grows into the dorsal mesentery and becomes constricted from the parent epithelium except for a thin neck which becomes the duct of Santorini (Fig. 278). A little later two other diverticula appear, one from each side of the common bile duct. It is uncertain whether only one or both of these take part in the formation of the pancreas, but it seems most probable that the left one disappears entirely. The right diverticulum continues to develop and becomes constricted from the parent epithelium, leaving only a thin neck which becomes the duct of Wirsung.

<div id="Fig278"></div>
[[File:Bailey278_279.jpg|600px]]

'''Figs. 278 and 279. From models of the developing liver and pancreas of rabbit embryos of 8 mm. and 10 mm''', respectively. Both seen from the right side. Hammar, Bonnet.

The smaller ventral pancreas grows to the right and then dorsally in the mesentery (Fig. 260), passing over the right surface of the portal vein, until it meets and fuses with the proximal part of the larger dorsal pancreas. The fusion takes place in the sixth week, and the two anlagen then form a single mass. A communication is established between the two ducts, and the dorsal duct (Santorini) usually disappears, leaving the ventral (Wirsung) as the permanent duct opening into the ductus choledochus. In a general way it may be said that the ventral anlage gives rise to the head, the dorsal anlage to the body and tail of the pancreas (compare Figs. 278 and 279).

As the pancreas grows into the dorsal mesentery it comes to lie in the dorsal mesogastrium between the greater curvature of the stomach and the vertebral column, and since the dorsal mesogastrium at first lies in the medial sagittal plane, the pancreas is similarly situated. After the sixth week, however, as the stomach changes its position (p. 305) , the pancreas is carried along with the mesogastrium and comes to lie in a transverse plane, with its head to the right and embedded in the bend of the duodenum, and its tail reaching to the spleen on the left. The organ as a whole is at first movable along with the mesentery, but when it assumes its transverse position it lies close to the dorsal abdominal wall. The mesentery then fuses with the adjacent peritoneum (see p. 350), and the pancreas is firmly fixed.

<div id="Fig280"></div>
[[File:Bailey280.jpg|600px]]

'''Fig. 280. From a transverse section through the region of the duodenum of a pig embryo of 14 mm.''' Photograph.

The connective tissue of the pancreas is derived from the mesodermal tissue of the mesentery. As the processes or buds which form the ducts and terminal tubules grow out from the primary masses, they penetrate the mesodermal tissue and are surrounded by it. Groups of tubules form lobes and lobules, and the entire gland is surrounded by a capsule of connective tissue.

Histogenesis of the Pancreas. The masses of entodermal cells forming the anlagen of the pancreas develop further by a process of budding, which goes on until finally a compound tubular gland is produced. According to some investigators the primary evaginations are hollow, their lumina beinj continuous with the lumen of the gut. According to others they are solid al first and acquire their lumina secondarily. The same uncertainty exists regard to the later outgrowths or buds.

<div id="Fig281"></div>
[[File:Bailey281.jpg|600px]]

'''Fig. 281. Sections of the developing pancreas of a guinea-pig embryo of 12 mm.''' (a); of 33 mm. (&) ; of Torpedo marmorata (c) . Hetty.

:c t Capillaries; Dg, ducts; Gz, duct cells; Lz, Langhans' cells. The cells in c show distinct zymogen granules

The early entodermal cells proliferate, and the resulting cells change according to their position in the gland. Those lining the larger ducts become high columnar, with more or less homogeneous cytoplasm; those lining the intermediate (intercalated) ducts become low; those lining the terminal secreting tubules become pyramidal and more highly specialized, and also acquire certain constituents the zymogen granules (Fig. 281, c) which vary with the functional activities of the gland. The centro-tubular cells in the terminal tubules are probably to be explained on a developmental basis. While a few maintain that they are "wandering" cells, it is quite generally accepted that they are simply continuations of the flat cells lining the intermediate ducts, the result being that the cells of the terminal tubules seem to spread out over the ends of the intermediate ducts in the form of cap-like structures.

It was once thought that the islands of Langerhans were derived from the mesodermal tissue. Recently it has been pretty clearly demonstrated that they are derived from entoderm. In guinea-pig embryos of 5 to 6 mm., at a time when the dorsal pancreas has merely begun its constriction from the gut, certain cells in the mass appear darker and slightly larger than the others. They show darker areas of cytoplasm around the nuclei, and later the darker areas extend throughout the cells and the nuclei become larger and more vesicular. When lumina appear in the outgrowths or buds, these cells occupy a position on or near the surface of the buds (Fig. 281, a). In further development they tend to separate themselves from the buds and collect in clumps (Fig. 281, b). Capillaries then penetrate the clumps and break them up into the trabeculae of cells characteristic of the islands of Langerhans (Fig. 281, c). Studies on the development of the islands in the human pancreas indicate a similar origin and mode of development.

==Anomalies==

One of the most striking anomalies of the organs of alimentation is found in connection with a more general anomalous condition known as transposition of the viscera (situs viscerum inversus) . The transposition may be so complete that the minor asymmetries normally present on the two sides are all repeated in reverse order, the functions of the organs being unimpaired. As regards the alimentary tract, this means that the position of the stomach is reversed in the abdominal cavity; that the duodenum crosses from left to right; that the various coils of the jejunum and ileum occupy positions opposite to the normal; that the caecum and ascending colon are situated on the left side and the descending colon on the right; and that the larger lobe of the liver lies on the left side. The other visceral organs are transposed accordingly, the heart being inclined toward the right side, the left lung consisting of three lobes and the right of two, the left kidney being lower than the right, etc. Such cases are not uncommon, two hundred being on record.

Various theories as to the causes of transposition of the organs have been advanced. In the most plausible of these the anomalous condition is considered as due to the influence of the large veins in the embryo. It seems best, therefore, to consider first the transposition of the heart (dextrocardia, referred to on page 255).

After the tvvo anlagen unite in the midventral line, the heart constitutes a simple straight tube which lies in a longitudinal direction in the primitive pericardial cavity, and which is joined caudally by the two omphalomesenteric veins and cranially by the ventral aortic trunk (p. 197) . Normally the left omphalomesenteric vein is the*larger and pours a greater quantity of blood into the heart tube than the right. This condition is regarded as the primary factor in the deflection of the tube toward the right side (p. 199; also Fig. 158). If the conditions were reversed, that is, if the right omphalomesenteric vein were the larger and poured the greater quantity of blood into the heart tube, the primary bend of the latter would be toward the left side. Consequently the heart would continue to develop in the transposed position and eventually come to lie on the side opposite to the normal.

Although dextrocardia is very frequently associated with transposition of the abdominal organs, it is not necessarily so, for there are cases of the latter in which the heart occupies the normal position. Consequently it seems that further influences must be present to account for transposition of the abdominal organs when the thoracic organs are normal. A number of investigators have emphasized the importance of the influence of the large venous trunks in the abdominal region, especially on the position of 'the liver and stomach.

Primarily the omphalomesenteric veins pass cranially through the mesentery. Later they form two loops or rings around the duodenum. Then the left half of the upper ring and the right half of the lower disappear, the common venous trunk thus following a spiral course around the duodenum (p. 231 ; also Fig. 201). This primary relation of the omphalomesenteric vein is retained in the relation of the portal vein to the duodenum. The stomach lies to the left of the portal vein. After the allantoic (placental) circulation is established the umbilical veins pass cranially in the lateral body walls. After the veins come into connection with the liver, the right atrophies and the left increases in size and becomes the single large umbilical vein of later stages (p. 230; also Fig. 202). The right lobe of the liver becomes the larger.

If, as is maintained by some investigators, the usual position of the stomach and liver is due to the persistence of the left venous trunks, a persistence of the right venous trunks would afford a plausible explanation of the transposition of these organs. It is not unreasonable to attribute also the transposition of the other abdominal organs directly or indirectly to the persistence of the right venous trunks. Certainly a reversal in the position of the stomach would cause a reversal in the position of the duodenum.

If these conditions are the real ones, the fact that the thoracic organs can be transposed without a transposition of the abdominal organs, or vice versa, is accounted for. The primary bend of the heart tube occurs at a very early period, before the changes in the vessels in the region of the liver. Consequently a reversal of the conditions of the omphalomesenteric at a very early stage only would be likely to affect the heart. The principal changes in size of the venous trunks in the abdominal region take place after their channels have been broken up in the liver. In other words, the modifications in the veins in the liver occur after the definite relations of the heart have been established. Therefore the transposition of the abdominal organs may take place after the heart has begun to develop normally.

===The Mouth===

Anomalies in the mouth region, due to defective fusion of the processes that bound it, have been considered elsewhere (p. 180).

Anomalies of the tongue sometimes arise as the result of imperfect development of one or more of its anlagen. Imperfect development of the tuberculum impar results in total or partial lack of the anterior part. Defects in the root are probably due to imperfect development of one or both of the paired anlagen (p. 289). Malformations of the lower jaw (micrognathus, agnathus) are usually accompanied by malformations of the tongue, both structures being derived largely from the first pair of branchial arches.

===The Pharynx===

The pharynx is the seat of cysts, fistulae and diverticula which have been considered in connection with the anomalies in the region of the branchial arches and grooves (Chap. XX).

The thyreoid gland is not infrequently the seat of certain anomalies that arise as the result of abnormal development. Persistent portions of the thyreoglossal duct, the upper end of which is indicated by the foramen caecum linguae, may give rise to cystic structures extending to the region of the hyoid bone. Persistent portions of the duct may even give rise to accessory thyreoid (suprahyoid, prehyoid) glands (p. 301; also Fig. 260). Considerable variation also exists in the isthmus and lateral lobes of the thyreoid, due to variation in the manner of development of the medial anlage.

Impaired development of the thymus gland sometimes leads to cysts which come to lie in the anterior mediastinum.

===The Oesophagus===

Very rarely the oesophagus is entirely lacking, being represented by a mere cord of tissue. More frequently it is defective in certain parts. Tne atresia may begin just below the pharynx or just above the stomach, the intermediate portion being composed of a cord of fibrous tissue. Occasionally the non-atretic portion opens into the trachea. Possibly this represents an imperfect separation between the primitive gut and the anlage of the respiratory system (p. 330).

===The Stomach===

Occasionally the stomach is smaller than the normal. It may even be a narrow tube resembling the other portions of the gut, owing to lack of dilatation. Other congenital malformations, apart from transposition (p. 323), are very rare.

===The Intestines===

One of the most common anomalies is the persistence of the proximal end of the yolk stalk, forming MeckeVs diverticulum (see p. 581). This usually is attached to the ileum about three feet from the caecum. In exceptional cases it retains its lumen and, when the stump of the umbilical cord disappears, forms a congenital umbilical fistula. Usually, however, the diverticulum is shorter and ends blindly. Occasionally it becomes constricted from the intestine and forms a cystic structure. (See also Chap. XX.)

Congenital stenosis and atresia may occur in different regions of the intestine, the duodenum being the most common site. Normally the lumen of the duodenum becomes closed for a brief period during development (p. 307) , and congenital closure of the lumen may represent a persistence of the early embryonic condition.

A conspicuous malformation is the persistence of the cloaca. The septum which normally separates the latter structure into rectum and urogenital sinus fails to develop, thus leaving a common cavity (see Figs. 323 and 324). In addition to this the cloacal membrane may fail to rupture and the cloaca become much distended. More often the septum develops in part, leaving only a small opening between the rectum and urogenital sinus. After the latter undergoes further development, the rectum comes to open into the urethra or bladder, or into the vagina or uterus.

Atresia of the anus is not infrequently met with. The cloacal (or anal) membrane fails to rupture and the rectum ends blindly. In other cases the rectum opens into the urogenital sinus, as described in the preceding paragraph. Occasionally the lumen of the rectum is closed atresia recti and the gut ends blindly some distance from the surface, being connected with the anal region by a cord of fibrous tissue.

Variations in the position of the intestinal loops, apart from transposition (p. 323), are of frequent occurrence. It is not customary to include these variations among malformations (see p. 308) . The caecum (and appendix) and colon present some striking variations. The caecum may be situated high up in the abdominal cavity, the ascending colon being absent. Or it may be situated at any intermediate point between that and its usual position in the right iliac fossa. These variations are due to different degrees of development of the ascending colon (p. 309).

===The Liver===

Congenital malformations of the liver are rare. The most frequent, apart from transposition, include anomalies in the size and number of lobes. Accessory lobes may occur within the falciform ligament. One case of lack of development of the gall bladder has been observed. Stenosis of the bile passages is occasionally met with.

===The Pancreas===

Occasionally accessory glands are found in the intestinal or gastric wall. These probably represent aberrant portions of the main gland, and may give rise to cystic structures. Very recently, however, a number of intestinal diverticula have been observed in certain mammalian embryos and also in human embryos. Although the history of these unusual diverticula has not been traced, their presence may offer a clue to the origin of accessory pancreatic structures. The ducts of the pancreas are subject to distinct variations, which, however, are not usually considered as anomalies. Not infrequently the duct of the dorsal anlage (duct of Santorini) persists and opens directly into the duodenum. It may persist along with the duct of the ventral anlage (duct of Wirsung), or the latter may disappear (p. 321; compare Figs. 2 78 and 279).

:'''Next:''' [[Book_-_Text-Book_of_Embryology_13|Respiratory]]

==References for Further Study==

BADERTSCHER, J. A. : The Development of the Thymus in the Pig. I, Morphogenesis. II, Histogenesis. Am. Jour, of Anat., Vol. XVII, 1915.

{{Ref-Bardeen1914}}

{{Ref-Bell1905}}

BERRY, J. M.: On the Development of the Villi of the Human Intestine. Anat. Anz., Bd. XVI, 1900.

BONNET, R.: Lehrbuch der Entwickelungsgeschichte. Berlin, 1907.

BORN, G.: Ueber die Derivate der embryonalen Schlundbogen und Schlundspalten bei Saugetiere. Arch.}, mik. Anat., Bd. XXII, 1883.

BRACKET, A. : Die Entwickelung und Histogenese der Leber und des Pancreas. Ergebnisse der Anat. u. Entwick., Bd. VI, 1897.

CHIEVITZ, J. C.: Beitrage zur Entwickelungsgeschichte der Speicheldriisen. Arch. f. Anat. u. Physiol., Anat. Abth., 1885.

CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.

Fox, H.: The Pharyngeal Pouches and their Derivatives in the Mammalia. Am. Jour, of Anat., Vol. VIII, No. 3, 1908.

FUSARI, R.: Sur les phenomenes, que Ton observe dans la muqueuse du canal digestif durant le developement du fcetus humain. Arch. ital. Biol., T. XLII, 1904.

GOPPERT, E.: Die Entwickelung des Mundes und der Mundhohle mit Driisen und Zunge; die Entwickelung der Schwimmblase, der Lunge und des Kehlkopfes der Wirbeltiere. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere. Bd. II, Teil I, 1902.

HAMMAR, J. A.: Einige Plattenmodelle zur Beleuchtung der friiheren embryonalen Leberentwickelung. Arch.f. Anat. u. Physiol., Anat. Abth., 1893.

HAMMAR, J. A.: Allgemeine Morphologic der Schlundspalten beim Menschen. Entwickelung des Mittelohrraumes und des ausseren Gehorganges. Arch. f. mik. Anat., Bd. LIX, 1902.

HAMMAR, J. A. : Das Schicksal der zweiten Schlundspalte. Zur vergleichenden Embryologie und Morphologic der Tonsille. Arch.f. mik. Anat., Bd. LXI, 1903.

HELLY, K.: Studien iiber Langerhanssche Inseln. Arch. f. mik. Anat., Bd. LXVII, 1907.

HERTWIG, O. : Lehrbuch der Entwickehmgsgeschichte der Wirbeltiere und des Menschen. Jena, 1906.

HENDRICKSON, W. F.: The Development of the Bile Capillaries as Revealed by Golgi's Method. Johns Hopkins Hosp. Bull., 1898.

His, W.: Anatomic menschlicher Embryonen. Leipzig, 1880-1885.

His, W.: Die Entwickelung der menschlichen und tierischen Physiognomien. Arch, f. Anat. u. Physiol., Anat. Abth., 1892.

JACKSON, C, M.: On the Development and Topography of the Thoracic and Abdominal Viscera. Anat. Record, Vol. Ill, 1909.

{{Ref-Johnson1910}}

JOHNSON, F. P.: The Development of the Mucous Membrane of the Large Intestine and Vermiform Appendix in the Human Embryo. Am. Jour. of. Anat., Vol. XIV, 1903

JOHNSON, F. P. : The Development of the Rectum in the Human Embryo. Am. Jour. of Anat., Vol. XVI, 1914.

KINGSBURY, B. F.: The Development of the Human Pharynx. I, The Pharyngeal Derivatives. Am. Jour, of Anat., Vol. XVIII, 1918.

KOHN, A.: Die Epithelkorperchen. Ergebnisse der Anat. u. Entwick., Bd. IX, 1899.

KOLLMANN, J.: Die Entwickelung der Lymphknotchen in dem Blinddarm und in dem Processus vermiformis. Die Entwickelung der Tonsillen und die Entwickelung der Milz. Arch.f. Anat. u. Physiol., Anat. Abth., 1900.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

MALL, F. P.: Ueber die Entwickelung des menschlichen Darmes und seiner Lage beim Erwachsenen Arch.f. Anat. u. Physiol., Anat. Abth. Suppl., 1897.

MAURER, F.: Die Entwickelung des Darmsystems. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere., Bd. II, Teil I, 1902.

McMuRRiCH, J. P. : The Development of the Human Body. Third Ed. Philadelphia, 1907.

MUMMERY, J. H.: The Microscopic Anatomy of the Teeth, 1919.

{{Ref-Norris1918}}

{{Ref-Pearce1903}}

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

POLZL, A.: Zur Entwickelungsgeschichte des menschlichen Gaumens. Anat. Hefte, 1905

ROSE, C.: Ueber die Entwickelung der Zahne des Menschen. Arch. f. mik. Anat., Bd. XXXVIII, 1891.

STEIDA, A.: Ueber Atresia ani congenita und die damit verbundenen Missbildungen. Arch.], klin. Chir., Bd. LXX, 1903.

STOHR, P.: Ueber die Entwickelung der Darmlymphknotchen und iiber die Riickbildung von Darmdriisen. Arch. f. Anat. u. Physiol., AnaL Abth., 1898.

TANDLER, J.: Zur Entwickelungsgeschichte des menschlichen Duodenum in friihen Embryonalstadien. Morph. Jahrb., Bd. XXIX, 1900.

TOLDT und ZUCKERHANDL Ueber die Form und Texturveranderungen der menschlichen Leber wahrend Wachsthums. Sitzungsber. d. kaiser. Akad. d. Wissensch., Wien. Math.-Naturwiss. Klasse., Bd. LXXII, 1875.

TOURNEUX ET VERDUN: Sur les premiers developpements de la Thyroide, du Thymus et des glandes parathyroidiennes chez I'homme. Jour. de. I' Anat. et. de la Physiol., T. XXXIII, 1897

{{Bailey_1921_Footer}}

[[Category:Gastrointestinal Tract]] [[Category:Tooth]]

Book - Text-Book of Embryology 11

2024-01-25T00:46:13Z

Z8600021:

{{Bailey 1921}}

=The Development of the Muscular System=

Anatomy and Histology show that there are, in a sense, two muscular systems in the body, and Embryology teaches that the two systems have different origins.

# The skeletal musculature. This, as the name indicates, is closely associated with the skeletal system. It is made up of striated muscle fibers arranged to form definite bundles or muscles. The skeletal musculature is under the voluntary control of the central nervous system.
# The visceral musculature. This is. found in connection with and forms integral parts of certain organs. It is made up of two different kinds of fibers smooth muscle fibers or cells and striated fibers or cells (heart-muscle cells). The latter are found only in the wall of the heart. The visceral musculature is involuntary, being under the control of the sympathetic nervous system.

Both systems are derived from mesoderm but from distinct parts of the mesoderm. Furthermore, their developmental histories are quite different, as will be seen in the following paragraphs.

==The Skeletal Musculature==

In the chapters on the development of the germ layers it was said that throughout the length of the body region of the embryo the mesoderm on each side of the neural tube and notochord becomes divided into a definite number of segments the primitive segments or mesodermic somites (Figs. 24, 52, 51). These indicate the segmentation of the body, and the history of the greater part of the skeletal musculature dates from their differentiation from the axial mesoderm. Thus the skeletal musculature is, for the most part, primarily segmental in character.

At first the primitive segments are composed of closely packed, epitheliallike cells, and each segment contains a small cavity which represents a portion of the coelom (Fig. 103). The ventro-medial parts of the segments become differentiated to form the sclerotomes which are composed of more loosely arranged cells (Fig. 223), and which are destined to give rise to the vertebrae and to the various kinds of connective tissue in their neighborhood. The lateral parts of the segments become differentiated to form the cutis plates which are destined to give rise to a part of the corium of the skin. The remaining portions of the segments form the muscle plates or myotomes (Fig. 223), from which develop by far the greater part, at least, of the voluntary striated muscles.

The differentiation of the parts of the primitive segments begins in the cervical region by the end of the second week, and then gradually proceeds toward the tail. Three myotomes are also probably formed in the occipital region. The cells of the myotomes are at first of an epithelial character (Fig. 105). Contractile fibrils appear in the cells and the latter are transformed directly into muscle fibers. (For histogenesis see p. 276). The fibers later alter their direction in accordance with the particular muscle to which they belong. The muscle tissue first formed is thus segmented, being derived from the segmentally arranged myotomes, but as development proceeds the myotomes undergo extensive changes by which the segmental character is lost in the majority of cases. It is retained, however, in a few instances, such for example as the intercostal muscles. The course of the changes which obliterate the segmental character of the myotomes and give rise to the various muscles has not been observed in all cases. But since a nerve belonging to any particular segment and innervating the myotome of that segment always innervates the muscles derived from that myotome, it is possible to learn something of the history of the myotomes by studying the innervation of the muscles.

<div id="Fig223"></div>
[[File:Bailey223.jpg|600px]]

'''Fig. 223.''' Transverse section of human embryo of the 3rd week. Scl. 1 , Break in myotome at point where sclerotome is closely attached. Kottmann.

From a consideration of what is known concerning the individual histories of the muscles and concerning the innervation of the muscles, certain factors can be recognized, to one or more of which the changes in the myotomes may be referred. These factors are as follows:

1. Migration.- The myotomes may migrate in whole or in part, and the muscles derived from them may be situated far beyond their limits. For example, the latissimus dorsi is derived from cervical myotomes but ultimately becomes attached to the lumbar vertebrae and to the crest of the ilium. To this factor, possibly more than to any other, is due the loss of the segmental character in the musculature.

2. Fusion. Portions of two or more myotomes may fuse to form one muscle. For example, each oblique abdominal muscle is derived from several thoracic myotomes.

3. Longitudinal Splitting. Very frequently a myotome or a developing muscle splits longitudinally into two or more portions. The sternohyoid and the omohyoid, for example, are formed in this manner.

4. Tangential Splitting. A developing muscle may split tangentially into two or more plates or layers. The two oblique and the transverse abdominal muscles, for example, are formed in this way.

5. Degeneration. Myotomes may degenerate as a whole or in part and be converted into some form of connective tissue, such as fascia, ligament or aponeurosis. The aponeuroses of the transverse and oblique abdominal muscles are probably due to a degeneration of portions of the myotomes from which the muscles are derived.

6. Change of Direction. The muscle fibers may change their direction. As a matter of fact, the fibers of very few muscles retain their original direction.

==Muscles of the Trunk==

The myotomes are at first arranged serially along each side of the notochord and spinal cord (compare Fig. 2 24 with Figs. 105 and 223). By the end of the second week fourteen myotomes are differentiated in the human embryo. Differentiation continues until, by the end of the fourth week, the total number thirtyeight is present. Of the thirty-eight, three are occipital, eight cervical, twelve thoracic, five lumbar, five sacral, and five (or six) coccygeal. The occipital myotomes are transient structures that appear in relation with the hypoglossal (XII) nerve. The cervical, thoracic, lumbar, sacral and coccygeal myotomes correspond individually to the spinal nerves (Fig. 224). As stated on page 148, the myotomes alternate with the anlagen of the vertebrae. Consequently in the cervical region there are eight myotomes, corresponding to the eight cervical spinal nerves, and only seven vertebrae. The myotomes in the neck and body regions are destined to give rise to the dorsal musculature, to the thoracoabdominal musculature, to a part of the muscles of the neck, and to the muscles of the tail region. There is a possibility that they give rise also to the muscles of the tongue.

As the myotomes continue to develop, they become elongated in a ventral direction. Those of the thoracic region extend into the connective tissue of the somatopleure, or in other words, into the lateral body walls (compare Figs. 224 and 225). During the fifth week the myotomes give rise to a dorsoventral mass of developing muscle tissue, in which the segmental character largely disappears. The muscle mass then becomes divided longitudinally into two parts, (i) a dorsal and (2) a ventro-lateral (Figs. 224, 225 and 226).

<div id="Fig224"></div>
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'''Fig. 224.''' Lateral view of human embryo of 9 mm. (4! weeks). Bardeen and Lewis.

:The area from which the skin has been removed is drawn from reconstructions. The myotomes have fused to a certain extent, so that segmentation is becoming less distinct. Note that the myotomes correspond to the spinal nerves. The developing muscle mass (the myotomes collectively) extends ventrally in the body wall in the thoracic region, and is divided by a longitudinal groove into two parts a dorsal and a ventro-lateral (see text).

:In the region of the upper extremity, dense masses of " premuscle " tissue are represented which later form the muscles. In the region of the forearm and hand the " premuscle " tissue has been removed to disclose the anlagen of the skeletal elements (radius, ulna, and hand plate). In the region of the lower extremity the superficial tissue has been removed to disclose the border vien, the anlagen of the os coxae, and the lumbo-sacral nerve plexus.

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'''Fig. 225.''' Diagrammatic cross section through the sth-6th thoracic segments of a human embryo of 9 mm. (4! weeks). Bardeen and Lewis.

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'''Fig. 226.''' Drawing from a reconstruction of the region of the lower extremity of a human embryo of 9 mm. (4 weeks). Bardeen and Lewis.

:The visceral organs and the greater part of the left body wall have been removed. The 8th thoracic to the 5th sacral segments are shown. On the right side of the body the costal processes, the spinal nerves (including the lumbo-sacral plexus), and the lower extremity are shown. On the left side the costal processes, the spinal nerves, and the nth and i2th thoracic myotomes are represented. Note the dorsal, lateral, and sympathetic branches of the spinal nerves.

1. The dorsal part is destined to give rise to those dorsal muscles of the trunk that are not associated with the extremities, and is innervated by the dorsal rami of the spinal nerves (Fig. 225).

2. The ventro-lateral part again divides longitudinally into (a) a lateral and (b) between (a) a ventral part, although the line of division is not so distinct as the original (i) dorsal and (2) ventro-lateral parts (Fig. 227). The lateral part subdivides tangentially and gives rise in the cervical region to the longus capitis, longus colli, rectus capitis anterior, to the scaleni, and to parts of the trapezius and sternomastoideus (Figs. 228 and 229). In the thoracic region it gives rise to the intercostaks and to the transversus thoracis (Figs. 227 and 230); in the abdominal region to the psoas, quadratus lumborum, and to the obliqui and transversus abdominis (Figs. 229 and 230).

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Fig. 227. Diagrammatic cross section through the 6th~7th thoracic segments of a human embryo of 17 rnm. (5^ weeks). Bardeen and Lewis.

(b) The ventral part gives rise in the cervical region to the sternohyoideus, omohyoidem, sternothyreoideus and geniohyoideus. In the abdominal region the ventral part gives rise to the r edits abdominis and to the pyramidalis (Figs. 227 and 229). In the thoracic region there are no muscles derived from the ventral part, corresponding to those in the abdominal region. This is probably due to the development of the sternum.

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'''Fig. 228.''' Lateral view of a human embryo of n mm. (about 5 weeks). Bardeen and Lewis. The area from which the skin has been removed is drawn from reconstructions. The dorsal musculature has been removed from the region of the upper extremity, exposing the 4th to the 8th cervical and the ist to the 3d thoracic vertebrae. The dorsal musculature has likewise been removed from the 5th lumbar and first three sacral segments. Segmentation is practically lost in the dorsal musculature in the thoracic region, but is still evident in the lumbar, sacral and coccygeal regions. The ventro-lateral musculature is distinctly separated from the dorsal, and is beginning to differentiate into the muscles of the thorax and abdomen.

The ventro-lateral portions of the lumbar myotomes and of the first two sacral myotomes, corresponding to the ventro-lateral portions of the thoracic myotomes, apparently do not take part in the production of muscles which belong to the body wall proper. It is even questionable whether they give rise to any muscles of the lower extremities. The ventro-lateral portions of the third and fourth sacral myotomes give rise to the levator ani, the coccygeus, the sphincter ani externus and the perineal muscles. The dorsal parts of the myotomes as far as the fifth sacral probably give rise to the sacrospinalis (Fig. 228). THE DIAPHRAGM. In addition to certain structures which are considered in connection with the pericardium (parietal mesoderm, mesocardium and common mesentery Chapter XIV), two myotomes on each side enter into the formation of the diaphragm. These are the third and fourth cervical myotomes, parts of which grow into the developing diaphragm in the earlier stages when it is situated far forward in the cervical region (p. 346 and Fig. 298), and give rise to its muscular elements.

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'''Fig. 229.''' Drawing from a reconstruction of a human embryo of 20 mm. (about 7 weeks). Bardeen and Lewis. The superficial tissues have been removed from the extremities, the body wall, and the back.

==Muscles of the Head==

Primitive segments (mesodermic somites) are not clearly demonstrable in the heads of human embryos, nor, in fact, in the heads of any of the higher Vertebrates. In some of the lower forms, however, they are very distinct. It seems possible, even probable, that their indistinctness in the higher animals is due to an abbreviation or condensation in the development of the head region. Such condensations are known to occur in the development of other structures. In a human embryo 3.5 mm. long, three structures, resembling segments have been seen somewhat caudal to the region of the ootic vesicle on one side. On the other side there were seven similar but smaller structures. All were composed of epithelial-like cells surrounding small cavities. Whether these segment-like structures bear any relation to the mesenchymal condensations which appear regularly in the occipital region (p. 157). seems not to have been determined.

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Fig. 230. Drawing from a reconstruction of the right side of a human embryo of 20 mm. (about 7 weeks). Bardeen and Lewis.

The left body wall and viscera have been removed. Note especially the following muscles: The deltoid and biceps, just to the left of the brachial plexus and below the clavicle; the internal intercostals; the diaphragm, attached to the body wall; the transverse abdominal and the rectus abdominis; the quadratus lumborum, just to the right of the transverse abdominal; the psoas, cut just above the lumbo-sacral plexus; the levator ani, running obliquely upward from the coccygeal region.

Although the transformation of head segments into muscles has not been followed in detail in mammalian embryos, it may be inferred from the study of lower forms that three segments are involved in the formation of the eye muscles. The most cephalic (anterior) segment gives rise to the recti superior, inferior and medialis (internus) and to the obliquus inferior, all of which are innervated by the occulomotor (III) nerve. The next segment gives rise to the obliquus superior which is innervated by the pathetic (IV) nerve. The most caudal segment gives rise to the rectus lateralis (externus) which is innervated by the abducens (VI) nerve.

The development and innervation of the other muscles of the head and" of the hyoid musculature present certain peculiarities which have caused these muscles to be considered as more closely related to the visceral musculature than to the myotomic musculature. In the first place they are derived from the branchial arches (hence are often called branchiomeric muscles), and not directly from the myotomes of the neck region. This places them in closer relation to the visceral muscles, although they are structurally and functionally different from the latter. In the second place the nerves which supply them are fundamentally different from those which supply the myotomic muscles (Chap. XVII).

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'''Fig. 231.''' Transverse section through the eighth cervical segment of a human embryo of 2.1 mm. Lewis

The first branchial arch on each side gives rise to the temporalis, masseter and pterygoidei, to the mylohyoideus and digastricus (venter anterior) and to the tensor tympani and tensor veli palatini. All these muscles are innervated by the trigeminal (V) nerve.

The second arch, which is often called the hyoid arch, gives rise to a large sheet of myogenic tissue which produces many of the facial muscles, such as the platysma and epicranius, the muscles of expression quadratus labii superiority risorius, triangularis , mentalis, etc.; also two muscles connected with the hyoid bone digastricus (venter posterior) and stylohyoideus and the stapedius of the middle ear. The facial (VII) nerve corresponds to the second arch and supplies all these muscles.

The glossopharyngeal (IX) nerve corresponds to the third branchial arch, and this fact indicates the muscles derived from that arch. Some, at least, of the constrictor muscles of the pharynx are derived from the third arch. The stylo-pharyngeus is also a derivative of the same arch.

The vagus (X) nerve is associated with the fourth and fifth arches and consequently innervates the muscles derived from these arches, viz., the rest of the constrictors of the pharynx (see above), the laryngeal muscles and the muscles of the soft palate (except the tensor veli palatini which is derived from the first arch (p. 271). The glossopalatinus and chondroglossus are also derived from the fourth and fifth arches, while the rest of the extrinsic muscles of the tongue are of myotomic origin.

Two other muscles are probably derived in part from the branchial arches, for fibers of the spinal accessory (XI) nerve afford a part of their innervation. These are the trapezius and the sternomastoideus , the remaining parts of which are of myotomic origin (p. 267).

==Muscles of the Extremities==

The question as to whether the muscles of the extremities are derivatives of the myotomes or of the mesenchymal tissue in the limb buds has not been settled. In some of the lower Vertebrates, especially in some of the Fishes, it seems to have been pretty clearly demonstrated that bud-like processes from the myotomes grow into the anlagen of the extremities (fins), and there give rise to muscles. In other lower forms no such buds from the myotomes have been demonstrated, but the muscles are apparently derived directly from the mesenchymal tissue in the anlagen of the extremities. In the higher vertebrates, especially in Mammals, no distinct myotome buds have been traced into the extremities. Some investigators hold, however, that instead of myotome buds some cells from the myotomes myoblasts wander into the limb buds and give rise to muscles. Other investigators are inclined to the view that the musculature of the extremities is not of myotomic origin, but that it is derived from the mesenchymal tissue of the limb buds.

A most striking feature of the musculature of the extremities is its distinctly segmental nerve supply. This, of course, is in favor of, although it does not prove, its myotomic origin. If the muscles of the extremities are of myotomic origin, it is very probable that several myotomes take part in their formation.

In the first place among the lower Vertebrates the muscles of each extremity are derived from several myotomes and are innervated by segmental nerves corresponding to these myotomes. In the second place among the higher Vertebrates, although the myotomic origin of the muscles has not been clearly demonstrated, the nerve supply in each extremity comes through several segmental spinal nerves.

Knowledge concerning the development of the individual muscles of the extremities in the human embryo is incomplete. Especially is this true of the muscles of the lower extremities.

The upper limb bud first appears in embryos of 2-3 mm. (during the third week) as a slight swelling ventro-lateral to the myotomes in the lower cervical region (Fig. 231; see also Fig. 87). The swelling gradually enlarges and by the time the embryo has reached a length of 4-5 mm. lies opposite the last four cervical and the first thoracic myotomes. At this time it is filled with closely packed mesenchymal cells. No buds from the myotomes can be seen extending into the mesenchyme (Fig. 232).

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'''Fig. 232.''' Transverse section through the eighth cervical segment of a human embryo of 4.5 mm. Lewis.

In succeeding stages the limb bud enlarges still more, and the mesenchymal tissue becomes denser (Figs. 233 and 234). During these stages no growths, either of buds or of individual cells, from the myotomes are apparent. Some of the cervical nerves, however, enter the limb buds (Fig. 234).

Apparently the tissue from which the muscles, as well as the skeletal elements, are to develop, is the condensed mesenchymal tissue. The first indication of differentiation occurs during the fourth week (embryo of about 8 mm.). The central portion or core of the mesenchymal mass becomes still denser to form the anlage of the skeletal elements of the extremity. The tissue of the core shades off into the surrounding tissue of a lesser density, which is destined to give rise to the muscles and which is known as the premuscle sheath.

During these processes of differentiation in the limb bud proper, masses of premuscle tissue have also become differentiated around the base of the limb bud. These are the forerunners of certain extrinsic muscles of the upper extremity, such as the pectoralisj levator scapula, trapezius, latissimus dorsi, serratus, etc. (Fig. 235; compare with Fig. 236).

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Fig. 233. Transverse section through the 8th cervical segment of a human embryo of 5 mm. Lewis.

By the end of the fifth week the premuscle sheath in the limb bud proper becomes more or less differentiated into muscles or groups of muscles. The differentiation is most complete at the proximal end. From this the transition is gradual to the distal end where the premuscle sheath is intact

By the end of the sixth week most of the muscles of the upper extremity are recognizable (Figs. 236 and 237).

By the end of the seventh week practically all the muscles can be recognized and are composed of muscle fibers.

During the differentiation of the muscles, the limb bud and certain extrinsic muscles migrate a considerable distance caudally. For example, the pectoralis and latissimus dorsi migrate from the base of the arm to the thoracic wall. Their nerves are naturally pulled with them. The trapezius muscle, which originates well forward in the cervical region, migrates so that it finally reaches as far as the last thoracic vertebra. The sternomastoideus also originates well forward in the cervical region, but finally extends to the clavicle and sternum. The migration of the upper extremity causes the brachial plexus to have a caudal inclination.

The lower limb buds arise very soon after the upper. As stated on page 115, the upper limbs always maintain a slight advance over the lower in development. As in the case of the upper, the lower limb buds appear as swellings on the ventro-lateral surface of the body, opposite the fifth lumbar and first sacral myotomes. The interior of each swelling is at first composed of closely packed mesenchymal tissue, but whether any part of the myotomes enters it is questionable. At all events several spinal nerves do enter the tissue and supply the nro.3cles. The differentiation of a central core as the anlage of the skeleton, and the differentiation of the surrounding tissue as the premuscle sheath, take place in the same manner as in the upper extremity (p. 274). From this premuscle sheath all the muscles of the lower extremity are developed.

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Fig. 234. Transverse section through the 8th cervical segment of a human embryo of 7 mm. (about 4 weeks). Lewis.

==Histogenesis of Striated Voluntary Muscle Tissue==

The majority of the striated voluntary muscles of the body are derived from the myotomes. Some are derived from the mesenchymal tissue in the branchial arches, some possibly from the mesenchymal tissue in the limb buds. Thf primitive segments are at first composed of closely arranged, epithelial-like cells that radiate from a small centrally placed cavity (Fig. 103). The cavity represents part of the ccelom and from this point of view it can be said that the muscle is a derivative of the epithelial lining of the ccelom. A part of each primitive segment becomes the sclerotome and cutis plate. The remaining part becomes the myotome or muscle plate (Fig. $ 23).

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Fig. 235. Drawing from a reconstruction of the upper limb region of a human

embryo of 9 mm. (4 weeks) ; ventral view. Lewis.

Inf. hy., infrahyoid; Lev. scap., levator scapulae; My., myotome mass; Rhom., rhomboid; Trap., trapezius.

The cells of the myotome are at first not essentially different from those of the rest of the primitive segment. Soon, however, changes take place in them and they become the so-called myoblasts or muscle-forming cells, which are destined to give rise to the muscle fibers. Opinions differ as to the manner in which the myoblasts produce the muscle fibers. It was once thought that each myoblast gave rise to a single muscle fiber in which there were several nuclei, all derived from the original myoblast nucleus by mitotic division. It was also thought that the muscle fibrillae represented highly modified and specialized parts of the cytoplasm, which arranged themselves longitudinally in the cell. Some of the later researches indicate that a muscle fiber represents a number of myoblasts fused together. This explanation is not, however, accepted by all investigators.

In contrast with the above, there is a quite general consensus of opinion in regard to the development of the internal structure of the muscle fiber. In the

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Fig. 236. Lateral view of a reconstruction of the muscles of the upper extremity of a human embryo of 16 mm. (about 6 weeks). Lewis.

The trapezius is the large muscle arising from the transverse processes of the vertebrae (at the right of the figure) and converging to its insertion on the clavicle. Just below the insertion of the trapezius is the deltoid, which partly hides the subscapular (on the right) and the pectoralis major (on the left). Arising beneath the deltoid and running downward to the elbow is the triceps. To the right of the triceps is the teres major (composed of two parts). The large sheet of muscle extending down the forearm and sending divisions to the ad, 3d, 4th and 5th digits is the extensor communis digitorum.

cytoplasm of the myoblasts there appear granules which soon arrange themselves in parallel rows and unite to form slender thread-like fibrils (Fig. 238). These fibrils are at first confined to one myoblast area. If several myoblasts fuse, the fibrils probably extend in a short time from one myoblast area to another. If one myoblast produces a fiber, the fibrils naturally are confined to a single myoblast area throughout development. The fibrils are usually formed first at the periphery of the cell and later in the interior (Figs. 239 and 240.) At the same time they increase in number by longitudinal splitting. The cytoplasm among the fibrils becomes the sarcoplasm.

After the granules which first appear unite to form the fibrils, the latter are apparently quite homogeneous. Later they become differentiated into two distinct substances which alternate throughout their length and produce the characteristic cross striation. The nature of this differentiation is not known. One investigator holds that both substances are derived from the original granules that unite to form the fibrils, alternate granules being composed of like substance and united by delicate strands of the other substance.

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Fig. 237. Medial view of a reconstruction of the muscles of the upper extremity of a human embryo of 16 mm. (about 6 weeks). Lewis.

The muscle arising on the scapula (at the left of the figure) and passing toward the right is the subscapular. The small muscle just below the subscapular is the teres major; below the latter and hanging downward is the latissimus dorsi. Note the cut end of the pectoralis minor just to the right of the narrow portion of the subscapular. Running from this cut end toward the right is the biceps. The muscle at the lower edge of the figure in the arm region is the triceps. In the forearm region, the muscle crossing the end of the biceps is the pronator teres. Below the pronator teres, extending from the elbow to the thumb region is the flexor carpi radialis. Below the latter and extending to a point opposite the thumb, is the palmaris longus. Beneath the palmaris longus and dividing into branches which pass to the 2d, ad, 4th, and 5th digits is the flexor sublimis digitorum. The muscle passing to the thumb is the flexor longus pollicis. The muscle at the lower border of the figure in the forearm region is the flexor carpi ulnaris.

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Fig. 238. Myoblasts in different stages of development. Godleivski.

The upper cell represents a myoblast with granular cytoplasm (from sheep embryo of 13 mm) ; the middle, a myoblast with fibrils in process of formation (from guinea-pig embryo of 10 mm.); the lower, a myoblast with still further differentiated, segmented fibrils (from a rabbit embryo of 8.5 mm.).

While the fibrils are being formed, the nuclei of the myoblasts undergo rapid mitotic division. When the cells are about filled with fibrils, the nuclei migrate to the periphery where they are situated in the fully formed fiber (Fig. 278). Each fiber thus possesses a number of nuclei, whether it is derived from one myoblast or from several.

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Fig. 239. From a cross section of developing voluntary striated muscle in the leg of a pig embryo of 45 mm., showing fibril bundles at the periphery of the cells. MacCallum.

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Fig. 240. From a cross section of developing voluntary striated muscle in the leg of a pig embryo of 75 mm., showing fibril bundles more numerous than in Fig. 239. A, Central vesicular nucleus; B, peripheral more compact nucleus. MacCallum.

For some time at least, the number of fibers in a developing muscle increases by division of those already formed. This process would produce a certain degree of enlargement of the muscle as a whole. Later the increase in the number of fibers ceases, and the muscle grows by enlargement of the individual fibers. It is not certain at what period in development the increase in the number of fibers ceases.

In many muscles development is further complicated by a retrograde processa degeneration of some of the fibers. This occurs quite regularly in the extremities. A well fibrillated fiber first presents a homogeneous appearance, then becomes vacuolated, the nuclei disintegrate, and finally the whole structure disappears. Mesenchymal (or connective) tissue takes its place, and the remaining fibers are thus grouped into bundles and the bundles into muscles. This would account to a certain extent for the intermuscular connective tissue, the perimysium and endomysium, the epimysium being derived from the mesenchymal tissue which originally surrounded the muscle.

==The Visceral Musculature==

The visceral musculature is derived wholly from the mesoderm, but not from the myotomes. The striated involuntary muscle or heart muscle is derived from the mesothelial lining of the coelom, the smooth muscle from the mesenchymal tissue in various regions of the body. The heart muscle develops only in connection with the heart and consequently occurs in the adult only in that organ. Smooth muscle develops to form integral parts of certain structures such, for example, as the alimentary tube, glands, blood vessels, and skin.

==Histogenesis of Heart Muscle==

When the simple tubular heart is first formed, the splanchnopleure projects into the ccelom (primitive pericardial cavity) along each side (Fig. 165; also p. 196). The mesothelium covering these projections is destined to give rise to the myocardium. The mesothelial cells which are at first closely packed together with but little intercellular substance, assume irregular branching forms and the branches anastomose freely (Fig. 241). After the cells become loosely arranged, they again become closely packed to form a compact syncytium, individual cells apparently assuming the shape of heavy bands (Fig. 242). Irregular transverse bands next appear, dividing the syncytium into the so-called heart muscle cells. These may or may not represent the original cells or myoblasts. At all events the muscle fibrils are continuous across the lines. The nuclei proliferate in the syncytium but remain in the central part of the bands or cells, instead of migrating to the periphery as in striated voluntary muscle.

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Fig. 241. From a section of developing heart muscle from a rabbit embryo of 9 mm. Godlewski,

a, Cell body with granules arranged in series; b, cell body with centrosome and attraction sphere;

c, branching fibril; d, fibrils extending through several cells.

While the cells are still loosely arranged, rows of granules appear in the cytoplasm, and the granules in each row unite to form a fibril (Fig. 241). The fibrils are at first confined to individual cell areas, but as the cells come closer together to form the compact syncytium, they extend through several cell areas and run in different directions (Fig. 242). As development proceeds the fibrils become more nearly parallel (Fig. 243). They are first formed in the peripheries of the cells, but later also in the interior, except in a small area immediately surrounding the nucleus, where a small amount of undifferentiated cytoplasm remains. The latter is continuous with the cytoplasm or sarcoplasm among the fibrils. As in voluntary seriated muscle the fibrils become differentiated into two distinct substances which alternate with each other, thus producing the transverse striation.

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Fig. 242. From a section of developing heart muscle in a rabbit embryo of 9 mm. Godlewski. The cells form a compact syncytium.

==Histogenesis of Smooth Muscle==

The mesenchymal cells which are destined to produce smooth muscle cells are not grouped into any particular primitive structures like the mesodermic somites. They are simply scattered through the general mass of mesenchymal tissue and, like other mesenchymal cells, possess irregular branching forms and distinct spherical nuclei. The internal changes by which these cells are converted into muscle cells are not well known. The contractile elements the fibrillae probably represent highly modified portions of the original cytoplasm but the manner in which the cytoplasm is transformed into fibrillae has not been determined. The external changes consist essentially in an elongation of the irregular mesenchymal cells. The result of this elongation is usually a spindle-shaped cell, but exceptionally cells forked at one or both ends are produced. The original spherical nucleus also shares in the elongation and becomes rod-shaped.

In some cases, for example in the muscular layers of the gastrointestinal tract, distinct bands or sheets of smooth muscle are formed in which the cells are closely packed and lie approximately parallel. In other cases, such as the mucosa of the intestine and the capsules of certain glands, the muscle cells develop in little groups or as isolated cells.

==Anomalies==

More or less of the muscular system is involved in some of the gross anomalies or malformations of the body. For example, congenital defects in the central nervous system (anencephaly, rachichisis, etc.) are necessarily accompanied by atrophy or faulty development of certain parts of the muscular system. In the case of ventral median fissure of the abdominal wall (gastroschisis) , the abdominal muscles are naturally involved. Such anomalies in the muscles are, however, secondary to the other malformations and are not due to primary defects in the muscles themselves.

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'''Fig. 243.''' From a section of developing heart muscle in a rabbit embryo of 10 mm. Godlewski. The fibrils are segmented, indicating the beginning of the cross striation characteristic of heart muscle.

Many of the minor variations in the muscular system occur in the same form or in similar forms in different individuals, thus indicating their relation to a fundamental type. Many of these are more or less accurate repetitions of normal structures found in lower animals. Such variations are probably rightly attributed to hereditary influences. On the other hand, there are variations which cannot be referred to conditions found in any of the lower animals. These constitute a class of variations which must be accounted for upon some other basis than that of heredity. As pointed out in the chapter on Teratogenesis (Chap. XX), external influences undoubtedly play an important part in the production of anomalies and it is probable that similar influences act upon the development of the muscular system.

The scope of this book does not permit a description, or even mention, of the great number of variations in the muscles. A few are described here as examples; for others the student is referred to the more extensive text-books of anatomy.

==Extrinsic Muscles of the Upper Extremity==

The trapezius is sometimes attached to less than the normal number of thoracic vertebrae. Its occipital attachment may be wanting. Occasionally the cervical and thoracic portions are more or less separated as in some of the lower animals.

The latissimus dorsi sometimes arises from less than the usual number of thoracic vertebrae, and from less than the normal number of ribs. The iliac origin may be wanting.

The rhomboidei vary in their vertebral and scapular attachments.

The number of the vertebral attachments of the levator scapulae may vary. A small part of the muscle is sometimes attached to the occipital bone.

The pectoralis major not infrequently varies in the extent of its attachment to the ribs and sternum.

The serrati vary in their attachment to the ribs.

The above mentioned extrinsic muscles of the upper extremity vary principally in their attachments. Since they all appear well forward in the cervical region in the embryo, and, along with the extremity, gradually migrate caudally before acquiring their final attachments, it is not unlikely that the variations in their attachments are due to variations in the extent of migration.

This serves to illustrate a factor which is probably important in producing variations in the attachments of many other muscles. As stated in paragraph i, on page 264, the myo tomes frequently migrate very extensively during their transformation into muscles, before the muscles have acquired their permanent attachment. Variations in the extent of this migration would naturally produce variations in the final attachments of these muscles.

Other factors related to the changes in the myo tomes, such as fusion, longitudinal and tangential splitting (paragraphs 2, 3 and 4, p. 264) probably also play a part in the production of variations.

A greater than normal degree of fusion between two or more myotomes might result in the union of muscles which are usually separate; a less than normal degree of fusion might result in the separation of parts usually united. Variations in the splitting of myotomes might produce similar results.

At the same time, however, heredity may be the active factor in some cases where abnormal fusions or separations between muscles or parts of muscles produce results resembling conditions found in lower animals.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_12|Alimentary tube and organs]]

==Reference for Further Study==

V BARDEEN, C. R. : The Development of the Musculature of the Body Wall in the Pig, Including its Histogenesis and its Relation to the Myotomes and to the Skeleton and to the Nervous Apparatus. Johns Hopkins Hospital Reports, Vol. XI.

{{Ref-BardeenLewis1901}}

BOLK, L.: Die Segmentaldifferenzierung des menschlichen Rumpfes und seiner Extremitaten. Morph. Jahrbuch, Bd. XXV, 1898.

FUTAMURA, R.: Ueber die Entwickelung der Facialismuskulatur des Menschen. Anat. Hefte, XXX, 1906.

GODLEWSKI, E.: Die Entwickelung des Skelet- und Herzmuskelgewebes der Saugetiere. Arch. f. mik. Anat., Bd. LX, 1902.

GRAFENBERG, E.: Die Entwickelung der menschlichen Beckenmuskulatur. Anat. Hefte, 1904.

HEIDENHAIN, M.: Structur der contractilen Materie. Ergebnisse der Anat. u. Entwick., Bd. VIII, 1898.

HEIDENHAIN, M.: Ueber die Structur des menschlichen Herzmuskels. Anal. Anz., Bd. XX, 1901.

KASTNER, S.: Ueber die Bildung von animalen Muskelfasern aus dem Urwirbel. Arch. f. Anat. u. Physiol., Anat. Abth., Suppl., 1890.

KEIBEL, F., and MALL, F. P.: Manual of Human Embryology, Vol. I, 1910.

KOLLMANN, J.: Die Rumpfsegmente menschlicher Embryonen von 13-35 Urwirbeln. Arch. f. Anat. u. Physiol., Anat. Abth., 1891.

{{Ref-Lewis1902}}

MAURER, F.: Die Entwickelung des Muskelsystems und der elektrischen Organe. Also Bibliography. In Hertwig's Handbuch der vergl. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil I, 1904.

MACCALLUM, J. B.: On the Histology and Histogenesis of the Heart-muscle Cell. Anat. Anz., Bd. XIII, 1897.

MACCALLUM, J. B.: On the Histogenesis of the Striated Muscle Fiber and the Growth of the Human Sartorius Muscle. Johns Hopkins Hospital Bulletin, Vol. IX, 1898.

MALL, F. P. : Development of the Ventral Abdominal Walls in Man. Jour, of Morphology, Vol. XIV, 1898.

McGiLL, CAROLINE: The Histogenesis of Smooth Muscle in the Alimentary Canal and Respiratory Tract of the Pig. Internal. Monatsch. Anat. u. Phys., Bd. XXIV, 1907.

MCMURRICH, J. P. : The Phylogeny of the Forearm Flexors. American Jour, of Anat., Vol. II, 1903.

MCMURRICH, J. P.: The Phylogeny of the Palmar Musculature. American Jour, oj Anat., Vol. II, 1903.

MCMURRICH, J. P.: The Phylogeny of the Crural Flexors. American Jour, of Anat., Vol. IV, 1904.

MCMURRICH, J. P.: The Phylogeny of the Plantar Musculature. American Jour, oj Anat., Vol. VI, 1907.

POPOWSKY, I.: Zur Entwickelungsgeschichte der Dammmuskulatur beim Menschen. Anat. Hefte, 1899.

SUTTON, J. B.: Ligaments, Their Nature and Morphology. London, 1897.

ZIMMERMANN: Ueber die Metamerie des Wirbeltierkopfes. Verhandl. d. Anat. Gesettsch. Jena, 1891.

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Book - Text-Book of Embryology 11

2024-01-25T00:43:10Z

Z8600021:

{{Bailey 1921}}

=The Development of the Muscular System=

Anatomy and Histology show that there are, in a sense, two muscular systems in the body, and Embryology teaches that the two systems have different origins.

# The skeletal musculature. This, as the name indicates, is closely associated with the skeletal system. It is made up of striated muscle fibers arranged to form definite bundles or muscles. The skeletal musculature is under the voluntary control of the central nervous system.
# The visceral musculature. This is. found in connection with and forms integral parts of certain organs. It is made up of two different kinds of fibers smooth muscle fibers or cells and striated fibers or cells (heart-muscle cells). The latter are found only in the wall of the heart. The visceral musculature is involuntary, being under the control of the sympathetic nervous system.

Both systems are derived from mesoderm but from distinct parts of the mesoderm. Furthermore, their developmental histories are quite different, as will be seen in the following paragraphs.

==The Skeletal Musculature==

In the chapters on the development of the germ layers it was said that throughout the length of the body region of the embryo the mesoderm on each side of the neural tube and notochord becomes divided into a definite number of segments the primitive segments or mesodermic somites (Figs. 24, 52, 51). These indicate the segmentation of the body, and the history of the greater part of the skeletal musculature dates from their differentiation from the axial mesoderm. Thus the skeletal musculature is, for the most part, primarily segmental in character.

At first the primitive segments are composed of closely packed, epitheliallike cells, and each segment contains a small cavity which represents a portion of the coelom (Fig. 103). The ventro-medial parts of the segments become differentiated to form the sclerotomes which are composed of more loosely arranged cells (Fig. 223), and which are destined to give rise to the vertebrae and to the various kinds of connective tissue in their neighborhood. The lateral parts of the segments become differentiated to form the cutis plates which are destined to give rise to a part of the corium of the skin. The remaining portions of the segments form the muscle plates or myotomes (Fig. 223), from which develop by far the greater part, at least, of the voluntary striated muscles.

The differentiation of the parts of the primitive segments begins in the cervical region by the end of the second week, and then gradually proceeds toward the tail. Three myotomes are also probably formed in the occipital region. The cells of the myotomes are at first of an epithelial character (Fig. 105). Contractile fibrils appear in the cells and the latter are transformed directly into muscle fibers. (For histogenesis see p. 276). The fibers later alter their direction in accordance with the particular muscle to which they belong. The muscle tissue first formed is thus segmented, being derived from the segmentally arranged myotomes, but as development proceeds the myotomes undergo extensive changes by which the segmental character is lost in the majority of cases. It is retained, however, in a few instances, such for example as the intercostal muscles. The course of the changes which obliterate the segmental character of the myotomes and give rise to the various muscles has not been observed in all cases. But since a nerve belonging to any particular segment and innervating the myotome of that segment always innervates the muscles derived from that myotome, it is possible to learn something of the history of the myotomes by studying the innervation of the muscles.

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'''Fig. 223.''' Transverse section of human embryo of the 3rd week. Scl. 1 , Break in myotome at point where sclerotome is closely attached. Kottmann.

From a consideration of what is known concerning the individual histories of the muscles and concerning the innervation of the muscles, certain factors can be recognized, to one or more of which the changes in the myotomes may be referred. These factors are as follows:

1. Migration.- The myotomes may migrate in whole or in part, and the muscles derived from them may be situated far beyond their limits. For example, the latissimus dorsi is derived from cervical myotomes but ultimately becomes attached to the lumbar vertebrae and to the crest of the ilium. To this factor, possibly more than to any other, is due the loss of the segmental character in the musculature.

2. Fusion. Portions of two or more myotomes may fuse to form one muscle. For example, each oblique abdominal muscle is derived from several thoracic myotomes.

3. Longitudinal Splitting. Very frequently a myotome or a developing muscle splits longitudinally into two or more portions. The sternohyoid and the omohyoid, for example, are formed in this manner.

4. Tangential Splitting. A developing muscle may split tangentially into two or more plates or layers. The two oblique and the transverse abdominal muscles, for example, are formed in this way.

5. Degeneration. Myotomes may degenerate as a whole or in part and be converted into some form of connective tissue, such as fascia, ligament or aponeurosis. The aponeuroses of the transverse and oblique abdominal muscles are probably due to a degeneration of portions of the myotomes from which the muscles are derived.

6. Change of Direction. The muscle fibers may change their direction. As a matter of fact, the fibers of very few muscles retain their original direction.

==Muscles of the Trunk==

The myotomes are at first arranged serially along each side of the notochord and spinal cord (compare Fig. 2 24 with Figs. 105 and 223). By the end of the second week fourteen myotomes are differentiated in the human embryo. Differentiation continues until, by the end of the fourth week, the total number thirtyeight is present. Of the thirty-eight, three are occipital, eight cervical, twelve thoracic, five lumbar, five sacral, and five (or six) coccygeal. The occipital myotomes are transient structures that appear in relation with the hypoglossal (XII) nerve. The cervical, thoracic, lumbar, sacral and coccygeal myotomes correspond individually to the spinal nerves (Fig. 224). As stated on page 148, the myotomes alternate with the anlagen of the vertebrae. Consequently in the cervical region there are eight myotomes, corresponding to the eight cervical spinal nerves, and only seven vertebrae. The myotomes in the neck and body regions are destined to give rise to the dorsal musculature, to the thoracoabdominal musculature, to a part of the muscles of the neck, and to the muscles of the tail region. There is a possibility that they give rise also to the muscles of the tongue.

As the myotomes continue to develop, they become elongated in a ventral direction. Those of the thoracic region extend into the connective tissue of the somatopleure, or in other words, into the lateral body walls (compare Figs. 224 and 225). During the fifth week the myotomes give rise to a dorsoventral mass of developing muscle tissue, in which the segmental character largely disappears. The muscle mass then becomes divided longitudinally into two parts, (i) a dorsal and (2) a ventro-lateral (Figs. 224, 225 and 226).

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'''Fig. 224.''' Lateral view of human embryo of 9 mm. (4! weeks). Bardeen and Lewis.

:The area from which the skin has been removed is drawn from reconstructions. The myotomes have fused to a certain extent, so that segmentation is becoming less distinct. Note that the myotomes correspond to the spinal nerves. The developing muscle mass (the myotomes collectively) extends ventrally in the body wall in the thoracic region, and is divided by a longitudinal groove into two parts a dorsal and a ventro-lateral (see text).

:In the region of the upper extremity, dense masses of " premuscle " tissue are represented which later form the muscles. In the region of the forearm and hand the " premuscle " tissue has been removed to disclose the anlagen of the skeletal elements (radius, ulna, and hand plate). In the region of the lower extremity the superficial tissue has been removed to disclose the border vien, the anlagen of the os coxae, and the lumbo-sacral nerve plexus.

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'''Fig. 225.''' Diagrammatic cross section through the sth-6th thoracic segments of a human embryo of 9 mm. (4! weeks). Bardeen and Lewis.

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'''Fig. 226.''' Drawing from a reconstruction of the region of the lower extremity of a human embryo of 9 mm. (4 weeks). Bardeen and Lewis.

:The visceral organs and the greater part of the left body wall have been removed. The 8th thoracic to the 5th sacral segments are shown. On the right side of the body the costal processes, the spinal nerves (including the lumbo-sacral plexus), and the lower extremity are shown. On the left side the costal processes, the spinal nerves, and the nth and i2th thoracic myotomes are represented. Note the dorsal, lateral, and sympathetic branches of the spinal nerves.

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1. The dorsal part is destined to give rise to those dorsal muscles of the trunk that are not associated with the extremities, and is innervated by the dorsal rami of the spinal nerves (Fig. 225).

2. The ventro-lateral part again divides longitudinally into (a) a lateral and (b) between (a) a ventral part, although the line of division is not so distinct as the original (i) dorsal and (2) ventro-lateral parts (Fig. 227). The lateral part subdivides tangentially and gives rise in the cervical region to the longus capitis, longus colli, rectus capitis anterior, to the scaleni, and to parts of the trapezius and sternomastoideus (Figs. 228 and 229). In the thoracic region it gives rise to the intercostaks and to the transversus thoracis (Figs. 227 and 230); in the abdominal region to the psoas, quadratus lumborum, and to the obliqui and transversus abdominis (Figs. 229 and 230).

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Fig. 227. Diagrammatic cross section through the 6th~7th thoracic segments of a human embryo of 17 rnm. (5^ weeks). Bardeen and Lewis.

(b) The ventral part gives rise in the cervical region to the sternohyoideus, omohyoidem, sternothyreoideus and geniohyoideus. In the abdominal region the ventral part gives rise to the r edits abdominis and to the pyramidalis (Figs. 227 and 229). In the thoracic region there are no muscles derived from the ventral part, corresponding to those in the abdominal region. This is probably due to the development of the sternum.

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'''Fig. 228.''' Lateral view of a human embryo of n mm. (about 5 weeks). Bardeen and Lewis. The area from which the skin has been removed is drawn from reconstructions. The dorsal musculature has been removed from the region of the upper extremity, exposing the 4th to the 8th cervical and the ist to the 3d thoracic vertebrae. The dorsal musculature has likewise been removed from the 5th lumbar and first three sacral segments. Segmentation is practically lost in the dorsal musculature in the thoracic region, but is still evident in the lumbar, sacral and coccygeal regions. The ventro-lateral musculature is distinctly separated from the dorsal, and is beginning to differentiate into the muscles of the thorax and abdomen.

The ventro-lateral portions of the lumbar myotomes and of the first two sacral myotomes, corresponding to the ventro-lateral portions of the thoracic myotomes, apparently do not take part in the production of muscles which belong to the body wall proper. It is even questionable whether they give rise to any muscles of the lower extremities. The ventro-lateral portions of the third and fourth sacral myotomes give rise to the levator ani, the coccygeus, the sphincter ani externus and the perineal muscles. The dorsal parts of the myotomes as far as the fifth sacral probably give rise to the sacrospinalis (Fig. 228). THE DIAPHRAGM. In addition to certain structures which are considered in connection with the pericardium (parietal mesoderm, mesocardium and common mesentery Chapter XIV), two myotomes on each side enter into the formation of the diaphragm. These are the third and fourth cervical myotomes, parts of which grow into the developing diaphragm in the earlier stages when it is situated far forward in the cervical region (p. 346 and Fig. 298), and give rise to its muscular elements.

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'''Fig. 229.''' Drawing from a reconstruction of a human embryo of 20 mm. (about 7 weeks). Bardeen and Lewis. The superficial tissues have been removed from the extremities, the body wall, and the back.

==Muscles of the Head==

Primitive segments (mesodermic somites) are not clearly demonstrable in the heads of human embryos, nor, in fact, in the heads of any of the higher Vertebrates. In some of the lower forms, however, they are very distinct. It seems possible, even probable, that their indistinctness in the higher animals is due to an abbreviation or condensation in the development of the head region. Such condensations are known to occur in the development of other structures. In a human embryo 3.5 mm. long, three structures, resembling segments have been seen somewhat caudal to the region of the ootic vesicle on

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Fig. 230. Drawing from a reconstruction of the right side of a human embryo of 20 mm. (about 7 weeks). Bardeen and Lewis.

++++++++++++++++++++++++++++++++++

the left body wall and viscera have been removed. Note especially the following muscles: The deltoid and biceps, just to the left of the brachial plexus and below the clavicle; the internal intercostals; the diaphragm, attached to the body wall; the transverse abdominal and the rectus abdominis; the quadratus lumborum, just to the right of the transverse abdominal; the psoas, cut just above the lumbo-sacral plexus; the levator ani, running obliquely upward from the coccygeal region.

one side. On the other side there were seven similar but smaller structures. All were composed of epithelial-like cells surrounding small cavities. Whether these segment-like structures bear any relation to the mesenchymal condensations which appear regularly in the occipital region (p. 157). seems not to have been determined.

Although the transformation of head segments into muscles has not been followed in detail in mammalian embryos, it may be inferred from the study of lower forms that three segments are involved in the formation of the eye muscles. The most cephalic (anterior) segment gives rise to the recti superior, inferior and medialis (internus) and to the obliquus inferior, all of which are innervated by the occulomotor (III) nerve. The next segment gives rise to the obliquus superior which is innervated by the pathetic (IV) nerve. The most caudal segment gives rise to the rectus lateralis (externus) which is innervated by the abducens (VI) nerve.

The development and innervation of the other muscles of the head and" of the hyoid musculature present certain peculiarities which have caused these muscles to be considered as more closely related to the visceral musculature than to the myotomic musculature. In the first place they are derived from the branchial arches (hence are often called branchiomeric muscles), and not directly from the myotomes of the neck region. This places them in closer relation to the visceral muscles, although they are structurally and functionally different from the latter. In the second place the nerves which supply them are fundamentally different from those which supply the myotomic muscles (Chap. XVII).

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'''Fig. 231.''' Transverse section through the eighth cervical segment of a human embryo of 2.1 mm. Lewis

The first branchial arch on each side gives rise to the temporalis, masseter and pterygoidei, to the mylohyoideus and digastricus (venter anterior) and to the tensor tympani and tensor veli palatini. All these muscles are innervated by the trigeminal (V) nerve.

The second arch, which is often called the hyoid arch, gives rise to a large sheet of myogenic tissue which produces many of the facial muscles, such as the platysma and epicranius, the muscles of expression quadratus labii superiority risorius, triangularis , mentalis, etc.; also two muscles connected with the hyoid bone digastricus (venter posterior) and stylohyoideus and the stapedius of the middle ear. The facial (VII) nerve corresponds to the second arch and supplies all these muscles.

The glossopharyngeal (IX) nerve corresponds to the third branchial arch, and this fact indicates the muscles derived from that arch. Some, at least, of the constrictor muscles of the pharynx are derived from the third arch. The stylo-pharyngeus is also a derivative of the same arch.

The vagus (X) nerve is associated with the fourth and fifth arches and consequently innervates the muscles derived from these arches, viz., the rest of the constrictors of the pharynx (see above), the laryngeal muscles and the muscles of the soft palate (except the tensor veli palatini which is derived from the first arch (p. 271). The glossopalatinus and chondroglossus are also derived from the fourth and fifth arches, while the rest of the extrinsic muscles of the tongue are of myotomic origin.

Two other muscles are probably derived in part from the branchial arches, for fibers of the spinal accessory (XI) nerve afford a part of their innervation. These are the trapezius and the sternomastoideus , the remaining parts of which are of myotomic origin (p. 267).

==Muscles of the Extremities==

The question as to whether the muscles of the extremities are derivatives of the myotomes or of the mesenchymal tissue in the limb buds has not been settled. In some of the lower Vertebrates, especially in some of the Fishes, it seems to have been pretty clearly demonstrated that bud-like processes from the myotomes grow into the anlagen of the extremities (fins), and there give rise to muscles. In other lower forms no such buds from the myotomes have been demonstrated, but the muscles are apparently derived directly from the mesenchymal tissue in the anlagen of the extremities. In the higher vertebrates, especially in Mammals, no distinct myotome buds have been traced into the extremities. Some investigators hold, however, that instead of myotome buds some cells from the myotomes myoblasts wander into the limb buds and give rise to muscles. Other investigators are inclined to the view that the musculature of the extremities is not of myotomic origin, but that it is derived from the mesenchymal tissue of the limb buds.

A most striking feature of the musculature of the extremities is its distinctly segmental nerve supply. This, of course, is in favor of, although it does not prove, its myotomic origin. If the muscles of the extremities are of myotomic origin, it is very probable that several myotomes take part in their formation.

In the first place among the lower Vertebrates the muscles of each extremity are derived from several myotomes and are innervated by segmental nerves corresponding to these myotomes. In the second place among the higher Vertebrates, although the myotomic origin of the muscles has not been clearly demonstrated, the nerve supply in each extremity comes through several segmental spinal nerves.

Knowledge concerning the development of the individual muscles of the extremities in the human embryo is incomplete. Especially is this true of the muscles of the lower extremities.

The upper limb bud first appears in embryos of 2-3 mm. (during the third week) as a slight swelling ventro-lateral to the myotomes in the lower cervical region (Fig. 231; see also Fig. 87). The swelling gradually enlarges and by the time the embryo has reached a length of 4-5 mm. lies opposite the last four cervical and the first thoracic myotomes. At this time it is filled with closely packed mesenchymal cells. No buds from the myotomes can be seen extending into the mesenchyme (Fig. 232).

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'''Fig. 232.''' Transverse section through the eighth cervical segment of a human embryo of 4.5 mm. Lewis.

In succeeding stages the limb bud enlarges still more, and the mesenchymal tissue becomes denser (Figs. 233 and 234). During these stages no growths, either of buds or of individual cells, from the myotomes are apparent. Some of the cervical nerves, however, enter the limb buds (Fig. 234).

Apparently the tissue from which the muscles, as well as the skeletal elements, are to develop, is the condensed mesenchymal tissue. The first indication of differentiation occurs during the fourth week (embryo of about 8 mm.). The central portion or core of the mesenchymal mass becomes still denser to form the anlage of the skeletal elements of the extremity. The tissue of the core shades off into the surrounding tissue of a lesser density, which is destined to give rise to the muscles and which is known as the premuscle sheath.

During these processes of differentiation in the limb bud proper, masses of premuscle tissue have also become differentiated around the base of the limb bud. These are the forerunners of certain extrinsic muscles of the upper extremity, such as the pectoralisj levator scapula, trapezius, latissimus dorsi, serratus, etc. (Fig. 235; compare with Fig. 236).

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Fig. 233. Transverse section through the 8th cervical segment of a human embryo of 5 mm. Lewis.

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By the end of the fifth week the premuscle sheath in the limb bud proper becomes more or less differentiated into muscles or groups of muscles. The differentiation is most complete at the proximal end. From this the transition is gradual to the distal end where the premuscle sheath is intact

By the end of the sixth week most of the muscles of the upper extremity are recognizable (Figs. 236 and 237).

By the end of the seventh week practically all the muscles can be recognized and are composed of muscle fibers.

During the differentiation of the muscles, the limb bud and certain extrinsic muscles migrate a considerable distance caudally. For example, the pectoralis and latissimus dorsi migrate from the base of the arm to the thoracic wall. Their nerves are naturally pulled with them. The trapezius muscle, which originates well forward in the cervical region, migrates so that it finally reaches as far as the last thoracic vertebra. The sternomastoideus also originates well forward in the cervical region, but finally extends to the clavicle and sternum. The migration of the upper extremity causes the brachial plexus to have a caudal inclination.

The lower limb buds arise very soon after the upper. As stated on page 115, the upper limbs always maintain a slight advance over the lower in development. As in the case of the upper, the lower limb buds appear as swellings on the ventro-lateral surface of the body, opposite the fifth lumbar and first sacral myotomes. The interior of each swelling is at first composed of closely packed mesenchymal tissue, but whether any part of the myotomes enters it is questionable. At all events several spinal nerves do enter the tissue and supply the nro.3cles. The differentiation of a central core as the anlage of the skeleton, and the differentiation of the surrounding tissue as the premuscle sheath, take place in the same manner as in the upper extremity (p. 274). From this premuscle sheath all the muscles of the lower extremity are developed.

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Fig. 234. Transverse section through the 8th cervical segment of a human embryo of 7 mm. (about 4 weeks). Lewis.

==Histogenesis of Striated Voluntary Muscle Tissue==

The majority of the striated voluntary muscles of the body are derived from the myotomes. Some are derived from the mesenchymal tissue in the branchial arches, some possibly from the mesenchymal tissue in the limb buds. Thf primitive segments are at first composed of closely arranged, epithelial-like cells that radiate from a small centrally placed cavity (Fig. 103). The cavity represents part of the ccelom and from this point of view it can be said that the muscle is a derivative of the epithelial lining of the ccelom. A part of each primitive segment becomes the sclerotome and cutis plate. The remaining part becomes the myotome or muscle plate (Fig. $ 23).

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Fig. 235. Drawing from a reconstruction of the upper limb region of a human

embryo of 9 mm. (4 weeks) ; ventral view. Lewis.

Inf. hy., infrahyoid; Lev. scap., levator scapulae; My., myotome mass; Rhom., rhomboid; Trap., trapezius.

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The cells of the myotome are at first not essentially different from those of the rest of the primitive segment. Soon, however, changes take place in them and they become the so-called myoblasts or muscle-forming cells, which are destined to give rise to the muscle fibers. Opinions differ as to the manner in which the myoblasts produce the muscle fibers. It was once thought that each myoblast gave rise to a single muscle fiber in which there were several nuclei, all derived from the original myoblast nucleus by mitotic division. It was also thought that the muscle fibrillae represented highly modified and specialized parts of the cytoplasm, which arranged themselves longitudinally in the cell. Some of the later researches indicate that a muscle fiber represents a number of myoblasts fused together. This explanation is not, however, accepted by all investigators.

In contrast with the above, there is a quite general consensus of opinion in regard to the development of the internal structure of the muscle fiber. In the

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Fig. 236. Lateral view of a reconstruction of the muscles of the upper extremity of a human embryo of 16 mm. (about 6 weeks). Lewis.

The trapezius is the large muscle arising from the transverse processes of the vertebrae (at the right of the figure) and converging to its insertion on the clavicle. Just below the insertion of the trapezius is the deltoid, which partly hides the subscapular (on the right) and the pectoralis major (on the left). Arising beneath the deltoid and running downward to the elbow is the triceps. To the right of the triceps is the teres major (composed of two parts). The large sheet of muscle extending down the forearm and sending divisions to the ad, 3d, 4th and 5th digits is the extensor communis digitorum.

cytoplasm of the myoblasts there appear granules which soon arrange themselves in parallel rows and unite to form slender thread-like fibrils (Fig. 238). These fibrils are at first confined to one myoblast area. If several myoblasts fuse, the fibrils probably extend in a short time from one myoblast area to another. If one myoblast produces a fiber, the fibrils naturally are confined to a single myoblast area throughout development. The fibrils are usually formed first at the periphery of the cell and later in the interior (Figs. 239 and 240.) At the same time they increase in number by longitudinal splitting. The cytoplasm among the fibrils becomes the sarcoplasm.

After the granules which first appear unite to form the fibrils, the latter are apparently quite homogeneous. Later they become differentiated into two distinct substances which alternate throughout their length and produce the characteristic cross striation. The nature of this differentiation is not known. One investigator holds that both substances are derived from the original granules that unite to form the fibrils, alternate granules being composed of like substance and united by delicate strands of the other substance.

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Fig. 237. Medial view of a reconstruction of the muscles of the upper extremity of a human embryo of 16 mm. (about 6 weeks). Lewis.

The muscle arising on the scapula (at the left of the figure) and passing toward the right is the subscapular. The small muscle just below the subscapular is the teres major; below the latter and hanging downward is the latissimus dorsi. Note the cut end of the pectoralis minor just to the right of the narrow portion of the subscapular. Running from this cut end toward the right is the biceps. The muscle at the lower edge of the figure in the arm region is the triceps. In the forearm region, the muscle crossing the end of the biceps is the pronator teres. Below the pronator teres, extending from the elbow to the thumb region is the flexor carpi radialis. Below the latter and extending to a point opposite the thumb, is the palmaris longus. Beneath the palmaris longus and dividing into branches which pass to the 2d, ad, 4th, and 5th digits is the flexor sublimis digitorum. The muscle passing to the thumb is the flexor longus pollicis. The muscle at the lower border of the figure in the forearm region is the flexor carpi ulnaris.

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Fig. 238. Myoblasts in different stages of development. Godleivski.

The upper cell represents a myoblast with granular cytoplasm (from sheep embryo of 13 mm) ; the middle, a myoblast with fibrils in process of formation (from guinea-pig embryo of 10 mm.); the lower, a myoblast with still further differentiated, segmented fibrils (from a rabbit embryo of 8.5 mm.). ++++++++++++++++++++++++++++++++++

While the fibrils are being formed, the nuclei of the myoblasts undergo rapid mitotic division. When the cells are about filled with fibrils, the nuclei migrate to the periphery where they are situated in the fully formed fiber (Fig. 278). Each fiber thus possesses a number of nuclei, whether it is derived from one myoblast or from several.

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Fig. 239. From a cross section of developing voluntary striated muscle in the leg of a pig embryo of 45 mm., showing fibril bundles at the periphery of the cells. MacCallum.

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Fig. 240. From a cross section of developing voluntary striated muscle in the leg of a pig embryo of 75 mm., showing fibril bundles more numerous than in Fig. 239. A, Central vesicular nucleus; B, peripheral more compact nucleus. MacCallum.

For some time at least, the number of fibers in a developing muscle increases by division of those already formed. This process would produce a certain degree of enlargement of the muscle as a whole. Later the increase in the number of fibers ceases, and the muscle grows by enlargement of the individual fibers. It is not certain at what period in development the increase in the number of fibers ceases.

In many muscles development is further complicated by a retrograde processa degeneration of some of the fibers. This occurs quite regularly in the extremities. A well fibrillated fiber first presents a homogeneous appearance, then becomes vacuolated, the nuclei disintegrate, and finally the whole structure disappears. Mesenchymal (or connective) tissue takes its place, and the remaining fibers are thus grouped into bundles and the bundles into muscles. This would account to a certain extent for the intermuscular connective tissue, the perimysium and endomysium, the epimysium being derived from the mesenchymal tissue which originally surrounded the muscle.

==The Visceral Musculature==

The visceral musculature is derived wholly from the mesoderm, but not from the myotomes. The striated involuntary muscle or heart muscle is derived from the mesothelial lining of the coelom, the smooth muscle from the mesenchymal tissue in various regions of the body. The heart muscle develops only in connection with the heart and consequently occurs in the adult only in that organ. Smooth muscle develops to form integral parts of certain structures such, for example, as the alimentary tube, glands, blood vessels, and skin.

==Histogenesis of Heart Muscle==

When the simple tubular heart is first formed, the splanchnopleure projects into the ccelom (primitive pericardial cavity) along each side (Fig. 165; also p. 196). The mesothelium covering these projections is destined to give rise to the myocardium. The mesothelial cells which are at first closely packed together with but little intercellular substance, assume irregular branching forms and the branches anastomose freely (Fig. 241). After the cells become loosely arranged, they again become closely packed to form a compact syncytium, individual cells apparently assuming the shape of heavy bands (Fig. 242). Irregular transverse bands next appear, dividing the syncytium into the so-called heart muscle cells. These may or may not represent the original cells or myoblasts. At all events the muscle fibrils are continuous across the lines. The nuclei proliferate in the syncytium but remain in the central part of the bands or cells, instead of migrating to the periphery as in striated voluntary muscle.

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[[File:Bailey241.jpg|600px]]

Fig. 241. From a section of developing heart muscle from a rabbit embryo of 9 mm. Godlewski,

a, Cell body with granules arranged in series; b, cell body with centrosome and attraction sphere;

c, branching fibril; d, fibrils extending through several cells.

++++++++++++++++++++++++++++++++++

While the cells are still loosely arranged, rows of granules appear in the cytoplasm, and the granules in each row unite to form a fibril (Fig. 241). The fibrils are at first confined to individual cell areas, but as the cells come closer together to form the compact syncytium, they extend through several cell areas and run in different directions (Fig. 242). As development proceeds the fibrils become more nearly parallel (Fig. 243). They are first formed in the peripheries of the cells, but later also in the interior, except in a small area immediately surrounding the nucleus, where a small amount of undifferentiated cytoplasm remains. The latter is continuous with the cytoplasm or sarcoplasm among the fibrils. As in voluntary seriated muscle the fibrils become differentiated into two distinct substances which alternate with each other, thus producing the transverse striation.

<div id="Fig242"></div>
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Fig. 242. From a section of developing heart muscle in a rabbit embryo of 9 mm. Godlewski. The cells form a compact syncytium.

==Histogenesis of Smooth Muscle==

The mesenchymal cells which are destined to produce smooth muscle cells are not grouped into any particular primitive structures like the mesodermic somites. They are simply scattered through the general mass of mesenchymal tissue and, like other mesenchymal cells, possess irregular branching forms and distinct spherical nuclei. The internal changes by which these cells are converted into muscle cells are not well known. The contractile elements the fibrillae probably represent highly modified portions of the original cytoplasm but the manner in which the cytoplasm is transformed into fibrillae has not been determined. The external changes consist essentially in an elongation of the irregular mesenchymal cells. The result of this elongation is usually a spindle-shaped cell, but exceptionally cells forked at one or both ends are produced. The original spherical nucleus also shares in the elongation and becomes rod-shaped.

In some cases, for example in the muscular layers of the gastrointestinal tract, distinct bands or sheets of smooth muscle are formed in which the cells are closely packed and lie approximately parallel. In other cases, such as the mucosa of the intestine and the capsules of certain glands, the muscle cells develop in little groups or as isolated cells.

==Anomalies==

More or less of the muscular system is involved in some of the gross anomalies or malformations of the body. For example, congenital defects in the central nervous system (anencephaly, rachichisis, etc.) are necessarily accompanied by atrophy or faulty development of certain parts of the muscular system. In the case of ventral median fissure of the abdominal wall (gastroschisis) , the abdominal muscles are naturally involved. Such anomalies in the muscles are, however, secondary to the other malformations and are not due to primary defects in the muscles themselves.

<div id="Fig243"></div>
[[File:Bailey243.jpg|600px]]

'''Fig. 243.''' From a section of developing heart muscle in a rabbit embryo of 10 mm. Godlewski. The fibrils are segmented, indicating the beginning of the cross striation characteristic of heart muscle.

Many of the minor variations in the muscular system occur in the same form or in similar forms in different individuals, thus indicating their relation to a fundamental type. Many of these are more or less accurate repetitions of normal structures found in lower animals. Such variations are probably rightly attributed to hereditary influences. On the other hand, there are variations which cannot be referred to conditions found in any of the lower animals. These constitute a class of variations which must be accounted for upon some other basis than that of heredity. As pointed out in the chapter on Teratogenesis (Chap. XX), external influences undoubtedly play an important part in the production of anomalies and it is probable that similar influences act upon the development of the muscular system.

The scope of this book does not permit a description, or even mention, of the great number of variations in the muscles. A few are described here as examples; for others the student is referred to the more extensive text-books of anatomy.

==Extrinsic Muscles of the Upper Extremity==

The trapezius is sometimes attached to less than the normal number of thoracic vertebrae. Its occipital attachment may be wanting. Occasionally the cervical and thoracic portions are more or less separated as in some of the lower animals.

The latissimus dorsi sometimes arises from less than the usual number of thoracic vertebrae, and from less than the normal number of ribs. The iliac origin may be wanting.

The rhomboidei vary in their vertebral and scapular attachments.

The number of the vertebral attachments of the levator scapulae may vary. A small part of the muscle is sometimes attached to the occipital bone.

The pectoralis major not infrequently varies in the extent of its attachment to the ribs and sternum.

The serrati vary in their attachment to the ribs.

The above mentioned extrinsic muscles of the upper extremity vary principally in their attachments. Since they all appear well forward in the cervical region in the embryo, and, along with the extremity, gradually migrate caudally before acquiring their final attachments, it is not unlikely that the variations in their attachments are due to variations in the extent of migration.

This serves to illustrate a factor which is probably important in producing variations in the attachments of many other muscles. As stated in paragraph i, on page 264, the myo tomes frequently migrate very extensively during their transformation into muscles, before the muscles have acquired their permanent attachment. Variations in the extent of this migration would naturally produce variations in the final attachments of these muscles.

Other factors related to the changes in the myo tomes, such as fusion, longitudinal and tangential splitting (paragraphs 2, 3 and 4, p. 264) probably also play a part in the production of variations.

A greater than normal degree of fusion between two or more myotomes might result in the union of muscles which are usually separate; a less than normal degree of fusion might result in the separation of parts usually united. Variations in the splitting of myotomes might produce similar results.

At the same time, however, heredity may be the active factor in some cases where abnormal fusions or separations between muscles or parts of muscles produce results resembling conditions found in lower animals.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_12|Alimentary tube and organs]]

==Reference for Further Study==

V BARDEEN, C. R. : The Development of the Musculature of the Body Wall in the Pig, Including its Histogenesis and its Relation to the Myotomes and to the Skeleton and to the Nervous Apparatus. Johns Hopkins Hospital Reports, Vol. XI.

{{Ref-BardeenLewis1901}}

BOLK, L.: Die Segmentaldifferenzierung des menschlichen Rumpfes und seiner Extremitaten. Morph. Jahrbuch, Bd. XXV, 1898.

FUTAMURA, R.: Ueber die Entwickelung der Facialismuskulatur des Menschen. Anat. Hefte, XXX, 1906.

GODLEWSKI, E.: Die Entwickelung des Skelet- und Herzmuskelgewebes der Saugetiere. Arch. f. mik. Anat., Bd. LX, 1902.

GRAFENBERG, E.: Die Entwickelung der menschlichen Beckenmuskulatur. Anat. Hefte, 1904.

HEIDENHAIN, M.: Structur der contractilen Materie. Ergebnisse der Anat. u. Entwick., Bd. VIII, 1898.

HEIDENHAIN, M.: Ueber die Structur des menschlichen Herzmuskels. Anal. Anz., Bd. XX, 1901.

KASTNER, S.: Ueber die Bildung von animalen Muskelfasern aus dem Urwirbel. Arch. f. Anat. u. Physiol., Anat. Abth., Suppl., 1890.

KEIBEL, F., and MALL, F. P.: Manual of Human Embryology, Vol. I, 1910.

KOLLMANN, J.: Die Rumpfsegmente menschlicher Embryonen von 13-35 Urwirbeln. Arch. f. Anat. u. Physiol., Anat. Abth., 1891.

{{Ref-Lewis1902}}

MAURER, F.: Die Entwickelung des Muskelsystems und der elektrischen Organe. Also Bibliography. In Hertwig's Handbuch der vergl. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil I, 1904.

MACCALLUM, J. B.: On the Histology and Histogenesis of the Heart-muscle Cell. Anat. Anz., Bd. XIII, 1897.

MACCALLUM, J. B.: On the Histogenesis of the Striated Muscle Fiber and the Growth of the Human Sartorius Muscle. Johns Hopkins Hospital Bulletin, Vol. IX, 1898.

MALL, F. P. : Development of the Ventral Abdominal Walls in Man. Jour, of Morphology, Vol. XIV, 1898.

McGiLL, CAROLINE: The Histogenesis of Smooth Muscle in the Alimentary Canal and Respiratory Tract of the Pig. Internal. Monatsch. Anat. u. Phys., Bd. XXIV, 1907.

MCMURRICH, J. P. : The Phylogeny of the Forearm Flexors. American Jour, of Anat., Vol. II, 1903.

MCMURRICH, J. P.: The Phylogeny of the Palmar Musculature. American Jour, oj Anat., Vol. II, 1903.

MCMURRICH, J. P.: The Phylogeny of the Crural Flexors. American Jour, of Anat., Vol. IV, 1904.

MCMURRICH, J. P.: The Phylogeny of the Plantar Musculature. American Jour, oj Anat., Vol. VI, 1907.

POPOWSKY, I.: Zur Entwickelungsgeschichte der Dammmuskulatur beim Menschen. Anat. Hefte, 1899.

SUTTON, J. B.: Ligaments, Their Nature and Morphology. London, 1897.

ZIMMERMANN: Ueber die Metamerie des Wirbeltierkopfes. Verhandl. d. Anat. Gesettsch. Jena, 1891.

{{Bailey_1921_Footer}}

Book - Text-Book of Embryology 10

2024-01-25T00:37:45Z

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=The development of the vascular system=

The blood vessels constitute such an extensive and complex system that it is obviously beyond the scope of this book to consider the entire system in detail. Consequently attention must be directed only to the development of the main channels, including the heart, and to the principles of vessel formation.

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[[File:Bailey156.jpg|600px]]

'''Fig. 156. Surface views of chick blastoderms.''' Ruckert, Hertwig.

:a, Blastoderm with primitive streak and head process; showing blood islands (dark spots in crescent-shaped area in lower part of figure).

:b, Blastoderm with 6 pairs of primitive segments. Reticulated appearance is due to blood islands (dark spots) and to developing vessels, the entire reticulated area being the area vasculosa.

The formation of blood vessels in all the higher vertebrates including mammals begins in the opaque area of the blastoderm (area opaca) while the germ layers still lie flat. Toward the end of the first day of incubation in the chick, about the time the primitive streak reaches the height of its development, the peripheral part of the area opaca caudal and lateral to the primitive streak presents a mottled appearance (Fig. 1560). This indicates the beginning of the area vasculosa, which subsequently extends forward in the peripheral portion of the opaque area, lateral to the developing body, and becomes reticulated in appearance (Fig. 156^).
<div id="Fig157"></div>
[[File:Bailey157.jpg|Thumb|'''Fig. 157. Section of blastoderm (area opaca) of chick of 27 hours' incubation.''' Photograph.]]

Sections of the blastoderm show that the mottled surface appearance is due to clusters of cells amidst the mesoderm, known as blood islands (Fig. 157). These are composed of rounded cells which have developed from the branched mesodermal (mesenchymal) cells, and are situated in close apposition to the entoderm. Subsequently, when the coelom appears in this region, they lie in the visceral, or splanchnic, layer of mesoderm (Fig. 158).

The early changes that occur in the blood islands are important as regards both developing vessels and blood cells. The superficial cells of an island are transformed into flat cells placed edge to edge which surround the remaining rounded cells. The flat cells constitute the endothelium of a primitive blood space, while the cells within the space comprise primitive blood cells (Fig. 158). These early spaces in the area vasculosa join one another and become continuous to form a net-work, or plexus, of channels to which is due the reticulated appearance referred to above (Fig. 1566). This is known as the vitelline plexus. The groups of primitive blood cells within the channels will be considered in detail in a subsequent section (page 236).

<div id="Fig158"></div>
[[File:Bailey158.jpg|600px]]

'''Fig. 158. Section of blastoderm of chick of 42 hours' incubation.''' Photograph. The cells of the blood islands are differentiated into primitive blood cells and the endothelium of the vessels.

During the second day of incubation in the chick the peripheral channels of the vascular area unite to form a vessel the sinus terminalis which is continuous around the border except at the head end of the embryo (Fig. 159). At the same time the vascularization of the visceral layer of mesoderm gradually extends through the clear area of the blastoderm (area pellucida) toward and finally into the embryonic body. Reaching the region just lateral to the notocord, the vessels unite longitudinally in the embryo to form a continuous channel, the primitive aorta, which thus constitutes a natural selvage to the vascular area on each side of the blastoderm (Fig. 159). Some of the channels of the vitelline plexus increase in size and coalesce to form a large trunk which is a branch of the primitive aorta on each side and leads off into the smaller vessels in the peripheral part of the vascular area. This trunk is known as the vitelline, or omphalomesenteric, artery and is at first located near the caudal end of the embryo. When circulation is established through contractions of the heart it carries blood from the aorta to the surface of the yolk sac (Fig. 159). Other channels of the vitelline plexus nearer the head end of the embryo likewise form a large trunk, the vitelline, or omphalomesenteric, vein which collects the blood from the surface of the yolk sac and conveys it to the heart (Fig. 159).

So long as the germ layers lie flat the two primitive aortae remain separate, but with the ventral flexion and fusion of the germ layers to form the tubular body the aortae fuse into a single medial vessel, the dorsal aorta, except in the cervical region where the two original vessels persist as the dorsal aortic roots. The proximal ends of the vitelline arteries also fuse into a single trunk, the two vitelline veins, however, remaining separate. In each branchial arch on each side a vessel develops which joins with the corresponding dorsal aortic root. These vessels the aortic arches arise from single vessel on each side ventral to the pharynx which is known as the ventral aortic root. The two ventral aortic roots arise from a single medial vessel, the aortic trunk, or truncus arteriosus, which in turn is a continuatioi of the early tubular heart.

<div id="Fig159"></div>
[[File:Bailey159.jpg|600px]]

'''Fig. 159. Dorsal surface view of chick embryo with 18 segments, including the area vasculosa.''' Photograph, X 15. The blood vessels were injected with India ink, the dark blotch in the upper left corner indicating some ink which escaped during the injection.

The heart, having developed and become a contractile organ in the meantime, receives the blood in its caudal end through the vitelline veins and ejects it from its cephalic end through the aortic trunk. The blood then passes through the aortic arches to the dorsal aorta whence it is distributed to the vitelline plexus by the vitelline arteries. The blood is collected by tributaries of the vitelline veins and carried to the heart. Thus the vitelline (yolk) circulation is completed (Fig. 160). From this time on, the area vasculosa gradually enlarges, as the germ layers extend farther and farther around the yolk, until it eventually surrounds the whole yolk mass. In mammals, as in the chick, the vascular rudiments develop first in the extraembryonic portion of the mesoderm as clusters of cells which give the area opaca a mottled appearance on surface view. This soon changes to a reticulated appearance as the cell clusters give rise to primitive blood spaces which join one another to form a plexus of channels. This plexus gradually extends across the area pellucida toward the embryo and terminates in a natural selvage as the primitive aorta on each side of the median line. The vitelline arteries and veins are formed out of the plexus and, with the heart, aortic arches and dorsal aorta as in the chick, constitute the vitelline circulatory system (Fig. 161). The vascular area in some mammals gradually enlarges until it embraces the "entire yolk sac (Fig. 162).

<div id="Fig160"></div>
[[File:Bailey160.jpg|600px]]

'''Fig. 160. Diagram of the vitelline (yolk) circulation of a chick embryo at the end of the third day of incubation.''' Ventral view. Balfour.

<div id="Fig161"></div>
[[File:Bailey161.jpg|600px]]

'''Fig. 161. Surface view of area vasculosa of a rabbit embryo of 11 days.''' van Beneden and Julin. The vessel around the border is the sinus terminalis; the two large vessels above the embryo are the vitelline (omphalomesenteric) veins ; the two large vessels converging below the embryo are the vitelline (omphalomesenteric) arteries.

<div id="Fig162"></div>
[[File:Bailey162.jpg|600px]]

'''Fig. 162. Human embryo of 3.2 mm.''' His. The arrows indicate the direction of the blood current.

It is seen from the foregoing account that the earliest circulation is associated with the yolk sac. In animals below the mammals, where a large amount of yolk is present in the sac, the vitelline circulation is of prime importance in supplying the growing embryo with nutritive materials. In mammals the vitelline circulatory system develops as extensively as in the lower forms but, since little yolk is present, does not assume the same important role of carrying food supply; yet the portions of the vessels inside the embryo, viz. : the heart, aortic arches, aorta, the proximal part of the vitelline artery, and the vitelline veins, form parts of the permanent vascular system. In reptiles and birds a second set olyessels develops in connection with the allantois and serves to carry away the waste products of the body and deposit them in that sac-like structure. Two arteries, one on each side, arise as branches of the dorsal aorta near its caudal end and pass out of the body along with the allantoic duct to ramify upon the surface of the allantois. These are the umbilical, or allantoic, arteries. The blood is collected and carried back by the umbilical veins which pass along the 'allantoic duct to the body and then forward, one on each side, through the somatic layer of mesoderm to join the ducts of Cuvier. The duct of Cuvier, formed on each side by the junction of the anterior and posterior cardinal veins, which will be considered in a subsequent section, pour their blood into the sinus venosus. This venous trunk is formed by the junction of the ducts of Cuvier with -the vitelline veins and empties directly into the heart.

<div id="Fig163"></div>
[[File:Bailey163.jpg|600px]]

'''Fig. 163. Diagram of the umbilical vessels in the belly stalk and chorion.''' Kollmann's Atlas.

In mammals in general the allantois is a rudimentary structure incapable of receiving the total waste of the embryo. The umbilical (allantoic) vessels develop, however, as in reptiles and birds but become associatec through the belly stalk with the placenta which establishes communication between the embryo and the mother (Fig. 163). The vessels within the embryo are at first disposed in the same manner as in the lower forms, the umbilical arteries arising from the caudal portion of the aorta and the umbilical veins passing forward in the ventro-lateral body wall to join the ducts of Cuvier. With the formation of the umbilical cord the two umbilical veins within this structure fuse into a single vessel (Fig. 164). The later changes in the umbilical veins are most conveniently considered subsequently. In mammals in general the umbilical (allantoic) circulatory system performs a two-fold function. The blood carries to the placenta the waste products of the embryo for deposition in the maternal circulation, the waste in the lower forms (reptiles and birds) being deposited in the allantois. The blood carries from the placenta the food materials derived from the maternal circulation, the food in the lower forms being taken from the yolk sac and conveyed to the embryo by the vitelline vessels.

<div id="Fig164"></div>
[[File:Bailey164.jpg|600px]]

'''Fig. 164. Reconstruction of a human embryo of 7 mm.''' Mall.

:Arteries represented in black. A.V., Auditory vesicle; B, bronchus; L, liver; K, anlage o kidney; T, thyreoid gland; III-XII, cranial nerve roots; 1, 2, 3, 4, branchial grooves; 1, 8, 12, 5 (on spinal nerve roots), 1st and 8th cervical, 12th dorsal, 5th lumbar spinal nerve respectively. Dotted outlines represent limb buds.

==Principles of Vasculogenesis==

Upon the thesis that tissues in general must receive materials which they build up into their own substances and must discharge the products of their activities, the vascular channels of the body can be considered as structural expressions of this functional necessity. For instance, a muscle which acts must receive materials to compensate it for its loss and must discharge the waste products that result from its action, and the blood vessels are peculiarly adapted to these functions. The lymph vessels, too, similar in structure to the blood vessels, although efferent relative to the tissues, play their part in conveying the products of metabolism.

Much controversy has arisen over the actual genesis, or origin, of blood vessels and lymphatics, and as yet the opposing views have not been reconciled. In brief there are two views: One that with a few exceptions every vessel in the body develops as a sprout from another vessel, that is, the endothelium arises from preexisting endothelium by proliferation of its own cells; the other that vessels in general arise in situ, that is, the lumen of a vessel represents an intercellular tissue space^or several such spaces, whose bordering cells have been transformed into the characteristic endothelial cells, and as a corollary, the continuity of a given vessel results from the union of such spaces. According to the latter view, the whole vascular system represents intercellular tissue spaces which, with their lining of flattened cells, have united to form a set of continuous channels.

In the case of either view it is recognized that the first vessels appear in the opaque area of the blastoderm. Here the blood islands originate as clusters of cells amidst the mesoderm, differentiating from mesenchymal elements in close approximation to the entoderm (Fig. 157). The superficial cells of the clusters are then transformed into flat cells placed edge to edge to form the endothelial wall of a primitive blood space. These blood spaces join one another and thus form a net-work of channels. From this point in development the two views diverge.

The evidence adduced in favor of either theory is too great in volume to set down here. The advocates of the theory of sprouting of the endothelium lay stress upon the evidence of injected specimens. By injecting developing blood vessels at successive stages it is found that the vascular field gradually becomes larger, and the inference is that the individual channels are extending farther and farther from the focus of origin through proliferation and migration of the endothelial elements. This method, of course, would demonstrate vessels only so far as the lumina are continuous. Solid cords of cells which extend beyond the field of injection are interpreted as cords of endothelial cells which subsequently acquire lumina and become capillary tubes. If this theory is correct then the vascularization of the area pellucida and of the embryonic body would be effected through true outgrowths of the original endothelium of the opaque area. Possible exceptions to this, as noted above, are the rudiments of the heart, the aorta and the cardinal veins which arise in situ as do the first vascular rudiments. Observations upon growing vessels in living embryos, in which strands of cells were seen to extend from the endothelium already present, have also been accepted as evidence in favor of this view.

The evidence afforded by injected specimens has been attacked by those who believe in the in situ origin of vessels, on the ground that the injection shows only vessels with continuous lumina and does not prove the nonexistence of isolated vascular rudiments beyond the field of injection. It is claimed that the vascular field becomes more extensive through the gradual addition of such isolated spaces to the channels already continuous, in the same manner that the primitive blood spaces unite to form a network, and the claim is supported by demonstration of these spaces in the mesenchymal tissue with every gradation between the bordering flattened cells (endothelium) and the branching irregular mesenchymal cells. The actual formation of intercellular spaces with flat bordering cells and their union with vascular channels have been observed in the living chick blastoderm. Experimental evidence has also been brought to bear in favor of the view that vessels arise in situ. The area opaca was entirely removed from the chick blastoderm before any vascular rudiments had appeared in the area pellucida and the blastoderm was then allowed to develop further; it was found that vascular rudiments appeared both in the area pellucida and embryonic body with practically the same disposition as in the normal embryo.

The concept that the vascular channels are structural expressions of the functional necessity of carrying nutritive materials to the tissues and waste products away from them leads to consideration of such factors as may be involved in the formation of vessels; that is, factors that would cause plastic cells, like those of the mesenchyme in which the earliest and simplest vessels appear, to change in character and rearrange themselves to form capillary tubes. In a mass of mesenchymal tissue, in which there is a resemblance to a sponge with the cellular elements representing the parenchyma of the sponge and the intercellular tissue spaces the interstices, the products of cell activity naturally accumulate in the intercellular spaces. Incident to this accumulation, pressure would be exerted upon the cells bordering the spaces. Seeking outlet from the confines of the spaces, the waste products would move, or flow, and cause friction against the cells past which they flow. Similarly, pressure and friction would result from the movement of nutritive materials to and through the tissue. The plastic mesenchymal cells, reacting to these mechanical influences, would tend to become flat, and the continued operatic of the factors would result in a smooth- walled tube in which the movement of fluid is greatly facilitated.

The reaction of the irregular mesenchymal cells to the mechanical influences of pressure and friction is, of course, the crux of the question. It has been shown experimentally that cells of this type do react to mechanical stimuli. Smooth non-irritating foreign bodies have been imbedded in the loose connective tissue of an animal and the cells in contact therewith became flat and formed a mosaic apparently identical with simple squamous epithelium or endothelium. In the growth of mesenchymal tissue outside of the body (in vitro) it has been observed that the cells flatten against foreign substances which may be present.

In the embryo it has been observed that where blood vessels disappear, which they do in certain regions, the endothelium does not degenerate but that the cells assume irregular branching forms. This would indicate that endothelium comprises merely modified mesenchymal cells and that upon removal of the factors incident to the pressure and friction of blood flow the cells reassume the indifferent character of mesenchyme, thus reverting to the mesenchymal type. It militates, therefore, against the view that endothelium is a specific tissue.

It is generally recognized, whether or not the endothelium originates in situ, that a capillary network precedes the formation of larger vessels. For instance, the vitelline plexus of capillaries (p. 186) antedates any of the larger vitelline vessels which later carry blood to and from the embryo. The establishment of vascular trunks in this plexus of small vessels seems to be dependent upon the same mechanical factors that were considered as operative in the origin of vessels; viz.: pressure and friction. If the volume of blood that flows through a given capillary network at a given rate is increased the flow will naturally follow the channels that offer the least resistance, and these channels will increase in size sufficiently to accommodate the greater volume. A few channels, or perhaps even only one, will form the most direct course, and the angles in the course will be still further reduced as the blood stream impinges upon the walls of the vessels. In this manner a large vessel, or main vascular trunk, is established and the remaining smaller vessels constitute its branches or tributaries. A rather crude analogy would be the draining of a swamp in which a small rivulet, once gaming slight supremacy over its fellows, would gradually cut its way deeper into the soil and pursue a straighter course, with the result that the other rivulets would flow into it as the main channel.

The concept that the main vascular trunks are preceded by a capillary plexus, out of which they develop in response to certain mechanical stimuli, offers a simple explanation of the numerous variations found in the vascular system. In the incipient stages of the larger vessels but slight influences, due to variations in the development of surrounding structures, would be sufficient to deflect their courses and cause them to occupy positions which do not accord with the normal. So far as the thickened walls of the larger vascular channels are concerned, they may be regarded as structural adaptations to the functions they perform. For example, the large amount of elastic tissue in the wall of the aorta and other large arteries tends to maintain a uniform diameter in these vessels against the force exerted by the blood expelled from the heart at each contraction.

==The Heart==
<div id="Fig165"></div>
[[File:Bailey165.jpg|thumb|300px|'''Fig. 165. Diagrams showing the two anlagen of the heart and their union to form a single structure'''; made from camera lucida tracings of transverse sections of chick embryos. In C the ventral mesocardium has disappeared (see text).]]
The heart has a peculiar origin in that it arises as two separate parts or anlagen which unite secondarily. In the chick, for example, it appears during the first day of incubation, at a time when the germ layers are still flat. The ccelom in the cephalic region becomes dilated to form the so-called primitive pericardial cavity (parietal cavity), and at the same time a space appears on each side, not far from the medial line, in the mesodermal layer of the splanchnopleure (Fig. 165). These spaces at first are filled with a gelatinous substance in which lie a few isolated cells. These cells then take on the appearance of endothelium and line the cavities, and the mesothelium in this vicinity is changed into a distinct, thickened layer of cells. Now by a bending ventrally of the splanchnopleure the cavities or vessels are carried toward the mid ventral line (Fig. 165). The bending continues until the entoderm of each side meets and fuses with that of the opposite side, thus closing in a flat cavity the fore-gut. The entoderm ventral to the cavity breaks away and allows the medial walls of the two endothelial tubes to come in contact. These walls then break away and the tubes are united in the midventral line to form a single tube (Fig. 165), which extends longitudinally for some distance in the cervical region of the embryo. The mesothelial layers of opposite sides meet dorsal and ventral to the endothelial tube, forming the dorsal and ventral mesocardium (Fig. 165). In the meantime the cephalic end of the tube has united with the arterial system, and the caudal end with the venous system ; and in a short time the dorsal and ventral mesocardia disappear and leave the heart suspended by its two ends in the primitive pericardial cavity. The conditions at this point may be summarized thus: The heart is a double-walled tube the inner wall composed of endothelium and destined to become the endocardium, the outer wall of a thicker mesothelial layer and destined to become the myocardium the two walls separated by a considerable space. The organ hangs, as it were, in the primitive pericardial cavity (ccelom), connected at its cephalic end with the ventral aortic trunk and at its caudal end with the omphalomesenteric veins.

In all mammals thus far studied the principle of development in the earlier stages is essentially the same as in the chick. The double origin of the heart is even more marked because of the relatively late closure, of the fore-gut. There are no observations on the origin of the heart in human embryos, but it is reasonable to assume that it has the same double origin as in other Mammals, although in embryos of 2 to 3 mm. the organ has already become a single tube (Figs. 166 and 167). At this stage the tube is somewhat coiled.

<div id="Fig166"></div>
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'''Fig. 166. Transverse section of a human embryo of 2.69 mm.''' von Spee, Kollmann's Atlas.

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'''Fig. 167. Ventral view of reconstruction of human embryo of 2.15 mm.''' His. The ventral body wall has been removed. The vessels (in black) at the sides of the duct of the liver are the omphalomesenteric veins.

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[[File:Bailey168.jpg|thumb|300px|'''Fig. 168.''' Ventral part of transverse section through the heart region of Salamandra maculosa embryo with 4 branchial arches. Rabl.]]

While the double origin of the heart is characteristic of all amniotic Vertebrates (Reptiles, Birds, Mammals), in all the lower forms the organ arises as a single anlage. In the region of the fore-gut the two halves of the ccelom are separated by a ventral mesentery which extends from the gut to the ventral body wall, and which is composed of two layers of mesothelium with a small amount of mesenchyme between them. In the mesenchyme a cavity appears and is lined by a single layer of flat (endothelial) cells. This cavity extends longitudinally for some distance in the cervical region and with its endothelial and mesothelial walls constitutes the simple cylindrical heart. On the dorsal side it is connected with the gut by a portion of the mesentery which is called the dorsal mesocardium; on the ventral side it is connected with the ventral body wall by the ventral mesocardium (Fig. 168). Thus the heart is primarily a single structure. The difference between the two types of development is not a fundamental one but simply depends upon the difference in the germ layers. In the lower forms the germ layers are closed in ventrally from the beginning, and the heart appears in a medial position. In the higher forms the germ layers for a time remain spread out upon the surface of the yolk or yolk sac, and the heart begins to develop before they close in on the ventral side of the embryo. Consequently the heart arises in two parts which are carried ventrally by the germ layers and unite secondarily.

The further development of the heart consists of various changes in the shape of the tube and in the structure of its walls. At the same time the dilatation of the ccelom (primitive pericardial cavity) in the cervical region is of importance in affording room for the heart to grow. In the chick, for example, the tube begins, toward the end of the first day of incubation, to bend to the right; during the second day it continues to bend and assumes an irregular S-shape. This bending process has not been observed in human embryos, but other Mammals show the same process as the chick. In a human embryo of 2.15 mm. the S-shaped heart is present (Fig. 167). The venous end, into which the omphalomesenteric veins open, is situated somewhat to the left, extends cranially a snort distance and then passes over into the ventricular portion. The latter turns ventrally and extends obliquely across to the right side, then bends dorsally and cranially to join the aortic bjulb which in turn joins the ventral aortic trunk in the medial line. The endothelial tube, which is still separated from the muscular wall by a considerable space, becomes somewhat constricted at its junction with the aortic bulb to form the so-called f return Halleri. During these changes the heart as a whole increases in diameter, especially the ventricular portion. Gradually the venous end of the heart moves cranially and in embryos of 4.2 mm. lies in the same transverse plane as the ventricular portion. The latter lies transversely across the body (Fig. 169). At the same time two e vagina tions appear on the venous end, which represent the anlagen of the atria. In embryos of about 5 mm. further changes have occurred, which are represented in Fig. 170. The two atrial anlagen are larger than in the preceding stage and surround, to a certain extent, the proximal end of the aortic trunk. As they enlarge still more in later stages, they come in contact, their medial walls almost entirely disappear, and they form a single chamber. The ventricular portion of the heart becomes separated into a right and a left part by the interventricular furrow (Fig. 1 70) ; the right part is the anlage of the right ventricle, the left part, of the left ventricle. At the same time the atrial portion has moved still farther cranially so that it lies to the cranial side of the ventricular portion. The venous and arterial ends of the heart have thus reversed their original relative positions. At this point it should be noted that the atrial end of the heart is connected with the large venous trunk formed by the union of the omphalomesenteric veins and the ducts of Cuvier the sinus venosus.
{|
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| <div id="Fig170"></div>
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| '''Fig. 169. Ventral view heart of human embryo of 4.2 mm.'''

:His. The atria are hidden behind the ventricular portion.
| '''Fig. 170. Ventral view of heart of human embryo of 5 mm.''' His.
|}
During the changes in the heart as a whole, certain changes also occur in the endothelial and muscular walls. The walls of the atria are composed of compact plates of muscle with the endothelium closely investing the inner surface. The walls of the ventricular portion, on the other hand, become thicker and are composed of an outer compact layer of muscle and an inner layer made up of trabeculae which are closely invested by the endothelium.

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'''Fig. 171. Dorsal half of heart (seen from ventral side) of a human embryo of 10 mm.''' His.

Everywhere the endothelium is closely applied to the inner surface of the myocardium, the space which originally existed between the endothelium and mesothelium being obliterated.

The embryonic heart in Mammals in the earlier stages resembles that of the adult in the lower Vertebrates (Fishes). The atrial portion receives the blood from the body veins and conveys it to the ventricular portion which in turn sends it out through the arteries to the body. The circulation is a single one. This condition changes during the foetal life of Mammals with the development of the lungs. The same transition occurs in the ascending scale of development in the vertebrate series in those forms in which gill breathing is replaced by lung breathing. The change consists of a division of the heart and circulation, so that the single circulation becomes a double circulation. In other words, the heart, is so divided that the lung (pulmonary) circulation is separated from the general circulation of the body. This division first appears in the Dipnoi (Lung Fishes) and Amphibians in which gill breathing stops and lung breathing begins, although here the division is not complete. In Reptiles the division is complete except for a small direct communication between the ventricles.

Fig. 171 represents the dorsal half of the heart at a stage when all the chambers are in open communication, and shows the conditions in a single circulation but with the beginning of a separation. The atria are rather thin-walled chambers, the ventricles have relatively thick walls. Between the atrial and ventricular portion is a canal the atrio-ventricular canal which affords a free passage for the blood. From the cephalic side of the atrial portion a ridge projects into the cavity. This ridge represents a remnant of the original medial walls of the two atria and marks the beginning of the future atrial septum. The opening of the sinus venosus is seen on the dorsal wall of the right atrium. Primarily both atria communicated directly with the sinus venosus,but in the course of development the opening of the latter migrated to the right and at this stage is found in the wall of the right atrium. The opening is guarded, as it were, by a lateral and a medial fold the significance of which will be described later. The vetricular portion also shows a ridge projecting from the caudal side, which corresponds to the interventricular groove and represents the beginning of the ventricular septum.

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'''Fig. 172. Dorsal half of heart showing chambers and septa.''' (Semidiagrammatic.) Modified from Born.

===The Septa===

The further changes are largely concerned with the separation of the heart into right and left sides, and with the development of the valves. The atria become separated by the further growth on the cephalic side, of the ridge which has already been mentioned and which is known as the septum superius (Figs. 171 and 172). This septum grows across the cavity of the atria until it almost reaches the atrio-ventricular canal, forming the septum atriorum. A portion of the septum then breaks away, leaving the two atria still in communication. This secondary opening is the foramen ovale which persists throughout foetal life, but closes soon after birth. The atrio-ventricular canal also becomes divided into two passages by a ridge from the dorsal wall and one from the ventral wall uniting with each other and finally with the septum atriorum (Fig. 172). Thus the two atria would be completely separated if it were not for the foramen ovale.

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'''Fig. 173. Dorsal half of heart (ventral view) of rabbit embryo of 5.8 mm.''' Born.

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'''Fig. 174. Ventricles and proximal ends of aorta and pulmonary artery of a 7.5 mm human embryo.''' Lower walls of ventricles have been removed. Kollmann's Atlas.

During the separation of the atria, a division of the ventricular portion of the heart also occurs. On the caudal side of the ventricular portion a septum appears and gradually grows across the cavity forming the septum ventriculorum (Figs. 171 and 172). This septum is situated nearer the right side and is indicated on the outer surface by a groove which becomes the sulcus longitudinalis anterior and posterior. The dorsal edge of this septum finally fuses with the septum dividing the atrio-ventricular canal, but for a time its ventral edge remains free, leaving an opening between the two ventricles (Figs. 173 and 174).

This opening then becomes closed in connection with the division of the aortic bulb and ventral aortic trunk. On the inner surface of the aortic trunk, at a point where the branches which form the pulmonary arteries arise, two ridges appear, grow across the lumen and fuse with each other, thus dividing the vessel into two channels. This partition the septum aorticum (Fig. 175) gradually grows toward the heart through the aortic bulb and finally unites with the ventral edge of the ventricular septum, thus closing the opening between the two ventricles. Corresponding with the edges of the septum aorticum, a groove appears on each side of the aortic trunk and gradually grows deeper and extends toward the heart, until finally the trunk and aortic bulb are split longitudinally into two distinct vessels, one of which is connected with the right ventricle and becomes the pulmonary artery, the other with the left ventricle and becomes the proximal part of the aortic arch (Fig. 174). The result of the formation of these various septa is the division of the entire heart into two sides. The atrium and ventricle of each side are in communication through the atrio- ventricular foramen, the two sides are in communication only by the foramen ovale which is but a temporary opening.

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'''Fig. 175. Diagrams representing the division of the ventral aortic trunk into aorta and pulmonary artery and the development of the semilunar valves.''' Hochsietter.

After the opening of the sinus venosus is shifted to the right atrium, the left atrium for a short period has no vessels opening into it. As soon, however, as the pulmonary veins develop, they form a permanent union with the left atrium (Fig. 173). At first two veins arise from each lung, which unite to form a single vessel on each side; the two single vessels then unite to form a common trunk which opens into the left atrium on the cephalic side. As development proceeds, the wall of the single trunk is gradually absorbed in the wall of the atrium, until the single vessel from each side opens separately. Absorption continuing, all four veins, two from each lung finally open separately. This is the condition usually found in the adult. A partial failure in the absorption may leave one, two, or three vessels opening into the atrium. Such variations are not infrequently met with in the pulmonary veins.

===The Valves===

If all the passageways between the different chambers of the heart and the large vascular trunks were to remain free and clear, there would be nothing to prevent the blood from flowing contrary to its proper course. Consequently five sets of valves develop in relation to these orifices, and are so arranged that they direct the blood in a certain definite direction. These appear (a) at the openings of the large venous trunks into the right atrium, (b) at the opening between the right atrium and right ventricle, (c) at the opening between the left atrium and left ventricle, (d) at the opening between right ventricle and pulmonary artery and (e) at the opening between the left ventricle and aorta. No valves develop at the openings of the pulmonary veins into the left atrium.

(a) The sinus venosus (which is formed by the union of the large body veins) opens into the right atrium on its cranial side, as has already been mentioned (p. 201). By a process of absorption, similar to that in the case of the pulmonary veins, the wall of the sinus is taken up into the wall of the atrium. The result is that the vena cava superior, vena cava inferior, and sinus coronarius (a remnant of the left duct of Cuvier) open separately into the atrium. As the sinus is absorbed, its wall forms two ridges on the inner surface of the atrium, one situated at the right of the opening and one at the left (Figs. 172 and 173). These two ridges valvulce venosce are united at their cranial ends with the septum spurium (Fig. 171), a ridge projecting from the cephalic wall of the atrium. The septum spurium probably has a tendency to draw the two valves together and prevent the blood from flowing back into the veins. The left valve and the septum spurium later atrophy to a certain extent and probably unite with the septum atriorum to form part of the limbus fossce ovalis (Vieussenii) . The right valve is the larger and in addition to its assistance in preventing a backward flow of blood into the veins, it also serves to direct the flow toward the foramen o\;ale. As the veins come to open separately, the cephalic part of the right valve disappears; the greater part of the remainder becomes the valvula Deuce cavce inferioris (Eustachii) and during fcetal life directs the blood toward the foramen ovale. In the adult it becomes a structure of variable size. A small part of the remainder of the right valve forms the valvula sinus coronarii (Thebesii) which guards the opening of the coronary sinus.

(b) and (c) The valves between the atrium and ventricle on each side develop for the most part from the walls of the triangular atrio-ventricular opening (ostium atrio-ventriculare) . Elevations or folds appear on the rims of the openings and project into the cavities of the ventricles where they become attached to the muscle trabeculae of the ventricle walls (Figs. 176 and 177). On the right side three of these folds appear, and develop into the valvula tricuspidalis which guards the right atrio-ventricular orifice. On the left side only two folds appear, and these become the valvula biscuspidalis (mitralis) which guards the left atrio-ventricular orifice. These valves, which are at first muscular, soon change into dense connective tissue. The muscle trabeculae to which they are attached also undergo marked changes. Some become condensed at the ends which are attached to the valves into slender tendinous cords the chorda tendinece, while at their opposite ends they remain muscular as the Mm. papillares; others remain muscular and lie in transverse planes in the ventricles, or fuse with the more compact part of the muscular wall, or form irregular, anastomosing bands and constitute the Irabecula carnea (Fig. 176).

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'''Fig. 176. Diagrams representing the development of the atrio-ventricular valves, chordae, tendineas, and papillary muscles.''' Gegenbaur.

(d) and (e) The valves of the pulmonary artery and aorta develop at the point where originally the endothelial tube was constricted to form the f return Halleri (p. 200) where the ventricular portion of the heart joined the aortic bulb. Before the aortic trunk and bulb are divided into the aortic arch and pulmonary artery, four protuberances appear in the lumen (Fig. 213). The septum aorticum then divides the two which are opposite so that each vessel receives three (Fig. 175). These then become concave on the side away from the heart, in a manner which has not been fully determined, and at the same time enlarge so that they close the lumen. Those in the pulmonary artery are known as the valvula semilunares arteria pulmonalis, those in the aorta as the valvula semilunares aorta.

===Changes after Birth===

The migratory changes of the heart from its original position in the cervical region to its final position in the thorax will be considered in connection with the development of the pericardium (Chap. XIV). With the exception of the septum atriorum, the heart acquires during fcetal life practically the form and structure characteristic of the adult (Fig. 178). So long as the individual continues to grow, the heart, generally speaking, increases in size accordingly. This increase takes place by intussusception in the endocardium and myocardium. At the time of birth the two atria are in communication through the foramen ovale which is simply an orifice in the atrial septum (Fig. 179). Thus the blood which is brought to the right atrium by the body veins is allowed to pass directly into the left atrium, thence to the left ventricle, and thence is forced out to the body again through the aorta. A certain amount of blood also passes from the right atrium into the right ventricle and thence into the pulmonary artery; but this blood does not enter the lungs but passes directly into the aorta through the ductus arteriosus (Fig. 178). After birth the lungs begin to function and the placental blood is cut off, so that the right atrium receives venous blood only and the left arterial blood only. If the foramen ovale were to persist it would allow a mingling of venous and arterial blood. Consequently the foramen ovale closes soon after birth and the two currents of blood are completely separated. At the same time the ductus arteriosus atrophies and becomes the ligamentum arteriosum. Consequently there is no direct communication between the pulmonary artery and aorta.

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'''Fig. 177. Transverse section of pig embryo of 14 mm.''' Photograph.

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'''Fig. 178. Ventral view of heart of foetus at term.''' Kollmann's Atlas.

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'''Fig. 179. Dorsal half of foetal heart.''' Bumm, Kollmann's Atlas.

Certain features of development have an important bearing on the theories regarding the physiology of the heart, particularly on the theory that the heart is an automatic organ. Whether the theory that the heart beats automatically, i.e., independently of stimuli from the nervous system, is true or not, it is a fact that in the embryo it begins to beat before any nerve cells appear in it and before any nerve fibers are connected with it. At least no technic has yet been devised by which it is possible to demonstrate nerve cells in, or fibers connected with it, at the time when it begins to perform its characteristic function. And, furthermore, at the time when the heart begins to beat, no heart muscle cells are developed. This last fact seems to indicate an inherent contractility in the mesothelial cells which form the anlage of the myocardium.

===The Arteries===

The simplest condition of the arterial system, following the establishment of the vitelline and allantoic circulation (p. 189 and p. 191), is as follows: The single ventral aortic trunk is given off from the cephalic end of the heart. This is a short vessel, soon dividing into the two vejntral aortic roots which pass forward beneath the pharynx (Fig. 180). Each ventral aortic root gives rise to branches which pass dorsally, one in each branchial arch, as the aortic arches to unite in a common stem along the dorsal wall of the pharynx. This common stem is the dorsal aortic root (Fig. 1 80) which fuses with its fellow of the opposite side in the middorsal line to form the dorsal aorta. The single dorsal aorta, situated ventral to the notochord, extends from the cervical region to the caudal end of the embryo. Somewhat caudal to the middle of the embryo a branch of the aorta passes ventrally through the mesentery as the vitelline artery which enters the umbilical cord (Fig. 164). Still farther caudally the paired umbilical (allantoic) arteries are given off from the aorta and pass out into the umbilical cord (Fig. 164).

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'''Fig. 180. From reconstruction of aortic arches (i, 2, 3, 4, 6) of left side and pharynx of a 5 mm human embryo.''' Tandler. I-IV, Inner branchial grooves.

The conditions which exist at this stage in the region of the aortic arches in mammalian embryos are indicative of the conditions which persist as a whole or in part throughout life in the lowest Vertebrates. The changes which occur in Mammals, however, are profound and the adult condition bears no resemblance to the embryonic. Yet certain features in the adult are intelligible only from a knowledge of their development. In the human embryo ,ix aortic arches appear on each side. The first, second, third, and fourth pass through the corresponding branchial arches. The fifth arch, which is merely a loop from the fourth, seems to pass through the fourth branchial arch. The sixth aortic arch passes through the region behind the fourth branchial. All these arches are present in embryos of 5 mm. (Fig. 180). In Fishes and larval Amphibians, where the branchial arches develop into the gills, the aortic arches are broken up into capillary networks which ramify in the gills, and the ventral aortic root becomes the afferent vessel, the dorsal aortic roots the efferent vessels. In the higher Vertebrates and in man the aortic arches begin, at a very early period, to undergo changes; some disappear and others become portions of the large arterial trunks which leave the heart. In connection with the following description, constant reference to Figs. 181 and 182 will assist the student in understanding <he changes.

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'''Fig. 181. Diagram of the aortic arches of a Mammal.''' Modified from Hochstetter.

The first and second arches soon atrophy and disappear. The third arch on each side becomes the proximal part of the internal carotid artery, while the continuation of the dorsal aortic root, cranially to the third arch, becomes its more distal part. The continuation of the ventral aortic root cranially to the third, arch, becomes L the proximal artery, while the portion of the ventral aortic root between the third and fourth arches becomes the common carotid artery. The portion of the dorsal aortic root between the third and fourth arches disappears. The fourth aortic arch on the left side enlarges and becomes the arch of the aorta (arcus aorta) which is then continued caudally through the left dorsal aortic root into the dorsal aorta. On the right side, the fourth arch becomes the proximal part of the subclavian artery. Since the third, foutth, fifth, and 'sixth arches really leave the ventral aortic trunk as a single vessel, it will be seen that these changes bring it about that the common carotid and subclavian on the right side arise by a common stem, the innominate artery, which in turn is a branch of the arch of the aorta. On the left side, for the same reason, the common carotid is a branch of the arch of the aorta. The fifth aortic arch from the beginning is rudimentary and disappears very early. The sixth arch on each side undergoes wide changes. A branch from each enters the corresponding lung. On the right side the portion of the sixth arch between the branch which enters the lung and the dorsal aortic root disappears, as does also that portion of the right dorsal aortic root between the subclavian artery and the original bifurcation of the dorsal aorta. On the left side, however, that portion of the sixth arch between the branch which enters the lung and the dorsal aortic root persists until birth as the ductus arteriosus (Botalli). This conveys the, blood from the right ventricle to the aorta until the lungs become functional (Fig. 178); it then atrophies and becomes the ligamentum arteriosum. In the meantime the septum aorticum has divided the original ventral aortic trunk into two vessels (see p. 204); one of the vessels communicates with the left ventricle and is the proximal part of the arch of the aorta, the other communicates with the right ventricle and becomes the large pulmonary artery (fig. 174).

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'''Fig. 182. Diagram representing the changes in the aortic arches of a Mammal.''' Compare with Fig. 181. Modified from Hochstetter.

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'''Fig. 183. Diagram of the aortic arches (III, IV, VI) and segmental cervical arteries of a 10 mm human embryo.''' His.

In human embryos of 10 mm. the dorsal aortic root on each side gives off several lateral branches the segmental cervical vessels (Fig. 183). The first of these (first cervical, suboccipital), which arises nearly opposite the fourth aortic arch, is a companion, as it were, to the hypoglossal nerve, and J sends a branch cranially which unites with its fellow of the opposite side inside the skull to form the basilar artery. The basilar artery again bifurcates and each branch unites with the corresponding internal carotid by means of the circulus arteriosus (Fig. 185). The other segmental cervical vessels arise from the aortic root at intervals, the eighth arising near the point of bifurcation of the aorta. In a short time a longitudinal anastomosis appears between these segmental arteries, which extends as far as the seventh (Fig. 184). The proximal ends of the first six disappear, and the longitudinal vessel forms the vertebral artery which then opens into the aortic root through the seventh segmental artery, and which is continued cranially as the basilar artery (Fig. 185). The seventh (it is held by some to be the sixth) segmental artery becomes the subclavian, and consequently the vertebral opens into the subclavian, as in the adult (Fig. 184). But it should be borne in mind that the right subclavian artery is more than equivalent to the left, since the proximal part of the former is made up of the fourth aortic arch and a part of the aortic root (see Figs. 181 and 182). Furthermore, changes occur in the position of the heart during development, which alter the relations of the vessels. The heart migrates from its original position in the cervical region into the thorax, and this produces an elongation of the carotid arteries and an apparent shortening of the arch of the aorta; consequently the subclavian artery on the left side arises relatively nearer the heart.

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'''Fig. 184. Diagram illustrating the formation of the vertebral and superior intercostal arteries'''. The broken lines represent the portions of the original segmental vessels that disappear. Modified from Hochstetter.

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'''Fig. 185. Brain and arteries of a human embryo of 6 mm(?).''' Mall.

The arteries of the brain arise as branches of the internal carotid and circulus arteriosus. The anterior cerebral artery and the middle cerebral artery arise primarily from a common stem which in turn is a branch of the most cranial part of the internal carotid (Figs. 185 and 186). The posterior cerebral artery arises as a branch of the circulus arteriosus (Fig. 185).

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'''Fig. 186. Brain, arteries and veins of a human embryo of 33 mm.''' Mall

From the point of its bifurcation to its caudal end the aorta gives off paired, segmental branches which accompany the segmental nerves. The last (eighth) cervical branch and the first two thoracic branches undergo longitudinal anastomoses, similar to those between the first seven cervical, to form the superior intercostal artery (A. intercostalis suprema) which opens into the subclavian (Fig. 184). The other thoracic branches persist as the intercostal arteries; the lumbar branches persist as the lumbar arteries. At the same time anastomoses are formed between the distal ends of the intercostal and lumbar arteries in the ventro-lateral region of the body wall, which give rise, on the one hand, to the internal mammary artery and, on the other hand, to the inferior epigastric artery. Of these two the former opens into the subclavian, the latter into the external iliac. By a further anastomosis the distal ends of the internal mammary and inferior epigastric are joined, thus forming a continuous vessel from the subclavian to the external iliac (Fig. 187). It is interesting to note that while originally all the lateral branches of the aorta are arranged segmentally, many of them lose their segmental character and are replaced or supplemented by longitudinal vessels.

In addition to the dorsal segmental branches of the aorta, which have been described, other branches develop which carry blood to the viscera. A number of these, or possibly all, are also primarily segmental vessels, although they lose every trace of their segmental character during development. The first of the visceral branches to appear is the omphalomesenteric artery which arises from the ventral side of the aorta and which has been mentioned in connection with the vitelline circulation. Originally it passes out through the mesentery and follows the yolk stalk to ramify on the surface of the yolk sac. But since the yolk sac is of slight importance, the distal part of the artery soon disappears, while the proximal part becomes the superior mesenteric artery (Fig. 188). The cceliac artery arises from the ventral side of the aorta a short distance cranially to the omphalomesenteric (Fig. 1 88) and gives rise in turn to the gastric, hepatic and splenic arteries. The inferior mesenteric artery also arises from the ventral side of the aorta some distance caudal to the omphalomesenteric (Fig. 188). In the early stages these visceral arteries arise relatively much farther cranially than in the adult. During development they gradually migrate caudally to their normal positions.

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'''Fig. 187. Diagram of human embryo of 13 mm.''' Showing the mode of development of the internal mammary and inferior epigastric arteries. Mall.

Other branches of the aorta develop in connection with the urinary and genital organs. Several lateral branches supply the mesonephroi, but when the latter atrophy and disappear the vessels also disappear. A periaortic plexus of vessels, with many branches from the aorta, supplies the developing kidneys until these organs reach their definitive position, when one of the branches on each side enlarges to become the renal artery. The developing genital glands are likewise supplied by several branches from the aorta. Later the majority of these vessels disappear, one pair only persisting as the internal spermatic arteries which differ in accordance with the sex of the individual. In both sexes they are at first very short; in the female, as the ovaries move farther into the pelvic region, they become considerably elongated to form the ovarian arteries; in the male, with the descent of the testes, they become very much elongated to form the testicular arteries.

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'''Fig. 188. Diagram of the visceral arteries in a human embryo of 12.5 mm.''' Numerals indicate segmental arteries.
Tandler.

The fifth (or fourth?) pair of segmental lumbar arteries primarily gives rise to the vessels which supply the lower extremities, viz., the iliac arteries. These then would be serially homologous to the subclavians. But certain changes occur in this region, which are due to the relations of the umbilical arteries. The latter, as has already been noted, arise as paired branches of the aorta in the lumbar region, pass ventrally through the genital cord (Chap. XV) and then follow the allantois (urachus) to the umbilical cord.

During foetal life they carry all the blood that passes to the placenta. At an early period a branch from each iliac artery anastomoses with the corresponding umbilical, and the portion of the umbilical artery between the aorta and the anastomosis then disappears. This makes the umbilical artery a branch of the iliac; and the blood then passes from the aorta into the proximal part of the liiac which becomes the common iliac artery of the adult. At birth, when the umbilical cord is cut, the umbilical arteries no longer carry blood to the placenta, and their intraembryonic portions, often called the hypogastric arteries, persist only in part; their proximal ends persist as the superior vesical arteries, while the portions which accompanied the urachus degenerate to form the lateral umbilical ligaments.

So far as a complete history of the growth of the arteries of the extremities is concerned, knowledge is lacking. The facts of comparative anatomy and the anomalies which occur in the human body have led to certain conclusions which have been largely confirmed by embryological observations; but much more work on the development of the arteries is yet necessary to complete their history. The extremities represent outgrowths from several segments oft the body, the nerve supply is derived from several segments, and the limb buds are likewise primarily supplied by plexuses of vessels arising from several branches of the aorta. In the upper extremity the subclavian, which represents the seventh cervical branch of the aortic root, is the single vessel which eventually develops out of the original plexus. In the lower extremity the common iliac, which represents the fifth lumbar branch of the aorta, is the single vessel which develops out of the plexus supplying the lower limb bud.

In the upper extremity the subclavian grows as a single vessel to the wrist and then divides into branches corresponding to the fingers. In the forearm it lies between the radius and ulna. In a short time a branch is given off just distal to the elbow and accompanies the median nerve. As this branch increases, the original vessel in the forearm diminishes to form the volar interosseous artery; and at the same time the branch unites again with the lower end of the interosseous, takes up the digital branches and becomes the chief vessel of the forearm at this stage, forming the median artery. Later, however, it diminishes in size as another vessel develops, the ulnar artery, which arises a short distance proximal to the origin of the median and, passing along the ulnar side of the forearm, unites with the median to form the superficial volar arch. From the artery of the arm, which is called the brachial artery, a branch develops about the middle and extends distally along the radial side of the forearm. A little later another branch grows out from the brachial just proximally to the origin of the ulnar and extends across to, and anastomoses with, the first branch. Then the portion of the first branch between its point of origin and the anastomosis atrophies, leaving only a small vessel which goes to the biceps muscle. The second branch and the remaining part of the first branch together form the radial artery (Fig. 189) (McMurrich).

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Fig. 189. Diagrams showing (A) an early and (B) a late stage in the development of the arteries of the upper extremity. McMurrich.

In the lower extremity the primary artery is a continuation of the common iliac which, in turn, is a branch of the aorta. This primary vessel, the sciatic artery, passes distally as far as the ankle. Below the knee it gives off a short branch which corresponds to the proximal part of the anterior tibial artery. Just above the ankle it gives off another branch which corresponds to the distal part of the anterior tibial. As will be seen, these two parts join at a later period to form a continuous vessel. At this early stage the external iliac artery is but a small branch of the common iliac; but it gradually increases in size, extends farther distally in the thigh as the femoral artery and unites with the sciatic near the knee. Just proximal to its union with the sciatic it gives off a branch which extends distally along the inner side of the leg to the plantar surface of the foot, where it gives off the digital branches. This vessel is the saphenous artery in the embryo, and disappears in part during further development. From this time on, the femoral and its direct continuation, the popliteal, increase in size; and at the same time the sciatic loses its primary connection and becomes much reduced to form the inferior gluteal artery. The direct continuation of the sciatic in the leg, which is now the direct continuation of the popliteal, becomes reduced to form the peroneal artery. The branch of the original sciatic, which was given off just below the knee, unites with the branch which was given off just above the ankle to form a continuous vessel, the anterior tibial artery. A new branch arises from the proximal portion of the peroneal, extends down the back of the leg, and unites with the distal part of the embryonic saphenous to form the posterior tibial artery. The proximal part of the saphenous then atrophies, leaving but one of the small genu branches of the popliteal (Fig. 190) (McMurrich).

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'''Fig. 190. Diagrams showing three stages in the development of the arteries of the lower extremity.''' McMurrich.

===The Veins===

The changes which occur during the development of the venous system are so complicated, and in some cases so varied, that the scope of this book permits only a brief outline of the growth of the more important of the venous trunks.

Corresponding to the arterial system, the first veins to appear are the omphalomesenteric veins. These vessels, which carry blood from the yolk sac to the heart, arise in the area vasculosa, enter the embryonic body at the sides of the yolk stalk, pass cranially along the intestinal tract, and join the caudal end of the heart (Figs. 160, 162, 164 and 193). Next in point of time to appear are the umbilical veins which carry back to the heart the blood which has been carried to the placenta by the umbilical arteries. These also are paired veins within the embryo, although they form a single trunk in the umbilical cord. They extend cranially on each side through the ventrolateral part of the body wall and join the duct of Cuvier (see below) in the septum transversum (Figs. 163, 164 and 193). Very soon after the appearance of the umbilical veins two other longitudinal vessels develop, one on each side of the aorta. In the cervical region they lie dorsal to the branchia arches and are called the anterior cardinal veins (Figs. 162 and 193). The more caudal parts of the vessels are situated in the region of the developing mesonephros and are called the posterior cardinal veins (Figs. 162 and 193). At a point about opposite the heart the anterior and posterior cardinals on each side unite to form a single vessel, the duct ofCuvier, which turns medially through the septum transversum and opens into the sinus venosus (Figs. 162 and 178). Thus three primary sets of veins are formed at a very early stage of development: (i) The omphalomesenteric veins; (2) the umbilical veins; (3) the cardinal veins.

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'''Fig. 191. Veins of the head of a 9 mm. human embryo.''' Mall.

The veins of the head and neck regions are derivatives of the anterior cardinals. The proximal parts of these vessels are present in embryos of 3.2 mm.; later they extend cranially along the ventro-lateral surface of the brain on the medial side of the roots of the cranial nerves. The position relative to the nerves is only temporary, however, for collaterals arising from the veins pass to the lateral side of the nerves and enlarge to form the main channels. The original channels atrophy except in the region of the trigeminal nerves where they still remain on the medial side of the nerves as the forerunners of the cavernous sinuses. The vessel thus formed laterally to the cranial nerves (except the trigeminal) on each side of the brain is known as the lateral vein of the head (vena lateralis capitis) (Fig. 191.) The blood is collected from the brain region by small vessels which unite to form three main stems; one of these, the superior cerebral vein, opens into the cranial end of the cavernous sinus; another, the middle cerebral vein, opens into the opposite end of the cavernous sinus; and the third, the inferior cerebral vein^ opens into the lateral vein of the head behind the ear vesicle (Figs. 191 and 186). The branches of the superior cerebral vein extend over the cerebral hemispheres and unite with their fellows of the opposite side to form the superior sagittal sinus which lies in the medial line (Figs. 186 and 192). The superior sagittal sinus is at first naturally drained by the superior cerebral veins; but later, as the cerebral hemispheres enlarge and extend farther toward the mid-brain region, it is carried back and joins the middle cerebral vein; still later, for the same reason, it joins the inferior cerebral vein (Fig. 192, A and B). During these later changes the connection between the superior sagittal sinus and the superior cerebral vein is lost (Fig. 192). The middle cerebral vein becomes the superior petrosal sinus which forms a communication between the cavernous sinus and transverse sinus. The transverse sinus represents the channel between the superior sagittal sinus and the cranial end of the cardinal vein; or in other words, its cranial portion represents the connection between the superior sagittal sinus and the inferior cerebral vein while its caudal portion represents the inferior cerebral vein itself (Fig. 192, compare C and D). The caudal end of the superior sagittal sinus becomes dilated to form the confluence of the sinuses (confluens sinuum). From the latter a new vessel grows out to form the straight sinus, and a further growth from the straight sinus forms the large vein of the cerebrum (vein of Galen). The inferior sagittal sinus also represents a new outgrowth at the point of junction of the large vein of the cerebrum and inferior sagittal sinus (Fig. 192, D). During the course of development the lateral vein of the head gradually atrophies and finally disappears, and the inferior petrosal sinus probably represents a new formation which extends from the cavernous sinus to the transverse sinus (Fig. 192, C and D). At the point where the inferior petrosal joins the transverse sinus the latter passes out of the skull through the jugular foramen to become the internal jugular vein (anterior cardinal). (Mall.)

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'''Fig. 192. Diagrams representing four stages in the development of the veins of the head in human embryos.''' Mall.

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'''Fig. 193. Diagram of the venous system of a human embryo of 2.6 mm.''' Slightly modified from Kollmann's Atlas.

As stated in a preceding paragraph, the anterior cardinal veins extend from the ducts of Cuvier to the head region, passing to the dorsal side of the branchial arches. They are at first paired and symmetrical, but, since the heart is situated in the cervical region, are comparatively short and receive blood from the cervical region through segmental branches which belong only to the most cranial of the cervical segments. The other segmented cervical I veins, including the subdavian veins, open at first into the posterior cardinals (Fig. 193). Later, however, as the heart recedes into the thorax the anterior cardinal veins are elongated and the segmental cervical veins, including the subclavians, come to open into them (Fig. 195). The bilateral symmetry is then broken by an anastomosing vessel which extends obliquely across from a point on the left cardinal about opposite the subclavian to a point nearer the heart on the right subclavian (Figs. 194, B, and 195). The portion of the left cardinal cranial to the subclavian becomes the left internal jugular vein which communciates with the intracranial sinuses. The anastomosis itself becomes the left innominate vein. The portion of the left cardinal between the subclavian and the duct of Cuvier, the duct of Cuvier itself, and the left horn of the sinus venosus together form the coronary sinus (Fig. 196). On the right side the more distal part of the cardinal becomes the internal jugular vein; the portion between the subclavian and the anastomosis (left innominate vein) becomes the right innominate vein ; and the common stem formed by the latter and the left innominate constitutes the superior vena cava which opens into the right atrium (see p. 205) . The external jugular vein on each side appears later than the superior cardinal as an independent vessel which comes to lie parallel to the internal jugular and opens into it near the subclavian. The opening, however, shifts to the subclavian, where it is usually found in the adult (Figs. 195 and 196).

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'''Fig. 194. Diagrams of two stages in the development of the anterior and posterior cardinal veins, the subcardinal veins (revehent veins of the primitive kidney), and the inferior vena cava.''' The small branches of the cardinals and subcardinals ramify in the primitive kidneys (mesonephroi). Slightly modified from Hochstetter.

The changes which occur in the posterior cardinal veins are very extensive and result in conditions which bear but little resemblance to those in the earlier stages. In connection with these changes the development of the inferior vena cava must be considered. The posterior cardinal veins appear very early as paired, bilaterally symmetrical vessels which extend from the duct of Cuvier to the tail region and are situated ventro-lateral to the aorta

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'''Fig.195, Diagram representing a stage (later than Fig. 194) in the development of the superior vena cava and the inferior vena cava, also of the azygos vein.''' Hochstetter.

(Fig. 193). From the first they receive blood from the body wall through segmental branches, and as the primitive kidneys (mesonephroi) develop they receive blood from them also, as well as from the mesentery. They return practically all the blood from the region of the body situated caudal to the heart, just as the anterior cardinals return the blood from the region of the body situated cranial to the heart. In other words, the two sets of cardinal veins are the body veins par excellence during the earlier stages of development. While the anterior set persists for the most part as permanent vessels and increases with the development of the body, the posterior set undergoes regressive changes, its function being taken by a new vessel the inferior vena cava.

Not long after the appearance of the posterior cardinals, another pair of longitudinal veins appears in the medial part of the mesonephroi. They increase in size as the mesonephroi increase and receive blood from the latter. They also communicate with the cardinals by means of transverse channels which, however, are later broken up as the mesonephroi become more complicated in structure. These vessels are known as the subcardinal veins, or revehent veins of the primitive kidneys (Fig. 194, A). After they have attained a considerable size, a large anastomosis is formed between them ventral to the aorta and just caudal to the omphalomesenteric (superior mesenteric) artery (Tig. "194, B). In the meantime, a branch of the ductus venosus (see p. 229) grows caudally through the dorsal part of the liver and the mesentery, and joins the right subcardinal vein a short distance cranial to the above mentioned anastomosis (Fig. 194, A and B). This branch forms the proximal part of the inferior vena cava. At the same time, also, each subcardinal forms a direct connection with the corresponding cardinal at a point opposite the first anastomosis; consequently the inferior vena cava, the subcardinals and the cardinals are all in direct communication (Fig. 194, B). Thus two ways are formed by which the blood may return to the heart: It may return via the cardinals and ducts of Cuvier, and via the inferior vena cava.

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'''Fig. 196. Diagram of final stage in the development of the superior vena cava and the azygos vein.''' (Compare with Fig. 195.)

It is obvious that while these conditions exist, that is, while the mesonephros is functional, and blood is carried to it by the cardinal veins and from it by the subcardinal veins, there is a true renal portal system. The blood from the body walls and lower extremities is collected by the segmental vessels and poured into the cardinal veins and is then distributed in the mesonephros by smaller channels or sinusoids (Minot), whence it is collected and carried off by the subcardinal veins. This passage of blood through purely venous channels simulates the conditions in the liver where there is a true hepatic portal system.

Frcm this time on, the changes are largely regressions in the cardinal and subcardinal systems, corresponding to the atrophy of the mesonephroi, and rapid increase in the vena cava and its branches. The cranial end of each cardinal becomes smaller; the left loses its connection with both the vena cava and the duct of Cuvier, the right its connection with the vena cava only (Fig. ig6j. Subsequent changes in these parts of the cardinals will be considered in the following paragraph. For a time the caudal ends of the two cardinals are of equal importance. Later, however, the right becomes larger, while the left atrophies. The right thus becomes a direct continuation and really a part of the vena cava (Figs. 195 and 198). This is brought about, of course, by the original anastomosis between the vena cava and the subcardinal and cardinal. On the left side the anastomosis persists simply as the proximal part of the renal vein (Fig. 198); on the right side the renal vein is a new structure which develops after the kidney has attained practically its final position, and opens into the vena cava secondarily. The inferior vena cava itself is a composite vessel derived from four different anlagen. i. The part which extends from the ductus venosus to the right subcardinal is of independent origin. 2. A short portion is derived from a part of the right subcardinal. 3. Another short portion is derived from the cross-anastomosis between the subcardinals and cardinals. 4. The caudal end is a derivative of the caudal part of the right cardinal (compare Figs. 194, 195, 198.)

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'''Fig. 197. From a transverse section of a 5 mm. human embryo, at the level of the omphalomesenteric (vitelline, superior mesenteric) artery.'''

Before the caudal end of the left cardinal vein atrophies, an interesting and important change occurs in the relations of the ureters and cardinals. Primarily the cardinal veins develop to the ventral side of the ureters. But later a collateral of each cardinal develops to the dorsal side of the ureter. These join the cardinal cranial and caudal to the ureter. In other words, a venous loop is formed around the ureter (Fig. 195). The ventral arm of the loop then atrophies and disappears, leaving the dorsal arm as the direct part of the cardinal vein. On the right side, where the cardinal persists as a portion of the vena cava, the latter vessel comes to lie ventral to the ureter (Fig. 198, A). On the left side the cardinal atrophies, leaving only the portion cranial to the loop as the proximal end of the internal spermatic (testicular or ovarian ) vein (Fig. 198, B). Since on the left side the original anastomosis between the subcardinals and cardinals persists as the renal vein, the left internal spermatic is a branch of the renal. The right internal spermatic vein probably represents a branch of the vena cava which is independent of the cardinal.

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'''Fig. 198. Diagrams representing final stages in the development of the inferior vena cava''' (compare with Fig. 195). Slightly modified from Hochstetter.

In the cat embryo the venous loop around the ureter is much more extensive than in the other forms. The dorsal arm of the loop, named the supracardinal vein, extends from the iliac vein to the original anastomosis between the subcardinals and cardinals. In the course of further development the supracardinals approach each other and finally fuse, forming a large single vessel which becomes the portion of vena cava caudal to the renal veins. In this event the portions of both cardinals forming the ventral arms of the venous loops atrophy and disappear.

Near the caudal end of each cardinal vein a branch arises which receives the blood from the corresponding lower extremity. Then a transverse anastomosis appears between the two cardinals at this point (Fig. 198, A). Since the portion of the left cardinal caudal to the renal vein atrophies, the anastomosis itself constitutes the left common iliac vein (Fig. 198, B). The right common iliac is, of course, the original branch of the right cardinal. As the iliacs enlarge they form the two great branches of the vena cava.

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'''Fig. 199. Diagrams illustrating two stages in the transformation of the omphalomesenteric and umbilical veins in the liver.''' Hochstetter.

With the atrophy of the mesonephroi, the subcardinal veins diminish in size and finally disappear for the greater part. The part of the right subcardinal cranial to the point of junction with the vena cava disappears entirely. The portion of the left subcardinal cranial to the anastomosis between the two subcardinals becomes much reduced in size, but persists as the left suprarenal vein. The left suprarenal vein is thus a branch of the left renal vein, since the latter represents the anastomosis itself (Figs. 194, 195, 198). The right suprarenal vein probably does not represent a persistent right subcardinal, but is a new vessel opening into the vena cava. The portion of each subcardinal caudal to the anastomosis probably disappears entirely, but this has not been definitely determined.

The observations on the development of the azygos veins in the human embryo are only fragmentary. In the rabbit the portions of the posterior cardinal veins immediately cranial to the anastomosis between the sub-cardinals and cardinals, that is, just cranial to the renal veins, disappear. The more cranial portion of the right cardinal persists as the azygos vein which receives the intercostal (segmental) branches and opens into the superior vena cava. An oblique anastomosis is formed, dorsal to the aorta, between the two cardinals (Fig. 195). This anastomosis and the portion of the left cardinal caudal to it together form the hemiazygos vein. The portion of the left cardinal cranial to the anastomosis loses its connection with the duct of Cuvier (or coronary sinus) and becomes the accessory hemiazygos vein (Fig. 196). The ascending lumbar veins, which join the azygos and hemiazygos, probably do not represent persistent parts of the caudal ends of the cardinals, but are formed by longitudinal anastomoses between the original segmental lumbar veins.

The changes which occur in the region of the liver are of much importance and result in conditions which bear no resemblance to the primary ones. As has already been noted, the omphalomesenteric veins enter the body at the umbilicus, pass cranially along the intestine and open into the caudal end of the heart. The umbilical veins, which appear soon after, enter the body at the umbilicus and pass cranially, one on each side, in the ventro-lateral part of the body wall; at the level of the heart they turn mesially through the septum transversum and join the corresponding omphalomesenteric veins to form a common trunk on each side, into which the duct of Cuvier then opens (Fig. 193). When the liver grows out as an evagination from the intestine, it comes in contact with the proximal ends of the omphalomesenteric veins and, as it enlarges, breaks them up into numerous smaller channels (Fig. 199).

The blood then, instead of having a direct channel, is forced to flow through these smaller channels which have been termed sinusoids. When the liver has attained a considerable size a more direct and definite channel is formed, which extends through the substance of the liver from the proximal end of the right omphalomesenteric vein obliquely caudally to the left omphalomesenteric vein. This newly formed channel is the ductus venosus (Figs. 199 and 200). In the meantime, three transverse anastomoses develop between the omphalomesenteric veins just caudal to the liver. The middle one is dorsal to the intestine, the other two ventral, so that the intestine is surrounded by two venous loops or rings (Figs. 199 and 200). At the same time a cross-anastomosis develops between the left umbilical vein, which is primarily the smaller, and the corresponding omphalomesenteric. This anastomosis joins the omphalomesenteric at about the point where the latter joins the ductus venosus, so that it seems to be a continuation of the ductus venosus. A similar cross-anastomosis also develops between the right umbilical and right omphalomesenteric (Figs. 199 and 200). Thus the blood that is brought in from the placenta by the umbilical veins may pass through the liver. Then the portion of each umbilical between the anastomosis and the duct of Cuvier atrophies and disappears (Fig. 200). The remaining portion of the left umbilical, which was originally the smaller, gradually increases in size and finally carries all the blood from the placenta. The right umbilical, on the other hand, loses its connection with the liver and persists only as a small vein in the body wall, which opens into the left umbilical vein near the umbilical cord (Fig. 201). Thus there is the peculiar phenomenon of a vessel carrying blood in different directions at different periods of its history. During the course of development of the septum transversum and diaphragm the left umbilical is withdrawn from the body wall and passes directly from the umbilicus to the ventral side of the liver. During fcetal life it conveys all the blood from the placenta to the liver. A part of the blood is distributed in the liver, a part is carried directly to the inferior vena cava by the ductus venosus (Fig. 202). After birth' the placental blood is cut off and the umbilical vein degenerates to form the round ligament of the liver.

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'''Fig. 200. Veins in the liver region of a human embryo of 4 mm.''' His, Kollmann's Atlas.

The venous rings around the intestine also undergo marked changes. The right side of the most caudal and the left side of the most cranial disappear; the remaining vessel finally loses its connection with the ductus venosus and becomes the portal vein (Figs. 199, 200, 201 and 202). The portal vein is thus a derivative of the omphalomesenterics. After birth, when the placental blood is cut off, blood is distributed in the liver by branches of the portal vein, which represent the advehent hepatic veins; it is collected again by branches which unite to form the revehent hepatic veins, or hepatic veins proper, and the latter open into the inferior vena cava. The advehent and revehent hepatic veins are formed by the enlargement of some of the original sinusoids (Figs. 199 and 201).

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Fig. 201. Veins in the liver region of a human embryo of 10 mm. Kollmann's Atlas.

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Observations on the development of the veins in the extremities of human embryos are so fragmentary that it seems advisable to make use of the work that has been done on the rabbit. In the upper extremity the first vein to develop is the primary ulnar vein which begins in the radial (cranial) side of the extremity near its proximal end, extends distally along the radial border, thence proximally along the ulnar (caudal) border, and opens into the anterior cardinal vein (internal jugular) near the duct of Cuvier (Fig. 203). This condition is present in rabbit embryos of thirteen days. A little later a second vessel, the cephalic vein, appears as a branch of the external jugular, extends along the radial side of the extremity and becomes connected with the digital veins (Fig. 204). When the digital veins are taken up by the cephalic, the distal portion of the primitive ulnar undergoes regression. These changes have taken place in rabbit embryos of fifteen days, and for a short period the cephalic vein is the chief vessel of the extremity. The primitive ulnar vein, however, develops more rapidly than the cephalic and,

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Fig. 202. Veins of the liver (seen from below) of a human foetus at term Kollmann's Atlas.

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with its branches, soon becomes the chief vessel; the portion in the forearm gives rise to either the ulnar or basilic vein; the portion in the arm becomes the brachial vein which then passes over into the axillary, and the latter in turn passes over into the subclavian. The cephalic vein of the embryo persists as the cephalic of the adult, and, during the period when it forms the chief vessel of the extremity, a branch arises from it which becomes the radial vein. Primarily the cephalic vein opens into the external jugular, but later a new connection is formed with the axillary, while the original connection persists as the j ugulocephalic (Fig. 205).

In a rabbit embryo of ten and one-half days a vein follows the border of the lower extremity all the way round, connecting on the cranial side with the umbilical and on the caudal side with the posterior cardinal. This is the primitive fibular vein, and from its course is homologous with the primitive ulnar vein of the upper extremity (Fig. 203). From this time on, however, the course of development in the lower extremity differs from that in the upper. The connection of the fibular vein with the umbilical is soon lost. In older embryos (fifteen days) two branches of the fibular vein have appeared; one of these, the anterior tibial vein, begins on the embryo of 14 days (n mm.), dorsum of the foot and extends diagonally proximally, to open into the fibular in the caudal border; the other, the so-called connecting branch, begins as twigs in the abdominal wall and tibial side of the extremity and opens into the fibular just proximal to the opening of the anterior tibial (Fig. 204). Later the distal part of the primitive fibular is broken up by the differentiation of the digits (toes) and disappears almost up to the point of junction with the anterior tibial. The latter enlarges and receives the digital branches, and appears as a continuation of the proximal part of the primitive fibular. The anterior tibial and primitive fibular together thus constitute the sciatic vein (Fig. 205). Another vessel appears in embryos of fifteen days, which represents the beginning of the femoral vein and opens into the cardinal, cranial to the opening of the sciatic (Fig. 205). From this time on the femoral, with its branches, enlarges at the expense of the other veins and becomes the principal vein of the lower extremity. In the human embryo the femoral anastomoses with the sciatic near the knee and the proximal portion of the sciatic then atrophies, the distal portion persisting as the small sephenous vein. The

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'''Fig. 203. Diagram of the veins in the extremities of a rabbit embryo of 14 days (11 mm).''' Modified from Lewis

{|
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| <div id="Fig204"></div>
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|-
| '''Fig. 204. Diagram of the veins in the extremities of a rabbit embryo of 14 days and 18 hours (14.5 mm.).''' Modified from Lewis.
| '''Fig. 205. Diagram of the veins in the extremities of a rabbit embryo of 17 days (21 mm.).''' Modified from Lewis.
|}

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'''Fig. 206. Diagram illustrating the foetal circulation.''' Compare with Fig. 207. Modified from Kollmann. The shading represents the relative impurity of the blood in different regions, the darkest shading representing the most impure blood large saphenous vein and the posterior tibial vein possibly are derivatives of the femoral, but this question has not been settled.

==Changes in the Circulation at Birth==

During fcetal life the course of the blood is adapted to the placental circulation, since the placenta is the only means by which the blood is purified and from which the foetus derives its nutriment. The pure blood from the placenta passes through the umbilical vein to the liver; there a part of it is distributed to the liver by some of the advehent veins, is collected again by the revehent veins and poured into the inferior vena cava; a part passes directly to the vena cava through the ductus venosus. At this point the blood acquires some impurity from the stream brought in by the vena cava itself and the portal vein. The slightly impure blood then flows into the right atrium, is directed by the Eustachian valve through the foramen ovale into the left atrium, thence flows into the left ventricle and is forced out into the aorta. A part of the blood flows on through the aorta, a part is carried to the upper extremities and head and neck regions by the subclavian and carotid arteries. The latter part, then becoming impure, is carried back to the right atrium by the subclavian and jugular veins and superior vena cava; from the right atrium the greater portion flows into the right ventricle and thence is forced out into the large pulmonary artery. But since the lungs are non-functional, this blood passes through the ductus arteriosus to join the stream in the aorta. The blood received by the more cranial portion of the foetus is but slightly impure, for the impure blood from the ductus arteriosus joins the aortic stream distal to the origin of tlie subclavian and carotid arteries. This accounts for the fact that the more cranial portion of the body generally is better developed than the more caudal portion. It is well to note here that the liver receives purer blood than any other part of the body, and this is undoubtedly correlated with the relatively enormous size of that organ in the foetus. The rather impure blood which starts through the dorsal aorta is in part distributed to the viscera, body walls, and lower extremities by the visceral and segmental arteries, and thence is collected by the branches of the portal vein and inferior vena cava to be returned as impure blood to the umbilical current at the liver; in part it is carried by the umbilical arteries to the placenta, there to be purified and collected by the branches of the umbilical vein (see Fig. 206).

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'''Fig. 207. Diagram illustrating the circulation in the adult.''' Compare with Fig; 206. The shading represents the relative impurity of the blood, the white being the purest blood.

At birth, when the placental circulation is cut off, the proximal end of the umbilical vein atrophies to form the round ligament of the liver; the ductus venosus also atrophies and becomes merely a connective-tissue cord in the liver. The hepatic portal circulation is still maintained by the portal vein. The foramen ovale is closed and the impure blood from the inferior vena cava as well as that from the superior, passes from the right atrium into the right ventricle and thence is forced out through the pulmonary artery to the lungs, which at this time become functional, and is returned to the left atrium by the pulmonary veins. The ductus arteriosus atrophies to form the ligamentum arteriosum. From the left atrium the pure blood flows into the left ventricle, thence is forced out through the aorta and its branches to all parts of the body. At the same time the more distal portions of the umbilical arteries in the embryo atrophy to form the lateral umbilical ligaments, their proximal portions persisting as the superior vesical arteries (see Fig. 207).

Haemopoiesis Histogenesis of the Blood Cells.

Two sharply contrasting views are held regarding the origin and genetic relationships of the different kinds of blood cells. The one view, expressed in the monophyletic theory, holds that there is differentiated out of the mesenchyme a certain type of cells the primitive blood cells, or haemoblasts and that from this single type all the cells of the blood arise through processes of development along divergent lines. The other view, expressed in the polyphyletic theory, holds that while the blood cells are of mesenchymal origin the red cells and white cells have a dual origin, each type arising from its own mother-cells; and further that perhaps each kind of white cells arises from a distinct parent-cell. The recent extensive studies of the problem have yielded evidence that turns the balance at present in favor of the monophyletic theory, and the following account is based in the main upon these studies, particularly those of Maximow on the rabbit and Dantschakoff on the chick.

The sites of blood formation, or haemopoiesis, are (i) the area opaca (yolk sac), (2) the body mesenchyme, including the endothelium of the early blood-vessels, (3) the liver and spleen, (4) bone marrow, and (5) the lymph glands. These various structures are functional at successive periods of development of the embryo, but overlap to a certain extent, the marrow and lymph glands being probably the only foci of origin of blood cells in the adult. In the area opaca blood-cell development is initiated in the formation of the blood islands. Some of the mesenchymal cells become less irregular in shape by retraction of their protoplasmic processes and isolation from the general syncytium. They assume amoeboid properties and the cytoplasm aquires a distinctly basophilic character (Fig. 208). These then represent primitive blood cells, or hcemoUasts. Maximow has given them the name primitive lymphocytes, or lymphoblasts , regarding them as the common ancestors of all the blood cells. Clusters of these cells constitute the blood islands which are involved in the development of the primitive blood spaces, the superficial cells being transformed into endothelium (see p. 186) and the central cells remaining as primitive lymphocytes. Other primitive lymphocytes also differentiate in the mesenchyme outside of the blood spaces, afterward probably entering the vessels by virtue of their amoeboid properties.

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Fig. 208. Mesenchyme from a rabbit embryo at the time of beginning blood formation.

Maximow.

m, Ordinary mesenchyme cells; m', mesenchyme cell in mitosis; /, primitive Wood cell

(primitive lymphocyte).

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There is a view that both the blood cells and the endothelium of blood vessels arise from certain mesam&boid cells of entodermal origin, which are insinuated between the entoderm and mesoderm but are not in the strict sense constituents of the latter, and which collectively have been called the | angioUast. While the mesamceboid cells are probably identical with the j primitive lymphocytes, the idea that they constitute a set of specific rudiments of entodermal origin, from which both blood cells and endothelium arise, has not been generally accepted. The view, however, is not discordant with the monophyletic concept of the origin of blood cells.

<div id="Fig209"></div>
[[File:Bailey209.jpg|600px]]

Fig. 209. Portion of a blood vessel from the yolk sac of a rabbit embryo, showing various

stages in the formation of erythrocytes. Maximow. fl, megaloblasts; a', megaloblast in mitosis; b, normoblasts; b', normoblast in mitosis; c, erythro

blasts; d, erythrocyte, not yet discoid; en, endothelium; /, primitive lymphocytes;

k, normoblast recently divided; n, shrunken erythroblasts (?); n' ', extruded nucleus.

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The primitive lymphocytes (of Maximow), constituting the parent stem from which all the blood cells arise according to the monophyletic theory, specialize at first in two general directions. In one direction the specialization leads toward the erythrocytes, or red blood corpuscles, and in the other toward the leucocyte, or white blood cell, series including the myelocytes. In the former case the lymphocytes become modified in that the cytoplasm becomes less basophilic and acquires a trace of haemoglobin; the nuclei become somewhat eccentric, the chromatin network a little denser and the nucleoli less conspicuous. While these changes are in progress the cells multiply by mitosis. The resulting cells are termed megaloblasts (Fig. 209, a). These continue to multiply by mitosis, the cytoplasm acquiring more haemoglobin and the nuclei becoming more dense, the resulting cells being somewhat smaller and known as normoblasts (Fig. 209, b) . The normoblasts, still dividing by mitosis, acquire still more haemoglobin and become erythroblasts (Fig. 209, c). These lose their nuclei and thus become erythrocytes, the definitive red blood corpuscles. The manner in which the nuclei are lost is a matter of dispute. Some claim it is absorbed (karyolysis) ; others claim it is extruded (karyorrhexis) (Fig. 210); recently the observation has been made that the nucleus with a small amount of surrounding cytoplasm escapes from the cell in a manner resembling constriction.

In the specialization leading to the white blood cell series, the parent stem cell (primitive lymphocyte) proliferates by mitosis and undergoes certain divergent changes in its nucleus and cytoplasm which yield the characters of the various kinds of leucocytes. Some of the cells become polymorphonuclear and acquire neutrophile granules to become neutrophile leucocytes; others acquire acidophile granules as acidophiles; still others, basophile granules as basophiles. The large mononuclear leucocytes, with the transitional forms having the horseshoe-shaped nuclei, possibly represent but slightly modified primitive lymphocytes. The definitive lymphocytes are probably derived from the primitive by division and but slight changes in character. Thus the various forms of white blood cells would not represent different stages in a series but divergent lines of specialization from a parent stem.

As mentioned before, the various blood forming organs function as such at successive stages of development of the embryo. The mesenchyme generally, both in the yolk sac and in the body, gives rise to blood cells during the earlier stages and may continue to do so until relatively late in embryonic life as has been demonstrated in the chick. It is interesting to note in this connection that in certain regions endothelial cells may also be transformed into primitive blood cells. In the earlier stages of liver development active haemopoiesis is observed in the sinusoids, probably partly from cells carried in by the blood stream and partly from primitive blood cells derived from the neighboring mesenchyme (Fig. 211). This function ceases in the liver in later embryonic life. The formation of blood cells takes place in the developing spleen but erythrocyte formation ceases after birth, although following severe haemorrhage the function may be resumed even in adult life. The formation of lymphocytes, however, goes on throughout life in the splenic corpuscles.

<div id="Fig210"></div>
[[File:Bailey210.jpg|600px]]

Fig. 210. Showing the escape of the nuclei from nucleated red blood cells. Howell.

I, 2, 3, 4, represent stages of extrusion observed in living cells; a, from circulating blood of adult cat after bleeding four times; b, from young kitten after bleeding; c, from 90 mm. cat embryo; others from marrow of adult cat. ++++++++++++++++++++++++++++++++++

<div id="Fig211"></div>
[[File:Bailey211.jpg|600px]]

Fig. 211. From the liver of a rabbit embryo, showing formation of red blood cells. Maximow. a, Megaloblasts; a', megaloblast in mitosis; b, normoblasts; c. erythroblasts; en, en', en'', endotheHal cells; h, liver cells; /, primitive lymphocytes; /', primitive lymphocyte in mitosis; , nucleus being extruded from small erythroblast.

++++++++++++++++++++++++++++++++++

The lymph glands are constant sources of lymphocytes, the parent cells being the large mononuclear cells found in the germinal centers. These cells are regarded as closely allied to the primitive lymphocytes, perhaps even identical, although here in this particular environment giving rise only to the lymphocyte line.

The bone marrow is an important source of blood cells in the embryo, and in the adult under normal conditions is regarded as the only source of red corpuscles. The parent stem cells, here called myeloblasts, are recognizable in the form of large mononuclear, non-granular cells, with the general characters of primitive lymphocytes, which give rise to the red blood cells through clearly distinguishable megaloblast and normoblast stages, and to the various forms of leucocytes and lymphocytes. In addition the parent cells also give rise to certain other cells which are normally confined to the marrow, viz., the myelocytes. These are large mononuclear cells, with vesicular nuclei, the cytoplasm containing neutrophile, acidophile, or basophile granules similar to those of the leucocyte series (Fig. 212). The genetic relationships of the "giant" cells, or myeloplaxes, in the marrow are not clear. The myeloplaxes are large masses (30 to 100 micra in diameter) of homogeneous or finely granular, slightly basophilic cytoplasm containing either a single lobulated, annular nucleus (megakaryocytes, Fig. 212, meg) or many nuclei (polykaryocytes). The polykaryocytes have been considered identical with the osteoclasts, which may represent fused osteoblasts, but this relationship has not been definitely established. Both kinds of cells have been considered as derivatives of the myeloblasts, the polykaryocytes being later stages of megakaryocytes.

<div id="Fig212"></div>
[[File:Bailey212.jpg|600px]]

Fig. 212. From a section of red marrow from the femur of a young rabbit. Schafer. e, Erythrocy tes ; e r , normoblasts; e", normoblast in mitosis; /, outlines of fat cells; ^, polymorphonuclear leucocytes; m, neutroohile myelocytes; m', myelocytes in mitosis; m", eosinophile myelocytes; m'". basophile myelocytes.

++++++++++++++++++++++++++++++++++

The blood platelets are now regarded by some authors as derivatives of the megakaryocytes; pseudopodia of the latter breaking off and gaining access to the blood stream. By others they are not believed to be formed constituents of the circulating blood, but appear only after shed blood comes in contact with a foreign substance.

The accompanying table, which is a tentative graphic scheme of the monophyletic theory, will assist the student in tracing the lineage of the blood cells.

==The Lymph Vascular System==

A controversy has arisen over the origin of the lymph channels and their endothelium, similar to the one that arose over the genesis of the blood vessels. There are therefore two main views, viz.: (i) that the endothelium of the lymph vessels arises as sprouts from the endothelium of veins and continues to grow by proliferation and migration of its own cells, the lymphatics thus being direct derivatives of the venous channels; (2) that the lymph vessels arise in situ through enlargement and coalescence of intercellular tissue spaces, the mesenchymal cells bounding these spaces becoming flattened and rearranged to form the endothelial walls of the vessels, and, as a corollary, that the junction of the lymph vessels with the veins, which occurs at certain definite points, is a secondary matter.

<div id="Fig213"></div>
[[File:Bailey213.jpg|400px]]

'''Fig. 213. Diagram showing the arrangement of the lymphatic vessels in a pig embryo of 40 mm.''' Sabin.

<div id="Fig214"></div>
[[File:Bailey214.jpg|thumb|300px|'''Fig. 214.''' Diagram showing network of lymphatic vessels in skin of pig embryos. Sabin. Area marked A shows extent of network in an embryo of 18 mm.; B, in embryo of 20 mm.; C, in embryo of 30 mm.; D, in embryo of 40 mm.]]

Here again the scope of the work does not permit presentation in detail of the evidence adduced in favor of either of these views. The advocates of the first view have placed much dependence upon the method of injection, which, as in the case of the origin of blood vessels, has been met with the criticism that injection shows only those lymph channels with continuous lumina and leaves undetermined the field beyond the injected area (see page 194). To supplement their studies by the injection method, the investigators who maintain that lymphatic endothelium grows by sprouting of preexisting endothelium have added studies on living tissues in which the sprouting phenomena are claimed to be clearly observable. Those who maintain that the lymphatics and their endothelium arise in situ from intercellular tissue spaces and the bordering cells, argue that the same principles underlie the formation of lymphatics that determine blood-vessel development and that it has been shown experimentally that blood vessels develop in regions which have been entirely cut off from any source of endothelium except the mesenchymal cells in situ (see page 194).

According to the first view lymphatic development can be divided into two stages: (i) the formation of isolated lymph sacs, derived from veins, which become united into a system, and (2) the peripheral growth of lymph vessels which sprout from the endothelium of these sacs and spread through the body. (i) The first sacs appear, one on each side, along the jugular (anterior cardinal) veins. The branches of these veins at first form a plexus; a portion of the plexus becomes cut off from the parent stems and lies as a series of isolated spaces in the mesenchyme ; these spaces then enlarge and coalesce to form an endothelial-lined sac the jugular lymph sac or heart which afterward joins the jugular vein by a new opening (Fig. 213). A second pair of sacs the posterior lymph sacs or hearts develops in the same manner from the more caudal branches of the posterior cardinal veins (Fig. 213). Two other saclike structures develop the cisterna chyli and retroperitoneal sac the former in the region of the renal veins and the latter in the vicinity of the suprarenal bodies. Through the longitudinal fusion of the chain of sac-like structures, the axial lymphatic drainage line of the body is established (Fig. 213). The thoracic duct probably represents the fused cisterna chyli and jugular lymph hearts. The lymph hearts in the avian and mammalian embryo become relatively smaller as development proceeds until in the adult they are barely discernible as slight dilatations in the lymph vessels. The cisterna chyli, however, may persist as a clearly distinguishable dilatation at the caudal end of the thoracic duct.

(2) The peripheral lymph channels, which drain into the thoracic duct, represent outgrowths from the lymph sacs. From the jugular sacs sprouts invade the neck, head, shoulders, and finally the entire upper extremities and upper part of the body wall (Fig. 214). Similarly, from the posterior lymph hearts sprouts invade the lower extremities and lower portion of the body wall (Fig. 214). Outgrowths from the original axial drainage line invade the various visceral organs (Fig. 213). Thus the lymphatic drainage of the body is effected through outgrowths from a few primary centers which represent derivatives of the venous channels. The lymph glands are secondary foci of development along the lymph vessels (see page 249).

<div id="Fig215"></div>
[[File:Bailey215.jpg|600px]]

'''Fig. 215. From cross-sections of cat embryos in successive stages''' (<z, b, c, d) of development, in the region of the jugular lymph sac; diagrammatic but amply supported by studies of serial sections and reconstructions. Huntington.
: i, Anterior cardinal vein; 2, somatic tributary of same; 4, developing blood cells in the mesenchyme; 5, mesenchymal intercellular spaces rudiments of the jugular lymph sac; 6, rudimerits of brachio-cephalic venous anastomosis; 7, brachio-cephalic venous anastomosis; 8, haemophoric lymphatic plexus forerunner of jugular lymph sac; u, thoracic duct'approach' of jugular lymph sac; 12, rudiments of thoracic duct; 13, jugular lymph sac preparing to rejoin vein and to establish secondary connection with rudiments of thoracic duct (12) and of other systemic lymphatics (14); 15, jugular lymph sac, which has rejoined vein through permanent lymphatico-venous tap (16); 17, thoracic duct; 1 8, jugular and cephalic systemic lymphatics.

<div id="Fig216"></div>
[[File:Bailey216.jpg|600px]]

'''Fig. 216. From a photograph (X 600) of a cross-section through the caudal end of a chick embryo of 15 mm.''' Showing enlarged mesenchymal intercellular spaces as rudiments of the posterior lymph sac. West. 3, Coccygeal vein; 6, caudal muscle plate; 8, isolated enlarged intercellular spaces, the bounding cells becoming flattened; 9, lateral branch of coccygeal vein; 10, lymphatics containing collections of developing blood cells.

The view that lymphatics arise as enlarged isolated intercellular spaces in the mesenchymal tissue does not include any dispute as to the general disposition of the lymph channels in the body, but comprises a fundamentally different concept of the origin of these vessels. Upon a long and exhaustive series of observations on closely graded series of embryos of Fishes, Amphibia, Reptiles, Birds, and Mammals is based the conclusion that not only the lymph sacs but the peripheral lymphatics as well originate independently of the veins; and that the opening of the main lymphatic drainage lines into the jugular or subclavian veins near their junction, and into the inferior vena cava and renal veins (in some monkeys) , is second* arily established. The same hydrodynamic mechanical factors regarded as operative in the formation of blood vessels, viz.: pressure and friction incident to blood flow (see page 195), are considered as effective likewise in the development of lymphatics. Fundamentally, therefore, the lymph vascular system from the viewpoint of development differs in no wise from the blood vascular system.

<div id="Fig217"></div>
[[File:Bailey217.jpg|600px]]

'''Fig. 217. Diagrams showing three stages (a, b, c) in the development of the thoracic duct in the cat embryo''', in which the jugular lymph sac has established two permanent venous connections (8 and 9). Huntington.
: i, Anterior cardinal vein; 2, duct of Cuvier; 3, posterior cardinal vein; 4, external jugularcephalic vein; 5, subclavian vein; 6, jugular lymph sac; 7, thoracic duct 'approach' of lymph sac; 8, common jugular opening of lymph sac; 9, jugulo-subclavian opening of lymph sac; 10, rudiments of thoracic duct; n, thoracic duct.

The lymph sacs, both jugular and posterior, arise through enlargement and confluence of mesenchymal intercellular spaces, the cells bounding the spaces becoming flattened and rearranged to form endothelium. In the case of the mammalian (cat) jugular sac, intercellular spaces in the region dorso-lateral to the anterior cardinal vein unite into an intricate plexus of channels which then opens into the vein (Fig. 215, a and b). Following this the components of the plexus enlarge and coalesce to form the sac, which then temporarily severs connection with the vein (Fig. 21 5, c) . Finally the sac effects a permanent connection with the vein through one or more openings which represent the lymphatico-venous communications of the adult (Fig. 215, d). In the case of the posterior sac, intercellular spaces dorsal to the posterior cardinal vein (Fig. 216, 8) first form a plexus the components of which then unite into a large endothelial-lined space which opens into the dorsal tributaries of the vein.

The thoracic duct also arises as a chain of isolated endothelial-lined spaces along the line of the aorta. These unite longitudinally into a continuous channel which joins the jugular lymph sac, thus forming the axial lymphatic drainage line of the body (Fig. 217, a, b, c). In reptilian embryos the spaces first fuse into a distinct periaortic plexus out of which the thoracic duct is established. In the avian embryo the chain of spaces follows the general line of the aorta but does not become so intimately associated with the great arterial trunk as in reptiles. In the mammalian forms rudiments of the thoracic duct follow the same general plan of development, but are associated topographically with the ventro-medial tributaries of the azygos veins. These tributaries finally become detached from the larger venous trunks, atrophy and disappear, being replaced by the thoracic duct.

On the same principles laid down for the development of the lymph sacs and thoracic duct, the peripheral lymphatics also are developed. In all the regions of the body not immediately drained by the lymph sacs or thoracic duct, mesenchymal intercellular spaces enlarge and coalesce, the cells bounding the coalesced spaces being transformed directly into endothelium; the spaces unite to form a plexus of endothelial-lined channels, and in this plexus certain channels increase in size to form the larger lymphatics which converge and eventually join the main axial drainage line. Thus the lymphatic drainage of the entire body is established.

One of the most interesting and significant phases of lymphatic development, which has been brought out through recent studies of the problem, is the role played by certain early lymph channels in conveying blood cells to the general circulation. It has been found that, in the region subsequently occupied by the lymph sacs, extensive blood cell formation (haemopoiesis) occurs prior to the formation of lymphatic rudiments. As the lymph spaces appear and unite into a plexus the developing blood cells are included within them (Fig. 215, a and Fig. 216, 10). When the lymphatic plexus joins the veins the blood cells are carried into the general circulation (Fig. 215, b). This haemophoric function of the early lymph channels is especially prominent in the case of the thoracic duct in the chick. Here extensive collections of blood cells develop in the mesenchymal tissue along the line of the aorta and become included within the rudiments of the thoracic duct and eventually, when the latter unites with the jugular lymph sac, are carried into the veins and thus enter the general circulation. After these early lymphatics, which transport blood cells and which have been defined as haemophoric lymphatics, or veno-lymphatics, fulfil their haemophoric function they are retained as permanent lymph channels in the general lymphatic organization. In a broader interpretation, the haemophoric function of certain lymph vessels during ontogeny is particularly significant in that it indicates essential and fundamental similarity of lymphatic vascular development to haemal vascular development.

==The Lymph Glands==

The lymph glands do not begin to develop for some time after the lymphatic vessels, since there are no indications of them in the human foetus until the latter part of the third month and none in pig embryos until thev

<div id="Fig218"></div>
[[File:Bailey218.jpg|600px]]

Fig. 218. From a section through the axilla of a human embryo of 125 mm. (4-5 months), showing an early stage of a lymph gland. Kling.

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have reached a length of 30 mm. While it is definitely settled that lymph glands originate in very close relation with the lymphatic vessels, certain points in their later development need further study. In the axilla and groin, for example, the lymphatic vessels form a dense network in the meshes of which are masses of connective tissue. These masses become more cellular and with the surrounding vessels constitute the anlagen of lymph glands (Fig. 218). The new cells which appear in the masses are lymphocytes which may pass through the walls of the neighboring blood vessels and lodge here or may be derived directly from connective tissue (mesenchymal) cells in situ. Whatever the origin of the lymphocytes may be, they have the opportunity here to divide freely. The mass becomes still more cellular and enlarges at the expense of the lymphatic vessels which then come to form a network around the mass. This network is the marginal plexus, and it communicates freely with the neighboring lymphatic channels. Within the mass of cells blood vessels are present from the beginning, and these are destined to be the blood vessels of the lymph gland, and the point of their entrance and exit marks the hilus. Outside of the marginal plexus the connective tissue condenses to form the capsule. The gland at this stage thus consists of a central compact cellular mass, made up of connective tissue and lymphocytes, in which blood vessels ramify; a plexus of lymphatic channels around the mass which communicate with the neighboring channels; and around the whole structure a capsule of connective tissue (Fig. 218). Further development consists of the breaking up of the cell mass by

<div id="Fig219"></div>
[[File:Bailey219.jpg|600px]]

Fig. 219. Diagram illustrating a stage (later than Fig. 218) in the development of a lymph gland. Stohr.

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iymj hatic channels and the formation of the follicles. It seems probable that branches from the marginal plexus invade the cell mass principally from an area around the hilus, thus breaking it up into smaller irregular masses or cords. At the side opposite the hilus the invading channels are less numerous, leaving larger parts of the mass which become the follicles (nodules) of the cortex. On all sides the invading channels communicate with the marginal plexus and form the so-called intermediary plexus. The gland as a whole enlarges and its peripheral part pushes outward into the surrounding tissue. Over the follicles the capsule is pushed outward, while between them it remains in place and comes to dip into the gland as the trabeculcz. The blood vessels tend to lie in the trabeculae, but a small branch probably passes to each follicle. In the follicles themselves the lymphocytes proliferate and the central part of each follicle becomes a germinal center. The connective tissue among the lymphatic vessels composing the marginal plexus becomes proportionately less as the vessels enlarge and finally exists only as strands of reticular tissue which, naturally, are covered by the endothelium ; thus the marginal plexus becomes the marginal sinus. The intermediary sinus is formed by the channels which originally invaded the cell mass. The reticular tissue is probably composed of remnants of the original connective tissue. All the channels converge at the hilus to form the efferent lymphatic vessels (Figs. 219 and 220).

<div id="Fig220"></div>
[[File:Bailey220.jpg|600px]]

Fig. 220. Diagram illustrating a late stage in the development of a lymph gland. Compare with Fig. 219. Stohr.

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The haemolymph glands are probably developed in much the same manner as the lymph glands except that in the former the sinuses are filled with red blood cells.

The first lymph glands to develop are those in the axilla, in the inguinal region, in the neck, and in the base of the mesentery. These are the so-called primary glands and develop during fcetal life. They are of constant occurrence in these regions, but vary in number in different individuals. The secondary lymph glands are those in the bend of the elbow, in the popliteal space, in the mesentery, and around the aorta. Some of these develop during foetal life and some later. While lymph glands are of constant occurrence in some regions throughout life, the number may vary at different times in any region; and there may also be variations in different individuals. Glands may be called into existence at any time during life, in almost any region, as the result of exceptional activity of some organ, or in pathological conditions. Such structures are known as tertiary lymph glands.

The origin of the lymph (plasma) itself is probably extremely complex. At one time it was considered as the result of nitration from the blood plasma through the capillary walls. If lymph originates in this way the nitration is selective, for the chemical composition of the lymph differs from that of the blood plasma. In all probability the lymph plasma consists of blood plasma which has escaped through the vessel walls plus the products of cell activity in the tissues.

==The Spleen==

Since the spleen is generally considered as a lymphatic organ and since recent researches have shown that its structure is quite comparable to that of the lymph glands, it seems advisable to consider it under the head of lymphatic organs. Its ultimate origin is not yet settled and the details of its later development are still obscure. The same difficulties are met with as in the case of the origin and development of blood cells, for it is known that the spleen plays a part in the formation of the blood cells. Its structure differs from that of the lymph glands chiefly in that it possesses no distinct lymphatic sinuses; but it does possess lymph follicles (splenic corpuscles) and densely cellular cords (pulp cords) which are separated by cavernous blood vessels (cavernous veins).

For some time the spleen was considered as a derivative primarily of the mesenchyme in the region of the dorsal mesogastrium. More recently, however, investigators have taken the view that it arises partly, or possibly entirely, from the mesothelium (coelomic epithelium) of the dorsal mesogastrium. In human embryos during the fifth week the anlage of the spleen appears as an elevation on the left (dorsal) side of the mesogastrium (Fig. 221). This elevation is produced by a local thickening and vascularization of the mesenchyme, accompanied by a thickening of the mesothelium which covers it; and, furthermore, the mesothelium is not so distinctly marked off from the mesenchyme as in other regions. Cells from the mesothelium then migrate into the subjacent mesenchyme and the latter becomes much more cellular (Fig. 222). The migration is brief, and in embryos of about forty-two days has ceased, and the mesothelium is again 1 reduced to a single layer of cells. The elevation becomes larger and projects ; into the body cavity. At first it is attached to the mesentery (mesogastrium) by a broad, thick base, but as development proceeds the attachment if becomes relatively smaller and finally forms only a narrow band of tissue 'j through which the blood vessels (splenic artery and vein) pass.

Further development of the substance of the spleen consists of the breaking up of the cellular mesenchymal tissue by blood vessels and the formation of the splenic corpuscles. The connective tissue trabeculce, as well as the jfj capsule of the spleen are derived from the original mesenchymal tissue. The blood vessels become dilated in parts of their course to form the cavernous vessels (cavernous veins) which are separated by the pulp cords. The connective (reticular) tissue of the pulp cords is a derivative of the mesenchyme, as are also the various types of cells in the cords. The adventitia of the walls of some of the small arteries becomes infiltrated with lymphocytes to form the splenic corpuscles (lymph follicles).

<div id="Fig221"></div>
[[File:Bailey221.jpg|600px]]

'''Fig. 221. From transverse section through stomach region of a 14 pig embryo.''' Photograph.

It is generally recognized that during foetal life the spleen is a hematopoietic organ, that is, both leucocytes and nucleated red blood cells ai.e produced within it. Normally, the formation of erythrocytes stops at or soon after birth. In severe anaemia or in pernicious anaemia in postnatal life, however, the presence of dividing nucleated red blood cells suggests a return to embryonic conditions. The reticular tissue constitutes the source of these nucleated forms (erythroblasts) . It has also been suggested that the spleen acts as a destroyer of worn-out erythrocytes, for in many cases apparent remnants of the latter have been observed within the cytoplasm of the "spleen cells." The lymphocytes proliferate to a certain extent in the splenic corpuscles, and in that way, at least, the spleen serves as a base of supply for leucocytes. There is a possible suggestion that the first leucocytes of the spleen have their origin in the mesenchymal cells of the spleen anlage. This would be in accord with the observations which indicate that leucocytes are derived from indifferent mesenchyme cells.

<div id="Fig222"></div>
[[File:Bailey222.jpg|600px]]

Fig. 222. From section through dorsal mesogastrium (anlage of spleen) of a chick embryo of 3 days and 21 hours incubation. Tonkofl.

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Glomus Coccygeum.

The coccygeal skein (coccygeal gland) was originally considered as belonging to the same category as the suprarenal glands, but the latest researches have indicated that its cells do not possess the characteristic chromamn reaction and that it belongs rather to the category of lymph glands. It develops ventral to the apex of the coccyx in relation with branches of the middle sacral artery.

Although the thymus gland becomes a lymphatic structure it is primarily derived from the epithelium (entoderm) of the branchial grooves and will be considered in connection with the development of the alimentary tract (Chap. XII). The tonsils also will be considered in the same connection.

==Anomalies==

===Anomalies of the Heart===

====Acardia====

The malformation known as acardia occurs in the case of twins that have but one chorion. The so-called acardiac condition does not necessarily imply the absence of the heart in the affected twin, for the latter may develop to a considerable degree and possess a functionating heart. On the other hand, the affected twin may be only an amorphous mass of tissue which derives its total blood supply through the agency of the stronger twin's heart. Or there may be any intermediate form between these two extremes. The point is that the acardiac monster (acardiacus) derives its blood wholly or in part through the agency of the stronger heart. A further discussion of acardiac monsters and their possible explanation will be found in Chap. XX.

====Double Heart====
But one or two cases of a double heart in a single human foetus have been recorded. In some of the lower forms (chick) it occurs more frequently. The explanation is probably to be found in the double origin of the heart in Amniotes (p. 196).

====Anomalous Position of the Heart====

Congenital anomalies in the position of the heart are rare. Dextrocardia (heart on the right side) is almost invariably associated with changes in the position of the viscera (see transposition of the viscera, page 304) . In the condition known as ectopia cordis, the heart, with the pericardium, protrudes through a cleft in the ventral wall of the thorax, the cleft being probably due to an imperfect fusion of the two sides of the body wall in that particular region.

====Anomalies of the Septa====
The most frequent anomaly in the atrial septum is the persistence of the foramen ovale. The entire foramen may remain patent, or, as is more frequently the case, a smaller opening may persist between the ventral (anterior) border of the foramen and the valve of the latter (p. 203).

The atrial septum may be wholly lacking, but this always occurs in conjunction with other defects. It sometimes happens that the primary atrial septum (septum superius), which grows from the cephalic side of the common chamber, fails to fuse with the septum of the atrio-ventricular aperture (p. 203 and Fig. 171).

Defects in the ventricular septum occur less frequently than in the atrial septum. It may happen that the cephalic (upper) border of the ventricular septum fails to fuse with the septum which divides the aortic trunk and bulb into the aorta and pulmonary artery. This affects the cephalic (upper) part of the septum sometimes called the pars membranacea (p. 204 and Fig. 174); and since the defect is situated near the opening of the aorta it brings about the so-called "origin of the aorta from both ventricles." Stenosis of the pulmonary artery usually accompanies this condition. Rarely is there a deficiency in the caudal (lower) part of the ventricular septum. Complete absence of the ventricular septum may occur, and along with it also an absence of the atrial septum, so that the heart is simply two-chambered; or the single ventricle may open into two atria. The causes of these defects ] are obscure.

====Anomalies of the Valves====
There may be congenital variations in the j size and number of the atrio-ventricular valves, depending upon abnormal position, fusion, or division of the pad-like masses from which the valves ! develop (p. 206).

There may be also a greater or lesser number of semilunar valves in the | aorta and pulmonary artery. This irregularity can probably be referred back to an atypical division of the aortic trunk and bulb, and a corresponding \ atypical division of the protuberances which give rise to the valves (p.. 206). Variations in the valves may or may not be accompanied by functional dis- i turbances. The congenital diminution in the number of valves should be distinguished from the acquired, where chronic endocarditis may cause a fusion.

===Anomalies of the Large Vascular Trunks===

====Anomalies of the Arteries====

There may be a transposition of the aorta \ and pulmonary artery. This results from an anomalous division of the aortic trunk and bulb. The partition develops in such a way as to put the aorta in communication with the right ventricle, and the pulmonary artery with 1 the j left ventricle (p. 204). Or the aorta and pulmonary artery may remain in \ direct communication on account of an imperfect development of the partition. Rarely the two vessels remain as a common stem.

Congenital stenosis (constriction) of the pulmonary artery may occur, j accompanied by an increase in the size of the aorta, possibly due to an unequal j division of the aortic trunk and bulb. After birth little or no blood can pass \ to the lungs, and the result is a general damming (stasis) of the venous blood ! with marked cyanosis. This is at least one explanation of the so-called "blue babies." Less frequently there is a stenosis of the proximal end of the aorta, with excessive size of the pulmonary artery, also due to an unequal division of the aortic trunk and bulb (p. 204) . These stenoses are usually, though not always, accompanied by defects in the ventricular septum.

Persistence of the ductus arteriosus may occur without any other defect; ;i but usually the persistence is associated with anomalous conditions of the aorta and pulmonary artery.

Occasionally the arch of the aorta is found on the right side. This condition is due to the persistence of the fourth aortic arch on the right side instead of the corresponding arch on the left side; this is the normal condition in Birds. Rarely both fourth aortic arches persist, which results in a double arch of the aorta the normal condition in Reptiles. (Compare Figs. 181 and 182.)

The dorsal aorta, particularly the abdominal part, is occasionally found to consist of two parallel, imperfectly separated vessels a condition known as double aorta. This anomaly is due to an imperfect fusion of the two primitive aortae (p. 187 and Fig. 165).

Numerous variations are met with in the larger branches of the aorta,, many of which are explained by referring them to embryonic conditions. Especially noteworthy are the branches from the arch of the aorta, since their development is so closely associated with the changes in the aortic arches. The normal arrangement passing from the heart, is innominate artery, left common carotid artery, left subclavin artery (see Fig. 182).

1. All these branches may be collected into a single trunk a condition characteristic of the horse.

2. Two branches may arise from the arch, (a) The left common carotid unites with the innominate, and the left subclavian arises separately. This is the normal arrangement among the apes, and is probably the most common variation in man. (b) Very rarely there are two innominate arteries, each formed by the union of a common carotid and subclavian a condition characteristic of Birds.

3. Three branches may arise from the arch but in a manner differing from the normal. Each subclavian arises separately and the two common carotids are united into a single vessel. This arrangement is found in some of the Cetacea.

4. Four vessels may arise from the arch, (a) These are, in order, innominate, left common carotid, left vertebral, left subclavian. (b) Or the order may be right common carotid, left common carotid, left subclavian, right subclavian. In this case the proximal part of the right subclavian represents the portion of the right dorsal aortic root just cranial to the bifurcation; the fourth arch on the right side disappears, (c) Or very rarely the order may be right subclavian, right common carotid, left common carotid, left subclavian.

5. Five branches of the arch are rare. In order they are right subclavian, right vertebral, right common carotid, left common carotid, left subclavian.

6. Very rarely there are six branches of the arch; right subclavian, right vertebral, right .common carotid, left common carotid, left vertebral, left subclavian.

====Anomalies of the Veins====

The two pulmonary veins on each side, more frequently those on the left side, many unite into a common trunk before opening into the atrium. This variation is probably due to the fact that the absorption of the originally single pulmonary trunk into the wall of the atrium does not proceed far enough to cause all four of the pulmonary veins to open separately (see p. 205) . The upper (more cephalic) vein on the right side may open into the superior vena cava; or the upper vein on the left side may open into the left innominate vein. A possible explanation for this is that the pulmonary veins are formed after the heart and other vessels have developed to a considerable degree, and some of them may unite with the other vessels instead of with the atrium.

Occasionally two superior vena cava are met with. In this case the right opens into the right atrium in the normal position; the left opens into the right atrium through the coronary sinus which naturally is much enlarged. This condition represents a persistence of the proximal end of the left anterior cardinal vein and the left duct of Cuvier, and is the normal arrangement in many of the lower Vertebrates. Even with two venae cavae there may be a small anastomosing branch in the position of the left innominate vein, which represents the normal structure in the Marsupials (see Figs. 194 and 195 and p. 223). There are a few cases on record of a single left superior vena cava.

The inferior vena cava is also subject to variations which represent the abnormal persistence of certain embryonic vessels. Perhaps the most striking of these variations is the condition known as double inferior vena cava. There may be two parallel vessels, of equal or unequal size, which unite at or above the level of the renal veins. This condition is to be explained by the persistence of parts of both posterior cardinal veins. It is met with not infrequently among the lower Mammals, especially the Marsupials (see Figs. 195 and 198).

Rarely the inferior vena cava opens into the superior, and in this case the hepatic veins open directly into the right atrium. This anomaly probably represents a failure of the absorption of the sinus venosus into the wall of the atrium (p. 205).

A left renal vein may open into the left common iliac, which condition represents a persistence of the more caudal part of the left posterior cardinal (Fig. 198). This anomaly is rare.

The azygos vein occasionally presents variations which are due to anomalous development. All the intercostal veins on the left side may be collected into a vessel which opens into the left innominate vein. There may be a single median azygos vein; or there may be a transposition of the azygos vein. It may be on the left side and open into the coronary sinus (normal conditions in the sheep and a few other Mammals). The latter condition represents a persistence of the more cephalic part of the left posterior cardinal vein (see Figs. 195 and 106).

Space does not permit a discussion of the great number of congenital variations that occur in the smaller blood vessels, both arteries and veins. The student is referred, however, to the more extensive text-books of anatomy.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_11|Muscular]]

==References for Further Study==

BORN, G.: Beitrage zur Entwicklungsgeschichte des Saugetierherzens. Archiv f. mik. Anat. Bd. XXXIII, 1899.

{{Ref-Bremer1915}}

CLARK, E. R.: Further Observations on Living Growing Lymphatics; their Relation to Mesenchymal Cells. Am. Jour, of Anat., Vol. XIII 1911.

CLARKE, W. C.: Experimental Mesothelium. Anat. Record, Vol. VIII, 1914.

DANTSCHAKOFF, W.: Untersuchungen iiber die Entwicklung des Blutes und Bindegewebes bei den Vogeln. Anat. Hefte, Bd. XXXVII, 1908.

DANCHAKOFF, V.: Origin of the Blood Cells. Development of the Haematopoietic Organs and Regeneration of the Blood Cells from the Standpoint of the Monophyletic School. Anat. Record, Vol. X, No. 5, 1916.

DANCHAKOFF, VERA: Cell Potentialities and Differential Factors in Relation to Erythropoiesis. Am. Jour, of Anat., Vol. XXIV, 1918.

ETERNOD, A. C. F.: Premiers stades de la circulation sanguine dans 1'ceuf et embryon humain. Anat. Anz., Bd. XV, 1899.

EVANS, H. M.: On the Earliest Blood Vessels in the Anterior Limb Buds of Birds and their Relation to the Primary Subclavian Artery. Am. Jour, of Anat., Vol. IX, 1909.

His, W.: Anatomic menschlicher Embryonen. Leipzig, 1880-1885. With Atlas.

HOCHSTETTER, F.: Die Entwickelung des Blutgefasssystems. In Hertwig's Handbuch der vergleich. und experiment. Entwickelungslehre. Bd. Ill, Teil II, 1901. Contains also extensive bibliography.

HOWELL, W. H.: The Life History of the Formed Elements of the Blood, Especially the Red Blood-corpuscles. Journal of Morph., Vol. IV, 1890.

HUNTINGTON, G. S., and McCLURE, C. F. W.: Development of Postcava and Tributaries in the Domestic Cat. Am. Jour, of Anat., Vol. VI, 1907.

J HUNTINGTON, G. S.: The Phylogenetic Relations of the Lymphatic and Blood Vascular Systems in Vetebrates. Anat. Record, Vol. IV, 1910.

HUNTINGTON, G. S.: The Genetic Principles of the Development of the Systemic Lymphatic Vessels in the Mammalian Embryo. Anat. Record, Vol. IV, 1910.

HUNTINGTON, G. S.: The Development of the Lymphatic System in Reptiles. Anat. Record, Vol. V, 1911.

HUNTINGTON, G. S.: The Anatomy and Development of the Systemic Lymphatic Vessels in the Domestic Cat. Memoirs of the Wistar Institute of Anatomy and Biology, No. i, 1911.

HUNTINGTON, G. S.: The Development of the Mammalian Jugular Lymph Sac, of the Tributary Primitive Ulnar Lymphatic and the Thoracic Ducts from the Viewpoint of recent Investigations of Lymphatic Ontogeny, Am. Jour, of Anat., Vol. XVI, No. 3, 1914.

HUNTINGTON, GEORGE S.: The Morphology of the Pulmonary Artery in the Mammalia. Anat. Record, Vol. XVII, 1919.

KLING, C. A.: Studien iiber die Entwicklung der Lymphdriisen beim Menschen. Archvo f. mik. Anat., Ed. LXIII, 1904.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen, Bd. II, 1907.

LEHMAN, H.: On the Embryonic History of the Aortic Arches in Mammals. Anat. Am., Bd. XXVI, 1905.

LEWIS, F. T.: The Development of the Vena Cava Inferior. Am. Jour, of Anat., Vol. I, 1902.

LEWIS, F. T.: The Development of the Veins in the Limbs of Rabbit Embryos. Am. Jour, of Anat. Vol. V, 1906.

MALL, F. P.: Development of the Internal Mammary and Deep Epigastric Arteries in Man. Johns Hopkins Hosp. Bull., 1898.

{{Ref-Mall1905}}

{{Ref-Mall1912}}

MAXIMOW, A.: Die Friihesten Entwicklungsstadien der Blut- und Bindegewebszellen beim Saugetierembryo, bis zum Anfang der Blutbildung in der Leber. Arch. f. mik. Anat., Bd. LXXIII, 1909.

MAXIMOW, A.: Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leber der Saugetiere. Folia Hdmatolog., Bd. VIII, 1909.

MAXIMOW, A.: Die embryonale Histogenese des Knochenmarks der Saugetiere. Arch.f. mik. Anat., Bd. LXXVI, 1910.

McCLURE, C. F. W.: The Development of the Lymphatic System in Fishes with Especial Reference to its Development in the Trout. Memoirs of the Wistar Institute of Anatomy and Biology, No. 4, 1915.

McCLURE, C. F. W., and SILVESTER, C. F.: A Comparative Study of theLymphatico- Venous Communications in Adult Mammals. Anat. Record, Vol. Ill, 1909.

MILLER, A. M.: Histogenesis and Morphogenesis of the Thoracic Duct in the Chick; Development of Blood Cells and their Passage to the Blood Stream via the Thoracic Duct. Am. Jour, of Anat., Vol. XV, 1913.

MINOT, C. S.: On a Hitherto Unrecognized Form of Blood Circulation without Capillaries in the Organs of Vertebrata. Proc. Boston Soc. Nat. Hist., Vol. XXIX, 1900.

REAGAN, F. P.: Experimental Studies on the Origin of Vascular Endothelium and of Erythrocytes. Am. Jour, of Anat., Vol. XXI, 1917.

ROSE, C.: Zur Entwickelungsgeschichte des Saugetierherzens. Morph. Jahrbuch, Bd. XV, 1889.

RUCKERT, J., and MOLLIER, S.: Die erste Entstehung der Gefasse und des Blutes bei Wirbeltiere. In Hertwig's Handbuch der vergleich und experiment. Entwickelungslehre, Bd. I, Teil I, 1906. Contains also extensive bibliography.

SABIN, F. R. : On the Origin of the Lymphatic System from the Veins and the Development of the Lymph Hearts and Thoracic Duct in the Pig. Am. Jour, of Anat., Vol. I, 1902.

SABIN, F. R.: The Origin and Development of the Lymphatic System. The Johns Hopkins Hospital Reports Monographs, New Series, No. 5, 1913.

SALA, L.: Svilluppo dei cuori linfatici e dei dotti toracici nelP embrione di polio. Ricerche fatte nel laboratorio de anatomia normale della R. Universita di Roma, Vol. VII, 1900.

SCAMMON, R. E., and NORRIS, E. H.: On the Time of the Post-natal Obliteration- of the Foetal Blood-passages (Foramen ovale, Ductus arteriosus, Ductus Venosus). Anat. Record, Vol. XV, 1918.

SCHULTE, H. VON W.: Early Stages of Vasculogenesis in the Cat (Felis domestica) with Especial Reference to the Mesenchymal Origin of Endothelium. Memoirs of the Wistar Institute of Anatomy and Biology, No. 3, 1914.

SCHULTE, H. VON W.: The Fusion of the Cardiac Anlages and the Formation of the Cardiac Loop in the Cat (Felis domestica). Am. Jour, of Anat., Vol. XX, 1916.

{{Ref-Senior1919}}

STOCKARD, CHAS. R.: The Origin of Blood and Vascular Endothelium in Embryos without a Circulation of the Blood and in the Normal Embryo. Am. Jour.] of Anat. t Vol. XVIII, No. 2, 1915.

STOERK, O.: Uber die Chromreaktion der Glandula coccygea und die Beziehung dieser Druse zum Nervus sympthathicus. Arch. f. mik. Anat., Bd. LXIX, 1906.

STOHR, P.: Uber die Entwicklung der Darmlymphknotchen und uber die Riickbildung von Darmdriisen. Arch. f. mik. Anat., Bd. LI, 1898.

{{Ref-Streeter1915}}

TANDLER, J.: Zur Entwickelungsgeschichte der menschlichen Darmarterien. Anat. Heft, Bd. XXIII, 1903.

TONKOFF, W.: Die Entwickelung der Milz bei den Amnioten. Archil), f. mik. Anat., Bd. LVI, 1900.

WEIDENREICH, F.: Die Morphologic der Blutzellen und ihre Beziehungen zu einander. Anat. Record, Vol. IV, 1910.

WEST, R.: The Origin and Early Development of the Posterior Lymph Heart in the Chick. Am. Jour, of Anpt., Vol. XVII, 1915.

WRIGHT, J. H.: The Origin and Nature of the Blood Plates. Boston Med. and Surg. Jour., Vol. CLIV, 1906.

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Book - Text-Book of Embryology 10

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=The development of the vascular system=

The blood vessels constitute such an extensive and complex system that it is obviously beyond the scope of this book to consider the entire system in detail. Consequently attention must be directed only to the development of the main channels, including the heart, and to the principles of vessel formation.

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[[File:Bailey156.jpg|600px]]

'''Fig. 156. Surface views of chick blastoderms.''' Ruckert, Hertwig.

:a, Blastoderm with primitive streak and head process; showing blood islands (dark spots in crescent-shaped area in lower part of figure).

:b, Blastoderm with 6 pairs of primitive segments. Reticulated appearance is due to blood islands (dark spots) and to developing vessels, the entire reticulated area being the area vasculosa.

The formation of blood vessels in all the higher vertebrates including mammals begins in the opaque area of the blastoderm (area opaca) while the germ layers still lie flat. Toward the end of the first day of incubation in the chick, about the time the primitive streak reaches the height of its development, the peripheral part of the area opaca caudal and lateral to the primitive streak presents a mottled appearance (Fig. 1560). This indicates the beginning of the area vasculosa, which subsequently extends forward in the peripheral portion of the opaque area, lateral to the developing body, and becomes reticulated in appearance (Fig. 156^).
<div id="Fig157"></div>
[[File:Bailey157.jpg|Thumb|'''Fig. 157. Section of blastoderm (area opaca) of chick of 27 hours' incubation.''' Photograph.]]

Sections of the blastoderm show that the mottled surface appearance is due to clusters of cells amidst the mesoderm, known as blood islands (Fig. 157). These are composed of rounded cells which have developed from the branched mesodermal (mesenchymal) cells, and are situated in close apposition to the entoderm. Subsequently, when the coelom appears in this region, they lie in the visceral, or splanchnic, layer of mesoderm (Fig. 158).

The early changes that occur in the blood islands are important as regards both developing vessels and blood cells. The superficial cells of an island are transformed into flat cells placed edge to edge which surround the remaining rounded cells. The flat cells constitute the endothelium of a primitive blood space, while the cells within the space comprise primitive blood cells (Fig. 158). These early spaces in the area vasculosa join one another and become continuous to form a net-work, or plexus, of channels to which is due the reticulated appearance referred to above (Fig. 1566). This is known as the vitelline plexus. The groups of primitive blood cells within the channels will be considered in detail in a subsequent section (page 236).

<div id="Fig158"></div>
[[File:Bailey158.jpg|600px]]

'''Fig. 158. Section of blastoderm of chick of 42 hours' incubation.''' Photograph. The cells of the blood islands are differentiated into primitive blood cells and the endothelium of the vessels.

During the second day of incubation in the chick the peripheral channels of the vascular area unite to form a vessel the sinus terminalis which is continuous around the border except at the head end of the embryo (Fig. 159). At the same time the vascularization of the visceral layer of mesoderm gradually extends through the clear area of the blastoderm (area pellucida) toward and finally into the embryonic body. Reaching the region just lateral to the notocord, the vessels unite longitudinally in the embryo to form a continuous channel, the primitive aorta, which thus constitutes a natural selvage to the vascular area on each side of the blastoderm (Fig. 159). Some of the channels of the vitelline plexus increase in size and coalesce to form a large trunk which is a branch of the primitive aorta on each side and leads off into the smaller vessels in the peripheral part of the vascular area. This trunk is known as the vitelline, or omphalomesenteric, artery and is at first located near the caudal end of the embryo. When circulation is established through contractions of the heart it carries blood from the aorta to the surface of the yolk sac (Fig. 159). Other channels of the vitelline plexus nearer the head end of the embryo likewise form a large trunk, the vitelline, or omphalomesenteric, vein which collects the blood from the surface of the yolk sac and conveys it to the heart (Fig. 159).

So long as the germ layers lie flat the two primitive aortae remain separate, but with the ventral flexion and fusion of the germ layers to form the tubular body the aortae fuse into a single medial vessel, the dorsal aorta, except in the cervical region where the two original vessels persist as the dorsal aortic roots. The proximal ends of the vitelline arteries also fuse into a single trunk, the two vitelline veins, however, remaining separate. In each branchial arch on each side a vessel develops which joins with the corresponding dorsal aortic root. These vessels the aortic arches arise from single vessel on each side ventral to the pharynx which is known as the ventral aortic root. The two ventral aortic roots arise from a single medial vessel, the aortic trunk, or truncus arteriosus, which in turn is a continuatioi of the early tubular heart.

<div id="Fig159"></div>
[[File:Bailey159.jpg|600px]]

'''Fig. 159. Dorsal surface view of chick embryo with 18 segments, including the area vasculosa.''' Photograph, X 15. The blood vessels were injected with India ink, the dark blotch in the upper left corner indicating some ink which escaped during the injection.

The heart, having developed and become a contractile organ in the meantime, receives the blood in its caudal end through the vitelline veins and ejects it from its cephalic end through the aortic trunk. The blood then passes through the aortic arches to the dorsal aorta whence it is distributed to the vitelline plexus by the vitelline arteries. The blood is collected by tributaries of the vitelline veins and carried to the heart. Thus the vitelline (yolk) circulation is completed (Fig. 160). From this time on, the area vasculosa gradually enlarges, as the germ layers extend farther and farther around the yolk, until it eventually surrounds the whole yolk mass. In mammals, as in the chick, the vascular rudiments develop first in the extraembryonic portion of the mesoderm as clusters of cells which give the area opaca a mottled appearance on surface view. This soon changes to a reticulated appearance as the cell clusters give rise to primitive blood spaces which join one another to form a plexus of channels. This plexus gradually extends across the area pellucida toward the embryo and terminates in a natural selvage as the primitive aorta on each side of the median line. The vitelline arteries and veins are formed out of the plexus and, with the heart, aortic arches and dorsal aorta as in the chick, constitute the vitelline circulatory system (Fig. 161). The vascular area in some mammals gradually enlarges until it embraces the "entire yolk sac (Fig. 162).

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[[File:Bailey160.jpg|600px]]

'''Fig. 160. Diagram of the vitelline (yolk) circulation of a chick embryo at the end of the third day of incubation.''' Ventral view. Balfour.

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[[File:Bailey161.jpg|600px]]

'''Fig. 161. Surface view of area vasculosa of a rabbit embryo of 11 days.''' van Beneden and Julin. The vessel around the border is the sinus terminalis; the two large vessels above the embryo are the vitelline (omphalomesenteric) veins ; the two large vessels converging below the embryo are the vitelline (omphalomesenteric) arteries.

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[[File:Bailey162.jpg|600px]]

'''Fig. 162. Human embryo of 3.2 mm.''' His. The arrows indicate the direction of the blood current.

It is seen from the foregoing account that the earliest circulation is associated with the yolk sac. In animals below the mammals, where a large amount of yolk is present in the sac, the vitelline circulation is of prime importance in supplying the growing embryo with nutritive materials. In mammals the vitelline circulatory system develops as extensively as in the lower forms but, since little yolk is present, does not assume the same important role of carrying food supply; yet the portions of the vessels inside the embryo, viz. : the heart, aortic arches, aorta, the proximal part of the vitelline artery, and the vitelline veins, form parts of the permanent vascular system. In reptiles and birds a second set olyessels develops in connection with the allantois and serves to carry away the waste products of the body and deposit them in that sac-like structure. Two arteries, one on each side, arise as branches of the dorsal aorta near its caudal end and pass out of the body along with the allantoic duct to ramify upon the surface of the allantois. These are the umbilical, or allantoic, arteries. The blood is collected and carried back by the umbilical veins which pass along the 'allantoic duct to the body and then forward, one on each side, through the somatic layer of mesoderm to join the ducts of Cuvier. The duct of Cuvier, formed on each side by the junction of the anterior and posterior cardinal veins, which will be considered in a subsequent section, pour their blood into the sinus venosus. This venous trunk is formed by the junction of the ducts of Cuvier with -the vitelline veins and empties directly into the heart.

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[[File:Bailey163.jpg|600px]]

'''Fig. 163. Diagram of the umbilical vessels in the belly stalk and chorion.''' Kollmann's Atlas.

In mammals in general the allantois is a rudimentary structure incapable of receiving the total waste of the embryo. The umbilical (allantoic) vessels develop, however, as in reptiles and birds but become associatec through the belly stalk with the placenta which establishes communication between the embryo and the mother (Fig. 163). The vessels within the embryo are at first disposed in the same manner as in the lower forms, the umbilical arteries arising from the caudal portion of the aorta and the umbilical veins passing forward in the ventro-lateral body wall to join the ducts of Cuvier. With the formation of the umbilical cord the two umbilical veins within this structure fuse into a single vessel (Fig. 164). The later changes in the umbilical veins are most conveniently considered subsequently. In mammals in general the umbilical (allantoic) circulatory system performs a two-fold function. The blood carries to the placenta the waste products of the embryo for deposition in the maternal circulation, the waste in the lower forms (reptiles and birds) being deposited in the allantois. The blood carries from the placenta the food materials derived from the maternal circulation, the food in the lower forms being taken from the yolk sac and conveyed to the embryo by the vitelline vessels.

<div id="Fig164"></div>
[[File:Bailey164.jpg|600px]]

'''Fig. 164. Reconstruction of a human embryo of 7 mm.''' Mall.

:Arteries represented in black. A.V., Auditory vesicle; B, bronchus; L, liver; K, anlage o kidney; T, thyreoid gland; III-XII, cranial nerve roots; 1, 2, 3, 4, branchial grooves; 1, 8, 12, 5 (on spinal nerve roots), 1st and 8th cervical, 12th dorsal, 5th lumbar spinal nerve respectively. Dotted outlines represent limb buds.

==Principles of Vasculogenesis==

Upon the thesis that tissues in general must receive materials which they build up into their own substances and must discharge the products of their activities, the vascular channels of the body can be considered as structural expressions of this functional necessity. For instance, a muscle which acts must receive materials to compensate it for its loss and must discharge the waste products that result from its action, and the blood vessels are peculiarly adapted to these functions. The lymph vessels, too, similar in structure to the blood vessels, although efferent relative to the tissues, play their part in conveying the products of metabolism.

Much controversy has arisen over the actual genesis, or origin, of blood vessels and lymphatics, and as yet the opposing views have not been reconciled. In brief there are two views: One that with a few exceptions every vessel in the body develops as a sprout from another vessel, that is, the endothelium arises from preexisting endothelium by proliferation of its own cells; the other that vessels in general arise in situ, that is, the lumen of a vessel represents an intercellular tissue space^or several such spaces, whose bordering cells have been transformed into the characteristic endothelial cells, and as a corollary, the continuity of a given vessel results from the union of such spaces. According to the latter view, the whole vascular system represents intercellular tissue spaces which, with their lining of flattened cells, have united to form a set of continuous channels.

In the case of either view it is recognized that the first vessels appear in the opaque area of the blastoderm. Here the blood islands originate as clusters of cells amidst the mesoderm, differentiating from mesenchymal elements in close approximation to the entoderm (Fig. 157). The superficial cells of the clusters are then transformed into flat cells placed edge to edge to form the endothelial wall of a primitive blood space. These blood spaces join one another and thus form a net-work of channels. From this point in development the two views diverge.

The evidence adduced in favor of either theory is too great in volume to set down here. The advocates of the theory of sprouting of the endothelium lay stress upon the evidence of injected specimens. By injecting developing blood vessels at successive stages it is found that the vascular field gradually becomes larger, and the inference is that the individual channels are extending farther and farther from the focus of origin through proliferation and migration of the endothelial elements. This method, of course, would demonstrate vessels only so far as the lumina are continuous. Solid cords of cells which extend beyond the field of injection are interpreted as cords of endothelial cells which subsequently acquire lumina and become capillary tubes. If this theory is correct then the vascularization of the area pellucida and of the embryonic body would be effected through true outgrowths of the original endothelium of the opaque area. Possible exceptions to this, as noted above, are the rudiments of the heart, the aorta and the cardinal veins which arise in situ as do the first vascular rudiments. Observations upon growing vessels in living embryos, in which strands of cells were seen to extend from the endothelium already present, have also been accepted as evidence in favor of this view.

The evidence afforded by injected specimens has been attacked by those who believe in the in situ origin of vessels, on the ground that the injection shows only vessels with continuous lumina and does not prove the nonexistence of isolated vascular rudiments beyond the field of injection. It is claimed that the vascular field becomes more extensive through the gradual addition of such isolated spaces to the channels already continuous, in the same manner that the primitive blood spaces unite to form a network, and the claim is supported by demonstration of these spaces in the mesenchymal tissue with every gradation between the bordering flattened cells (endothelium) and the branching irregular mesenchymal cells. The actual formation of intercellular spaces with flat bordering cells and their union with vascular channels have been observed in the living chick blastoderm. Experimental evidence has also been brought to bear in favor of the view that vessels arise in situ. The area opaca was entirely removed from the chick blastoderm before any vascular rudiments had appeared in the area pellucida and the blastoderm was then allowed to develop further; it was found that vascular rudiments appeared both in the area pellucida and embryonic body with practically the same disposition as in the normal embryo.

The concept that the vascular channels are structural expressions of the functional necessity of carrying nutritive materials to the tissues and waste products away from them leads to consideration of such factors as may be involved in the formation of vessels; that is, factors that would cause plastic cells, like those of the mesenchyme in which the earliest and simplest vessels appear, to change in character and rearrange themselves to form capillary tubes. In a mass of mesenchymal tissue, in which there is a resemblance to a sponge with the cellular elements representing the parenchyma of the sponge and the intercellular tissue spaces the interstices, the products of cell activity naturally accumulate in the intercellular spaces. Incident to this accumulation, pressure would be exerted upon the cells bordering the spaces. Seeking outlet from the confines of the spaces, the waste products would move, or flow, and cause friction against the cells past which they flow. Similarly, pressure and friction would result from the movement of nutritive materials to and through the tissue. The plastic mesenchymal cells, reacting to these mechanical influences, would tend to become flat, and the continued operatic of the factors would result in a smooth- walled tube in which the movement of fluid is greatly facilitated.

The reaction of the irregular mesenchymal cells to the mechanical influences of pressure and friction is, of course, the crux of the question. It has been shown experimentally that cells of this type do react to mechanical stimuli. Smooth non-irritating foreign bodies have been imbedded in the loose connective tissue of an animal and the cells in contact therewith became flat and formed a mosaic apparently identical with simple squamous epithelium or endothelium. In the growth of mesenchymal tissue outside of the body (in vitro) it has been observed that the cells flatten against foreign substances which may be present.

In the embryo it has been observed that where blood vessels disappear, which they do in certain regions, the endothelium does not degenerate but that the cells assume irregular branching forms. This would indicate that endothelium comprises merely modified mesenchymal cells and that upon removal of the factors incident to the pressure and friction of blood flow the cells reassume the indifferent character of mesenchyme, thus reverting to the mesenchymal type. It militates, therefore, against the view that endothelium is a specific tissue.

It is generally recognized, whether or not the endothelium originates in situ, that a capillary network precedes the formation of larger vessels. For instance, the vitelline plexus of capillaries (p. 186) antedates any of the larger vitelline vessels which later carry blood to and from the embryo. The establishment of vascular trunks in this plexus of small vessels seems to be dependent upon the same mechanical factors that were considered as operative in the origin of vessels; viz.: pressure and friction. If the volume of blood that flows through a given capillary network at a given rate is increased the flow will naturally follow the channels that offer the least resistance, and these channels will increase in size sufficiently to accommodate the greater volume. A few channels, or perhaps even only one, will form the most direct course, and the angles in the course will be still further reduced as the blood stream impinges upon the walls of the vessels. In this manner a large vessel, or main vascular trunk, is established and the remaining smaller vessels constitute its branches or tributaries. A rather crude analogy would be the draining of a swamp in which a small rivulet, once gaming slight supremacy over its fellows, would gradually cut its way deeper into the soil and pursue a straighter course, with the result that the other rivulets would flow into it as the main channel.

The concept that the main vascular trunks are preceded by a capillary plexus, out of which they develop in response to certain mechanical stimuli, offers a simple explanation of the numerous variations found in the vascular system. In the incipient stages of the larger vessels but slight influences, due to variations in the development of surrounding structures, would be sufficient to deflect their courses and cause them to occupy positions which do not accord with the normal. So far as the thickened walls of the larger vascular channels are concerned, they may be regarded as structural adaptations to the functions they perform. For example, the large amount of elastic tissue in the wall of the aorta and other large arteries tends to maintain a uniform diameter in these vessels against the force exerted by the blood expelled from the heart at each contraction.

==The Heart==
<div id="Fig165"></div>
[[File:Bailey165.jpg|thumb|300px|'''Fig. 165. Diagrams showing the two anlagen of the heart and their union to form a single structure'''; made from camera lucida tracings of transverse sections of chick embryos. In C the ventral mesocardium has disappeared (see text).]]
The heart has a peculiar origin in that it arises as two separate parts or anlagen which unite secondarily. In the chick, for example, it appears during the first day of incubation, at a time when the germ layers are still flat. The ccelom in the cephalic region becomes dilated to form the so-called primitive pericardial cavity (parietal cavity), and at the same time a space appears on each side, not far from the medial line, in the mesodermal layer of the splanchnopleure (Fig. 165). These spaces at first are filled with a gelatinous substance in which lie a few isolated cells. These cells then take on the appearance of endothelium and line the cavities, and the mesothelium in this vicinity is changed into a distinct, thickened layer of cells. Now by a bending ventrally of the splanchnopleure the cavities or vessels are carried toward the mid ventral line (Fig. 165). The bending continues until the entoderm of each side meets and fuses with that of the opposite side, thus closing in a flat cavity the fore-gut. The entoderm ventral to the cavity breaks away and allows the medial walls of the two endothelial tubes to come in contact. These walls then break away and the tubes are united in the midventral line to form a single tube (Fig. 165), which extends longitudinally for some distance in the cervical region of the embryo. The mesothelial layers of opposite sides meet dorsal and ventral to the endothelial tube, forming the dorsal and ventral mesocardium (Fig. 165). In the meantime the cephalic end of the tube has united with the arterial system, and the caudal end with the venous system ; and in a short time the dorsal and ventral mesocardia disappear and leave the heart suspended by its two ends in the primitive pericardial cavity. The conditions at this point may be summarized thus: The heart is a double-walled tube the inner wall composed of endothelium and destined to become the endocardium, the outer wall of a thicker mesothelial layer and destined to become the myocardium the two walls separated by a considerable space. The organ hangs, as it were, in the primitive pericardial cavity (ccelom), connected at its cephalic end with the ventral aortic trunk and at its caudal end with the omphalomesenteric veins.

In all mammals thus far studied the principle of development in the earlier stages is essentially the same as in the chick. The double origin of the heart is even more marked because of the relatively late closure, of the fore-gut. There are no observations on the origin of the heart in human embryos, but it is reasonable to assume that it has the same double origin as in other Mammals, although in embryos of 2 to 3 mm. the organ has already become a single tube (Figs. 166 and 167). At this stage the tube is somewhat coiled.

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'''Fig. 166. Transverse section of a human embryo of 2.69 mm.''' von Spee, Kollmann's Atlas.

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'''Fig. 167. Ventral view of reconstruction of human embryo of 2.15 mm.''' His. The ventral body wall has been removed. The vessels (in black) at the sides of the duct of the liver are the omphalomesenteric veins.

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[[File:Bailey168.jpg|thumb|300px|'''Fig. 168.''' Ventral part of transverse section through the heart region of Salamandra maculosa embryo with 4 branchial arches. Rabl.]]

While the double origin of the heart is characteristic of all amniotic Vertebrates (Reptiles, Birds, Mammals), in all the lower forms the organ arises as a single anlage. In the region of the fore-gut the two halves of the ccelom are separated by a ventral mesentery which extends from the gut to the ventral body wall, and which is composed of two layers of mesothelium with a small amount of mesenchyme between them. In the mesenchyme a cavity appears and is lined by a single layer of flat (endothelial) cells. This cavity extends longitudinally for some distance in the cervical region and with its endothelial and mesothelial walls constitutes the simple cylindrical heart. On the dorsal side it is connected with the gut by a portion of the mesentery which is called the dorsal mesocardium; on the ventral side it is connected with the ventral body wall by the ventral mesocardium (Fig. 168). Thus the heart is primarily a single structure. The difference between the two types of development is not a fundamental one but simply depends upon the difference in the germ layers. In the lower forms the germ layers are closed in ventrally from the beginning, and the heart appears in a medial position. In the higher forms the germ layers for a time remain spread out upon the surface of the yolk or yolk sac, and the heart begins to develop before they close in on the ventral side of the embryo. Consequently the heart arises in two parts which are carried ventrally by the germ layers and unite secondarily.

The further development of the heart consists of various changes in the shape of the tube and in the structure of its walls. At the same time the dilatation of the ccelom (primitive pericardial cavity) in the cervical region is of importance in affording room for the heart to grow. In the chick, for example, the tube begins, toward the end of the first day of incubation, to bend to the right; during the second day it continues to bend and assumes an irregular S-shape. This bending process has not been observed in human embryos, but other Mammals show the same process as the chick. In a human embryo of 2.15 mm. the S-shaped heart is present (Fig. 167). The venous end, into which the omphalomesenteric veins open, is situated somewhat to the left, extends cranially a snort distance and then passes over into the ventricular portion. The latter turns ventrally and extends obliquely across to the right side, then bends dorsally and cranially to join the aortic bjulb which in turn joins the ventral aortic trunk in the medial line. The endothelial tube, which is still separated from the muscular wall by a considerable space, becomes somewhat constricted at its junction with the aortic bulb to form the so-called f return Halleri. During these changes the heart as a whole increases in diameter, especially the ventricular portion. Gradually the venous end of the heart moves cranially and in embryos of 4.2 mm. lies in the same transverse plane as the ventricular portion. The latter lies transversely across the body (Fig. 169). At the same time two e vagina tions appear on the venous end, which represent the anlagen of the atria. In embryos of about 5 mm. further changes have occurred, which are represented in Fig. 170. The two atrial anlagen are larger than in the preceding stage and surround, to a certain extent, the proximal end of the aortic trunk. As they enlarge still more in later stages, they come in contact, their medial walls almost entirely disappear, and they form a single chamber. The ventricular portion of the heart becomes separated into a right and a left part by the interventricular furrow (Fig. 1 70) ; the right part is the anlage of the right ventricle, the left part, of the left ventricle. At the same time the atrial portion has moved still farther cranially so that it lies to the cranial side of the ventricular portion. The venous and arterial ends of the heart have thus reversed their original relative positions. At this point it should be noted that the atrial end of the heart is connected with the large venous trunk formed by the union of the omphalomesenteric veins and the ducts of Cuvier the sinus venosus.
{|
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| <div id="Fig170"></div>
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| '''Fig. 169. Ventral view heart of human embryo of 4.2 mm.'''

:His. The atria are hidden behind the ventricular portion.
| '''Fig. 170. Ventral view of heart of human embryo of 5 mm.''' His.
|}
During the changes in the heart as a whole, certain changes also occur in the endothelial and muscular walls. The walls of the atria are composed of compact plates of muscle with the endothelium closely investing the inner surface. The walls of the ventricular portion, on the other hand, become thicker and are composed of an outer compact layer of muscle and an inner layer made up of trabeculae which are closely invested by the endothelium.

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'''Fig. 171. Dorsal half of heart (seen from ventral side) of a human embryo of 10 mm.''' His.

Everywhere the endothelium is closely applied to the inner surface of the myocardium, the space which originally existed between the endothelium and mesothelium being obliterated.

The embryonic heart in Mammals in the earlier stages resembles that of the adult in the lower Vertebrates (Fishes). The atrial portion receives the blood from the body veins and conveys it to the ventricular portion which in turn sends it out through the arteries to the body. The circulation is a single one. This condition changes during the foetal life of Mammals with the development of the lungs. The same transition occurs in the ascending scale of development in the vertebrate series in those forms in which gill breathing is replaced by lung breathing. The change consists of a division of the heart and circulation, so that the single circulation becomes a double circulation. In other words, the heart, is so divided that the lung (pulmonary) circulation is separated from the general circulation of the body. This division first appears in the Dipnoi (Lung Fishes) and Amphibians in which gill breathing stops and lung breathing begins, although here the division is not complete. In Reptiles the division is complete except for a small direct communication between the ventricles.

Fig. 171 represents the dorsal half of the heart at a stage when all the chambers are in open communication, and shows the conditions in a single circulation but with the beginning of a separation. The atria are rather thin-walled chambers, the ventricles have relatively thick walls. Between the atrial and ventricular portion is a canal the atrio-ventricular canal which affords a free passage for the blood. From the cephalic side of the atrial portion a ridge projects into the cavity. This ridge represents a remnant of the original medial walls of the two atria and marks the beginning of the future atrial septum. The opening of the sinus venosus is seen on the dorsal wall of the right atrium. Primarily both atria communicated directly with the sinus venosus,but in the course of development the opening of the latter migrated to the right and at this stage is found in the wall of the right atrium. The opening is guarded, as it were, by a lateral and a medial fold the significance of which will be described later. The vetricular portion also shows a ridge projecting from the caudal side, which corresponds to the interventricular groove and represents the beginning of the ventricular septum.

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'''Fig. 172. Dorsal half of heart showing chambers and septa.''' (Semidiagrammatic.) Modified from Born.

===The Septa===

The further changes are largely concerned with the separation of the heart into right and left sides, and with the development of the valves. The atria become separated by the further growth on the cephalic side, of the ridge which has already been mentioned and which is known as the septum superius (Figs. 171 and 172). This septum grows across the cavity of the atria until it almost reaches the atrio-ventricular canal, forming the septum atriorum. A portion of the septum then breaks away, leaving the two atria still in communication. This secondary opening is the foramen ovale which persists throughout foetal life, but closes soon after birth. The atrio-ventricular canal also becomes divided into two passages by a ridge from the dorsal wall and one from the ventral wall uniting with each other and finally with the septum atriorum (Fig. 172). Thus the two atria would be completely separated if it were not for the foramen ovale.

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'''Fig. 173. Dorsal half of heart (ventral view) of rabbit embryo of 5.8 mm.''' Born.

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'''Fig. 174. Ventricles and proximal ends of aorta and pulmonary artery of a 7.5 mm human embryo.''' Lower walls of ventricles have been removed. Kollmann's Atlas.

During the separation of the atria, a division of the ventricular portion of the heart also occurs. On the caudal side of the ventricular portion a septum appears and gradually grows across the cavity forming the septum ventriculorum (Figs. 171 and 172). This septum is situated nearer the right side and is indicated on the outer surface by a groove which becomes the sulcus longitudinalis anterior and posterior. The dorsal edge of this septum finally fuses with the septum dividing the atrio-ventricular canal, but for a time its ventral edge remains free, leaving an opening between the two ventricles (Figs. 173 and 174).

This opening then becomes closed in connection with the division of the aortic bulb and ventral aortic trunk. On the inner surface of the aortic trunk, at a point where the branches which form the pulmonary arteries arise, two ridges appear, grow across the lumen and fuse with each other, thus dividing the vessel into two channels. This partition the septum aorticum (Fig. 175) gradually grows toward the heart through the aortic bulb and finally unites with the ventral edge of the ventricular septum, thus closing the opening between the two ventricles. Corresponding with the edges of the septum aorticum, a groove appears on each side of the aortic trunk and gradually grows deeper and extends toward the heart, until finally the trunk and aortic bulb are split longitudinally into two distinct vessels, one of which is connected with the right ventricle and becomes the pulmonary artery, the other with the left ventricle and becomes the proximal part of the aortic arch (Fig. 174). The result of the formation of these various septa is the division of the entire heart into two sides. The atrium and ventricle of each side are in communication through the atrio- ventricular foramen, the two sides are in communication only by the foramen ovale which is but a temporary opening.

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'''Fig. 175. Diagrams representing the division of the ventral aortic trunk into aorta and pulmonary artery and the development of the semilunar valves.''' Hochsietter.

After the opening of the sinus venosus is shifted to the right atrium, the left atrium for a short period has no vessels opening into it. As soon, however, as the pulmonary veins develop, they form a permanent union with the left atrium (Fig. 173). At first two veins arise from each lung, which unite to form a single vessel on each side; the two single vessels then unite to form a common trunk which opens into the left atrium on the cephalic side. As development proceeds, the wall of the single trunk is gradually absorbed in the wall of the atrium, until the single vessel from each side opens separately. Absorption continuing, all four veins, two from each lung finally open separately. This is the condition usually found in the adult. A partial failure in the absorption may leave one, two, or three vessels opening into the atrium. Such variations are not infrequently met with in the pulmonary veins.

===The Valves===

If all the passageways between the different chambers of the heart and the large vascular trunks were to remain free and clear, there would be nothing to prevent the blood from flowing contrary to its proper course. Consequently five sets of valves develop in relation to these orifices, and are so arranged that they direct the blood in a certain definite direction. These appear (a) at the openings of the large venous trunks into the right atrium, (b) at the opening between the right atrium and right ventricle, (c) at the opening between the left atrium and left ventricle, (d) at the opening between right ventricle and pulmonary artery and (e) at the opening between the left ventricle and aorta. No valves develop at the openings of the pulmonary veins into the left atrium.

(a) The sinus venosus (which is formed by the union of the large body veins) opens into the right atrium on its cranial side, as has already been mentioned (p. 201). By a process of absorption, similar to that in the case of the pulmonary veins, the wall of the sinus is taken up into the wall of the atrium. The result is that the vena cava superior, vena cava inferior, and sinus coronarius (a remnant of the left duct of Cuvier) open separately into the atrium. As the sinus is absorbed, its wall forms two ridges on the inner surface of the atrium, one situated at the right of the opening and one at the left (Figs. 172 and 173). These two ridges valvulce venosce are united at their cranial ends with the septum spurium (Fig. 171), a ridge projecting from the cephalic wall of the atrium. The septum spurium probably has a tendency to draw the two valves together and prevent the blood from flowing back into the veins. The left valve and the septum spurium later atrophy to a certain extent and probably unite with the septum atriorum to form part of the limbus fossce ovalis (Vieussenii) . The right valve is the larger and in addition to its assistance in preventing a backward flow of blood into the veins, it also serves to direct the flow toward the foramen o\;ale. As the veins come to open separately, the cephalic part of the right valve disappears; the greater part of the remainder becomes the valvula Deuce cavce inferioris (Eustachii) and during fcetal life directs the blood toward the foramen ovale. In the adult it becomes a structure of variable size. A small part of the remainder of the right valve forms the valvula sinus coronarii (Thebesii) which guards the opening of the coronary sinus.

(b) and (c) The valves between the atrium and ventricle on each side develop for the most part from the walls of the triangular atrio-ventricular opening (ostium atrio-ventriculare) . Elevations or folds appear on the rims of the openings and project into the cavities of the ventricles where they become attached to the muscle trabeculae of the ventricle walls (Figs. 176 and 177). On the right side three of these folds appear, and develop into the valvula tricuspidalis which guards the right atrio-ventricular orifice. On the left side only two folds appear, and these become the valvula biscuspidalis (mitralis) which guards the left atrio-ventricular orifice. These valves, which are at first muscular, soon change into dense connective tissue. The muscle trabeculae to which they are attached also undergo marked changes. Some become condensed at the ends which are attached to the valves into slender tendinous cords the chorda tendinece, while at their opposite ends they remain muscular as the Mm. papillares; others remain muscular and lie in transverse planes in the ventricles, or fuse with the more compact part of the muscular wall, or form irregular, anastomosing bands and constitute the Irabecula carnea (Fig. 176).

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'''Fig. 176. Diagrams representing the development of the atrio-ventricular valves, chordae, tendineas, and papillary muscles.''' Gegenbaur.

(d) and (e) The valves of the pulmonary artery and aorta develop at the point where originally the endothelial tube was constricted to form the f return Halleri (p. 200) where the ventricular portion of the heart joined the aortic bulb. Before the aortic trunk and bulb are divided into the aortic arch and pulmonary artery, four protuberances appear in the lumen (Fig. 213). The septum aorticum then divides the two which are opposite so that each vessel receives three (Fig. 175). These then become concave on the side away from the heart, in a manner which has not been fully determined, and at the same time enlarge so that they close the lumen. Those in the pulmonary artery are known as the valvula semilunares arteria pulmonalis, those in the aorta as the valvula semilunares aorta.

===Changes after Birth===

The migratory changes of the heart from its original position in the cervical region to its final position in the thorax will be considered in connection with the development of the pericardium (Chap. XIV). With the exception of the septum atriorum, the heart acquires during fcetal life practically the form and structure characteristic of the adult (Fig. 178). So long as the individual continues to grow, the heart, generally speaking, increases in size accordingly. This increase takes place by intussusception in the endocardium and myocardium. At the time of birth the two atria are in communication through the foramen ovale which is simply an orifice in the atrial septum (Fig. 179). Thus the blood which is brought to the right atrium by the body veins is allowed to pass directly into the left atrium, thence to the left ventricle, and thence is forced out to the body again through the aorta. A certain amount of blood also passes from the right atrium into the right ventricle and thence into the pulmonary artery; but this blood does not enter the lungs but passes directly into the aorta through the ductus arteriosus (Fig. 178). After birth the lungs begin to function and the placental blood is cut off, so that the right atrium receives venous blood only and the left arterial blood only. If the foramen ovale were to persist it would allow a mingling of venous and arterial blood. Consequently the foramen ovale closes soon after birth and the two currents of blood are completely separated. At the same time the ductus arteriosus atrophies and becomes the ligamentum arteriosum. Consequently there is no direct communication between the pulmonary artery and aorta.

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'''Fig. 177. Transverse section of pig embryo of 14 mm.''' Photograph.

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'''Fig. 178. Ventral view of heart of foetus at term.''' Kollmann's Atlas.

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'''Fig. 179. Dorsal half of foetal heart.''' Bumm, Kollmann's Atlas.

Certain features of development have an important bearing on the theories regarding the physiology of the heart, particularly on the theory that the heart is an automatic organ. Whether the theory that the heart beats automatically, i.e., independently of stimuli from the nervous system, is true or not, it is a fact that in the embryo it begins to beat before any nerve cells appear in it and before any nerve fibers are connected with it. At least no technic has yet been devised by which it is possible to demonstrate nerve cells in, or fibers connected with it, at the time when it begins to perform its characteristic function. And, furthermore, at the time when the heart begins to beat, no heart muscle cells are developed. This last fact seems to indicate an inherent contractility in the mesothelial cells which form the anlage of the myocardium.

===The Arteries===

The simplest condition of the arterial system, following the establishment of the vitelline and allantoic circulation (p. 189 and p. 191), is as follows: The single ventral aortic trunk is given off from the cephalic end of the heart. This is a short vessel, soon dividing into the two vejntral aortic roots which pass forward beneath the pharynx (Fig. 180). Each ventral aortic root gives rise to branches which pass dorsally, one in each branchial arch, as the aortic arches to unite in a common stem along the dorsal wall of the pharynx. This common stem is the dorsal aortic root (Fig. 1 80) which fuses with its fellow of the opposite side in the middorsal line to form the dorsal aorta. The single dorsal aorta, situated ventral to the notochord, extends from the cervical region to the caudal end of the embryo. Somewhat caudal to the middle of the embryo a branch of the aorta passes ventrally through the mesentery as the vitelline artery which enters the umbilical cord (Fig. 164). Still farther caudally the paired umbilical (allantoic) arteries are given off from the aorta and pass out into the umbilical cord (Fig. 164).

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'''Fig. 180. From reconstruction of aortic arches (i, 2, 3, 4, 6) of left side and pharynx of a 5 mm human embryo.''' Tandler. I-IV, Inner branchial grooves.

The conditions which exist at this stage in the region of the aortic arches in mammalian embryos are indicative of the conditions which persist as a whole or in part throughout life in the lowest Vertebrates. The changes which occur in Mammals, however, are profound and the adult condition bears no resemblance to the embryonic. Yet certain features in the adult are intelligible only from a knowledge of their development. In the human embryo ,ix aortic arches appear on each side. The first, second, third, and fourth pass through the corresponding branchial arches. The fifth arch, which is merely a loop from the fourth, seems to pass through the fourth branchial arch. The sixth aortic arch passes through the region behind the fourth branchial. All these arches are present in embryos of 5 mm. (Fig. 180). In Fishes and larval Amphibians, where the branchial arches develop into the gills, the aortic arches are broken up into capillary networks which ramify in the gills, and the ventral aortic root becomes the afferent vessel, the dorsal aortic roots the efferent vessels. In the higher Vertebrates and in man the aortic arches begin, at a very early period, to undergo changes; some disappear and others become portions of the large arterial trunks which leave the heart. In connection with the following description, constant reference to Figs. 181 and 182 will assist the student in understanding <he changes.

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'''Fig. 181. Diagram of the aortic arches of a Mammal.''' Modified from Hochstetter.

The first and second arches soon atrophy and disappear. The third arch on each side becomes the proximal part of the internal carotid artery, while the continuation of the dorsal aortic root, cranially to the third arch, becomes its more distal part. The continuation of the ventral aortic root cranially to the third, arch, becomes L the proximal artery, while the portion of the ventral aortic root between the third and fourth arches becomes the common carotid artery. The portion of the dorsal aortic root between the third and fourth arches disappears. The fourth aortic arch on the left side enlarges and becomes the arch of the aorta (arcus aorta) which is then continued caudally through the left dorsal aortic root into the dorsal aorta. On the right side, the fourth arch becomes the proximal part of the subclavian artery. Since the third, foutth, fifth, and 'sixth arches really leave the ventral aortic trunk as a single vessel, it will be seen that these changes bring it about that the common carotid and subclavian on the right side arise by a common stem, the innominate artery, which in turn is a branch of the arch of the aorta. On the left side, for the same reason, the common carotid is a branch of the arch of the aorta. The fifth aortic arch from the beginning is rudimentary and disappears very early. The sixth arch on each side undergoes wide changes. A branch from each enters the corresponding lung. On the right side the portion of the sixth arch between the branch which enters the lung and the dorsal aortic root disappears, as does also that portion of the right dorsal aortic root between the subclavian artery and the original bifurcation of the dorsal aorta. On the left side, however, that portion of the sixth arch between the branch which enters the lung and the dorsal aortic root persists until birth as the ductus arteriosus (Botalli). This conveys the, blood from the right ventricle to the aorta until the lungs become functional (Fig. 178); it then atrophies and becomes the ligamentum arteriosum. In the meantime the septum aorticum has divided the original ventral aortic trunk into two vessels (see p. 204); one of the vessels communicates with the left ventricle and is the proximal part of the arch of the aorta, the other communicates with the right ventricle and becomes the large pulmonary artery (fig. 174).

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'''Fig. 182. Diagram representing the changes in the aortic arches of a Mammal.''' Compare with Fig. 181. Modified from Hochstetter.

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'''Fig. 183. Diagram of the aortic arches (III, IV, VI) and segmental cervical arteries of a 10 mm human embryo.''' His.

In human embryos of 10 mm. the dorsal aortic root on each side gives off several lateral branches the segmental cervical vessels (Fig. 183). The first of these (first cervical, suboccipital), which arises nearly opposite the fourth aortic arch, is a companion, as it were, to the hypoglossal nerve, and J sends a branch cranially which unites with its fellow of the opposite side inside the skull to form the basilar artery. The basilar artery again bifurcates and each branch unites with the corresponding internal carotid by means of the circulus arteriosus (Fig. 185). The other segmental cervical vessels arise from the aortic root at intervals, the eighth arising near the point of bifurcation of the aorta. In a short time a longitudinal anastomosis appears between these segmental arteries, which extends as far as the seventh (Fig. 184). The proximal ends of the first six disappear, and the longitudinal vessel forms the vertebral artery which then opens into the aortic root through the seventh segmental artery, and which is continued cranially as the basilar artery (Fig. 185). The seventh (it is held by some to be the sixth) segmental artery becomes the subclavian, and consequently the vertebral opens into the subclavian, as in the adult (Fig. 184). But it should be borne in mind that the right subclavian artery is more than equivalent to the left, since the proximal part of the former is made up of the fourth aortic arch and a part of the aortic root (see Figs. 181 and 182). Furthermore, changes occur in the position of the heart during development, which alter the relations of the vessels. The heart migrates from its original position in the cervical region into the thorax, and this produces an elongation of the carotid arteries and an apparent shortening of the arch of the aorta; consequently the subclavian artery on the left side arises relatively nearer the heart.

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'''Fig. 184. Diagram illustrating the formation of the vertebral and superior intercostal arteries'''. The broken lines represent the portions of the original segmental vessels that disappear. Modified from Hochstetter.

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'''Fig. 185. Brain and arteries of a human embryo of 6 mm(?).''' Mall.

The arteries of the brain arise as branches of the internal carotid and circulus arteriosus. The anterior cerebral artery and the middle cerebral artery arise primarily from a common stem which in turn is a branch of the most cranial part of the internal carotid (Figs. 185 and 186). The posterior cerebral artery arises as a branch of the circulus arteriosus (Fig. 185).

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'''Fig. 186. Brain, arteries and veins of a human embryo of 33 mm.''' Mall

From the point of its bifurcation to its caudal end the aorta gives off paired, segmental branches which accompany the segmental nerves. The last (eighth) cervical branch and the first two thoracic branches undergo longitudinal anastomoses, similar to those between the first seven cervical, to form the superior intercostal artery (A. intercostalis suprema) which opens into the subclavian (Fig. 184). The other thoracic branches persist as the intercostal arteries; the lumbar branches persist as the lumbar arteries. At the same time anastomoses are formed between the distal ends of the intercostal and lumbar arteries in the ventro-lateral region of the body wall, which give rise, on the one hand, to the internal mammary artery and, on the other hand, to the inferior epigastric artery. Of these two the former opens into the subclavian, the latter into the external iliac. By a further anastomosis the distal ends of the internal mammary and inferior epigastric are joined, thus forming a continuous vessel from the subclavian to the external iliac (Fig. 187). It is interesting to note that while originally all the lateral branches of the aorta are arranged segmentally, many of them lose their segmental character and are replaced or supplemented by longitudinal vessels.

In addition to the dorsal segmental branches of the aorta, which have been described, other branches develop which carry blood to the viscera. A number of these, or possibly all, are also primarily segmental vessels, although they lose every trace of their segmental character during development. The first of the visceral branches to appear is the omphalomesenteric artery which arises from the ventral side of the aorta and which has been mentioned in connection with the vitelline circulation. Originally it passes out through the mesentery and follows the yolk stalk to ramify on the surface of the yolk sac. But since the yolk sac is of slight importance, the distal part of the artery soon disappears, while the proximal part becomes the superior mesenteric artery (Fig. 188). The cceliac artery arises from the ventral side of the aorta a short distance cranially to the omphalomesenteric (Fig. 1 88) and gives rise in turn to the gastric, hepatic and splenic arteries. The inferior mesenteric artery also arises from the ventral side of the aorta some distance caudal to the omphalomesenteric (Fig. 188). In the early stages these visceral arteries arise relatively much farther cranially than in the adult. During development they gradually migrate caudally to their normal positions.

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'''Fig. 187. Diagram of human embryo of 13 mm.''' Showing the mode of development of the internal mammary and inferior epigastric arteries. Mall.

Other branches of the aorta develop in connection with the urinary and genital organs. Several lateral branches supply the mesonephroi, but when the latter atrophy and disappear the vessels also disappear. A periaortic plexus of vessels, with many branches from the aorta, supplies the developing kidneys until these organs reach their definitive position, when one of the branches on each side enlarges to become the renal artery. The developing genital glands are likewise supplied by several branches from the aorta. Later the majority of these vessels disappear, one pair only persisting as the internal spermatic arteries which differ in accordance with the sex of the individual. In both sexes they are at first very short; in the female, as the ovaries move farther into the pelvic region, they become considerably elongated to form the ovarian arteries; in the male, with the descent of the testes, they become very much elongated to form the testicular arteries.

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'''Fig. 188. Diagram of the visceral arteries in a human embryo of 12.5 mm.''' Numerals indicate segmental arteries.
Tandler.

The fifth (or fourth?) pair of segmental lumbar arteries primarily gives rise to the vessels which supply the lower extremities, viz., the iliac arteries. These then would be serially homologous to the subclavians. But certain changes occur in this region, which are due to the relations of the umbilical arteries. The latter, as has already been noted, arise as paired branches of the aorta in the lumbar region, pass ventrally through the genital cord (Chap. XV) and then follow the allantois (urachus) to the umbilical cord.

During foetal life they carry all the blood that passes to the placenta. At an early period a branch from each iliac artery anastomoses with the corresponding umbilical, and the portion of the umbilical artery between the aorta and the anastomosis then disappears. This makes the umbilical artery a branch of the iliac; and the blood then passes from the aorta into the proximal part of the liiac which becomes the common iliac artery of the adult. At birth, when the umbilical cord is cut, the umbilical arteries no longer carry blood to the placenta, and their intraembryonic portions, often called the hypogastric arteries, persist only in part; their proximal ends persist as the superior vesical arteries, while the portions which accompanied the urachus degenerate to form the lateral umbilical ligaments.

So far as a complete history of the growth of the arteries of the extremities is concerned, knowledge is lacking. The facts of comparative anatomy and the anomalies which occur in the human body have led to certain conclusions which have been largely confirmed by embryological observations; but much more work on the development of the arteries is yet necessary to complete their history. The extremities represent outgrowths from several segments oft the body, the nerve supply is derived from several segments, and the limb buds are likewise primarily supplied by plexuses of vessels arising from several branches of the aorta. In the upper extremity the subclavian, which represents the seventh cervical branch of the aortic root, is the single vessel which eventually develops out of the original plexus. In the lower extremity the common iliac, which represents the fifth lumbar branch of the aorta, is the single vessel which develops out of the plexus supplying the lower limb bud.

In the upper extremity the subclavian grows as a single vessel to the wrist and then divides into branches corresponding to the fingers. In the forearm it lies between the radius and ulna. In a short time a branch is given off just distal to the elbow and accompanies the median nerve. As this branch increases, the original vessel in the forearm diminishes to form the volar interosseous artery; and at the same time the branch unites again with the lower end of the interosseous, takes up the digital branches and becomes the chief vessel of the forearm at this stage, forming the median artery. Later, however, it diminishes in size as another vessel develops, the ulnar artery, which arises a short distance proximal to the origin of the median and, passing along the ulnar side of the forearm, unites with the median to form the superficial volar arch. From the artery of the arm, which is called the brachial artery, a branch develops about the middle and extends distally along the radial side of the forearm. A little later another branch grows out from the brachial just proximally to the origin of the ulnar and extends across to, and anastomoses with, the first branch. Then the portion of the first branch between its point of origin and the anastomosis atrophies, leaving only a small vessel which goes to the biceps muscle. The second branch and the remaining part of the first branch together form the radial artery (Fig. 189) (McMurrich).

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Fig. 189. Diagrams showing (A) an early and (B) a late stage in the development of the arteries of the upper extremity. McMurrich.

In the lower extremity the primary artery is a continuation of the common iliac which, in turn, is a branch of the aorta. This primary vessel, the sciatic artery, passes distally as far as the ankle. Below the knee it gives off a short branch which corresponds to the proximal part of the anterior tibial artery. Just above the ankle it gives off another branch which corresponds to the distal part of the anterior tibial. As will be seen, these two parts join at a later period to form a continuous vessel. At this early stage the external iliac artery is but a small branch of the common iliac; but it gradually increases in size, extends farther distally in the thigh as the femoral artery and unites with the sciatic near the knee. Just proximal to its union with the sciatic it gives off a branch which extends distally along the inner side of the leg to the plantar surface of the foot, where it gives off the digital branches. This vessel is the saphenous artery in the embryo, and disappears in part during further development. From this time on, the femoral and its direct continuation, the popliteal, increase in size; and at the same time the sciatic loses its primary connection and becomes much reduced to form the inferior gluteal artery. The direct continuation of the sciatic in the leg, which is now the direct continuation of the popliteal, becomes reduced to form the peroneal artery. The branch of the original sciatic, which was given off just below the knee, unites with the branch which was given off just above the ankle to form a continuous vessel, the anterior tibial artery. A new branch arises from the proximal portion of the peroneal, extends down the back of the leg, and unites with the distal part of the embryonic saphenous to form the posterior tibial artery. The proximal part of the saphenous then atrophies, leaving but one of the small genu branches of the popliteal (Fig. 190) (McMurrich).

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'''Fig. 190. Diagrams showing three stages in the development of the arteries of the lower extremity.''' McMurrich.

===The Veins===

The changes which occur during the development of the venous system are so complicated, and in some cases so varied, that the scope of this book permits only a brief outline of the growth of the more important of the venous trunks.

Corresponding to the arterial system, the first veins to appear are the omphalomesenteric veins. These vessels, which carry blood from the yolk sac to the heart, arise in the area vasculosa, enter the embryonic body at the sides of the yolk stalk, pass cranially along the intestinal tract, and join the caudal end of the heart (Figs. 160, 162, 164 and 193). Next in point of time to appear are the umbilical veins which carry back to the heart the blood which has been carried to the placenta by the umbilical arteries. These also are paired veins within the embryo, although they form a single trunk in the umbilical cord. They extend cranially on each side through the ventrolateral part of the body wall and join the duct of Cuvier (see below) in the septum transversum (Figs. 163, 164 and 193). Very soon after the appearance of the umbilical veins two other longitudinal vessels develop, one on each side of the aorta. In the cervical region they lie dorsal to the branchia arches and are called the anterior cardinal veins (Figs. 162 and 193). The more caudal parts of the vessels are situated in the region of the developing mesonephros and are called the posterior cardinal veins (Figs. 162 and 193). At a point about opposite the heart the anterior and posterior cardinals on each side unite to form a single vessel, the duct ofCuvier, which turns medially through the septum transversum and opens into the sinus venosus (Figs. 162 and 178). Thus three primary sets of veins are formed at a very early stage of development: (i) The omphalomesenteric veins; (2) the umbilical veins; (3) the cardinal veins.

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'''Fig. 191. Veins of the head of a 9 mm. human embryo.''' Mall.

The veins of the head and neck regions are derivatives of the anterior cardinals. The proximal parts of these vessels are present in embryos of 3.2 mm.; later they extend cranially along the ventro-lateral surface of the brain on the medial side of the roots of the cranial nerves. The position relative to the nerves is only temporary, however, for collaterals arising from the veins pass to the lateral side of the nerves and enlarge to form the main channels. The original channels atrophy except in the region of the trigeminal nerves where they still remain on the medial side of the nerves as the forerunners of the cavernous sinuses. The vessel thus formed laterally to the cranial nerves (except the trigeminal) on each side of the brain is known as the lateral vein of the head (vena lateralis capitis) (Fig. 191.) The blood is collected from the brain region by small vessels which unite to form three main stems; one of these, the superior cerebral vein, opens into the cranial end of the cavernous sinus; another, the middle cerebral vein, opens into the opposite end of the cavernous sinus; and the third, the inferior cerebral vein^ opens into the lateral vein of the head behind the ear vesicle (Figs. 191 and 186). The branches of the superior cerebral vein extend over the cerebral hemispheres and unite with their fellows of the opposite side to form the superior sagittal sinus which lies in the medial line (Figs. 186 and 192). The superior sagittal sinus is at first naturally drained by the superior cerebral veins; but later, as the cerebral hemispheres enlarge and extend farther toward the mid-brain region, it is carried back and joins the middle cerebral vein; still later, for the same reason, it joins the inferior cerebral vein (Fig. 192, A and B). During these later changes the connection between the superior sagittal sinus and the superior cerebral vein is lost (Fig. 192). The middle cerebral vein becomes the superior petrosal sinus which forms a communication between the cavernous sinus and transverse sinus. The transverse sinus represents the channel between the superior sagittal sinus and the cranial end of the cardinal vein; or in other words, its cranial portion represents the connection between the superior sagittal sinus and the inferior cerebral vein while its caudal portion represents the inferior cerebral vein itself (Fig. 192, compare C and D). The caudal end of the superior sagittal sinus becomes dilated to form the confluence of the sinuses (confluens sinuum). From the latter a new vessel grows out to form the straight sinus, and a further growth from the straight sinus forms the large vein of the cerebrum (vein of Galen). The inferior sagittal sinus also represents a new outgrowth at the point of junction of the large vein of the cerebrum and inferior sagittal sinus (Fig. 192, D). During the course of development the lateral vein of the head gradually atrophies and finally disappears, and the inferior petrosal sinus probably represents a new formation which extends from the cavernous sinus to the transverse sinus (Fig. 192, C and D). At the point where the inferior petrosal joins the transverse sinus the latter passes out of the skull through the jugular foramen to become the internal jugular vein (anterior cardinal). (Mall.)

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'''Fig. 192. Diagrams representing four stages in the development of the veins of the head in human embryos.''' Mall.

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'''Fig. 193. Diagram of the venous system of a human embryo of 2.6 mm.''' Slightly modified from Kollmann's Atlas.

As stated in a preceding paragraph, the anterior cardinal veins extend from the ducts of Cuvier to the head region, passing to the dorsal side of the branchial arches. They are at first paired and symmetrical, but, since the heart is situated in the cervical region, are comparatively short and receive blood from the cervical region through segmental branches which belong only to the most cranial of the cervical segments. The other segmented cervical I veins, including the subdavian veins, open at first into the posterior cardinals (Fig. 193). Later, however, as the heart recedes into the thorax the anterior cardinal veins are elongated and the segmental cervical veins, including the subclavians, come to open into them (Fig. 195). The bilateral symmetry is then broken by an anastomosing vessel which extends obliquely across from a point on the left cardinal about opposite the subclavian to a point nearer the heart on the right subclavian (Figs. 194, B, and 195). The portion of the left cardinal cranial to the subclavian becomes the left internal jugular vein which communciates with the intracranial sinuses. The anastomosis itself becomes the left innominate vein. The portion of the left cardinal between the subclavian and the duct of Cuvier, the duct of Cuvier itself, and the left horn of the sinus venosus together form the coronary sinus (Fig. 196). On the right side the more distal part of the cardinal becomes the internal jugular vein; the portion between the subclavian and the anastomosis (left innominate vein) becomes the right innominate vein ; and the common stem formed by the latter and the left innominate constitutes the superior vena cava which opens into the right atrium (see p. 205) . The external jugular vein on each side appears later than the superior cardinal as an independent vessel which comes to lie parallel to the internal jugular and opens into it near the subclavian. The opening, however, shifts to the subclavian, where it is usually found in the adult (Figs. 195 and 196).

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'''Fig. 194. Diagrams of two stages in the development of the anterior and posterior cardinal veins, the subcardinal veins (revehent veins of the primitive kidney), and the inferior vena cava.''' The small branches of the cardinals and subcardinals ramify in the primitive kidneys (mesonephroi). Slightly modified from Hochstetter.

The changes which occur in the posterior cardinal veins are very extensive and result in conditions which bear but little resemblance to those in the earlier stages. In connection with these changes the development of the inferior vena cava must be considered. The posterior cardinal veins appear very early as paired, bilaterally symmetrical vessels which extend from the duct of Cuvier to the tail region and are situated ventro-lateral to the aorta

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'''Fig.195, Diagram representing a stage (later than Fig. 194) in the development of the superior vena cava and the inferior vena cava, also of the azygos vein.''' Hochstetter.

(Fig. 193). From the first they receive blood from the body wall through segmental branches, and as the primitive kidneys (mesonephroi) develop they receive blood from them also, as well as from the mesentery. They return practically all the blood from the region of the body situated caudal to the heart, just as the anterior cardinals return the blood from the region of the body situated cranial to the heart. In other words, the two sets of cardinal veins are the body veins par excellence during the earlier stages of development. While the anterior set persists for the most part as permanent vessels and increases with the development of the body, the posterior set undergoes regressive changes, its function being taken by a new vessel the inferior vena cava.

Not long after the appearance of the posterior cardinals, another pair of longitudinal veins appears in the medial part of the mesonephroi. They increase in size as the mesonephroi increase and receive blood from the latter. They also communicate with the cardinals by means of transverse channels which, however, are later broken up as the mesonephroi become more complicated in structure. These vessels are known as the subcardinal veins, or revehent veins of the primitive kidneys (Fig. 194, A). After they have attained a considerable size, a large anastomosis is formed between them ventral to the aorta and just caudal to the omphalomesenteric (superior mesenteric) artery (Tig. "194, B). In the meantime, a branch of the ductus venosus (see p. 229) grows caudally through the dorsal part of the liver and the mesentery, and joins the right subcardinal vein a short distance cranial to the above mentioned anastomosis (Fig. 194, A and B). This branch forms the proximal part of the inferior vena cava. At the same time, also, each subcardinal forms a direct connection with the corresponding cardinal at a point opposite the first anastomosis; consequently the inferior vena cava, the subcardinals and the cardinals are all in direct communication (Fig. 194, B). Thus two ways are formed by which the blood may return to the heart: It may return via the cardinals and ducts of Cuvier, and via the inferior vena cava.

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'''Fig. 196. Diagram of final stage in the development of the superior vena cava and the azygos vein.''' (Compare with Fig. 195.)

It is obvious that while these conditions exist, that is, while the mesonephros is functional, and blood is carried to it by the cardinal veins and from it by the subcardinal veins, there is a true renal portal system. The blood from the body walls and lower extremities is collected by the segmental vessels and poured into the cardinal veins and is then distributed in the mesonephros by smaller channels or sinusoids (Minot), whence it is collected and carried off by the subcardinal veins. This passage of blood through purely venous channels simulates the conditions in the liver where there is a true hepatic portal system.

Frcm this time on, the changes are largely regressions in the cardinal and subcardinal systems, corresponding to the atrophy of the mesonephroi, and rapid increase in the vena cava and its branches. The cranial end of each cardinal becomes smaller; the left loses its connection with both the vena cava and the duct of Cuvier, the right its connection with the vena cava only (Fig. ig6j. Subsequent changes in these parts of the cardinals will be considered in the following paragraph. For a time the caudal ends of the two cardinals are of equal importance. Later, however, the right becomes larger, while the left atrophies. The right thus becomes a direct continuation and really a part of the vena cava (Figs. 195 and 198). This is brought about, of course, by the original anastomosis between the vena cava and the subcardinal and cardinal. On the left side the anastomosis persists simply as the proximal part of the renal vein (Fig. 198); on the right side the renal vein is a new structure which develops after the kidney has attained practically its final position, and opens into the vena cava secondarily. The inferior vena cava itself is a composite vessel derived from four different anlagen. i. The part which extends from the ductus venosus to the right subcardinal is of independent origin. 2. A short portion is derived from a part of the right subcardinal. 3. Another short portion is derived from the cross-anastomosis between the subcardinals and cardinals. 4. The caudal end is a derivative of the caudal part of the right cardinal (compare Figs. 194, 195, 198.)

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'''Fig. 197. From a transverse section of a 5 mm. human embryo, at the level of the omphalomesenteric (vitelline, superior mesenteric) artery.'''

Before the caudal end of the left cardinal vein atrophies, an interesting and important change occurs in the relations of the ureters and cardinals. Primarily the cardinal veins develop to the ventral side of the ureters. But later a collateral of each cardinal develops to the dorsal side of the ureter. These join the cardinal cranial and caudal to the ureter. In other words, a venous loop is formed around the ureter (Fig. 195). The ventral arm of the loop then atrophies and disappears, leaving the dorsal arm as the direct part of the cardinal vein. On the right side, where the cardinal persists as a portion of the vena cava, the latter vessel comes to lie ventral to the ureter (Fig. 198, A). On the left side the cardinal atrophies, leaving only the portion cranial to the loop as the proximal end of the internal spermatic (testicular or ovarian ) vein (Fig. 198, B). Since on the left side the original anastomosis between the subcardinals and cardinals persists as the renal vein, the left internal spermatic is a branch of the renal. The right internal spermatic vein probably represents a branch of the vena cava which is independent of the cardinal.

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'''Fig. 198. Diagrams representing final stages in the development of the inferior vena cava''' (compare with Fig. 195). Slightly modified from Hochstetter.

In the cat embryo the venous loop around the ureter is much more extensive than in the other forms. The dorsal arm of the loop, named the supracardinal vein, extends from the iliac vein to the original anastomosis between the subcardinals and cardinals. In the course of further development the supracardinals approach each other and finally fuse, forming a large single vessel which becomes the portion of vena cava caudal to the renal veins. In this event the portions of both cardinals forming the ventral arms of the venous loops atrophy and disappear.

Near the caudal end of each cardinal vein a branch arises which receives the blood from the corresponding lower extremity. Then a transverse anastomosis appears between the two cardinals at this point (Fig. 198, A). Since the portion of the left cardinal caudal to the renal vein atrophies, the anastomosis itself constitutes the left common iliac vein (Fig. 198, B). The right common iliac is, of course, the original branch of the right cardinal. As the iliacs enlarge they form the two great branches of the vena cava.

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'''Fig. 199. Diagrams illustrating two stages in the transformation of the omphalomesenteric and umbilical veins in the liver.''' Hochstetter.

With the atrophy of the mesonephroi, the subcardinal veins diminish in size and finally disappear for the greater part. The part of the right subcardinal cranial to the point of junction with the vena cava disappears entirely. The portion of the left subcardinal cranial to the anastomosis between the two subcardinals becomes much reduced in size, but persists as the left suprarenal vein. The left suprarenal vein is thus a branch of the left renal vein, since the latter represents the anastomosis itself (Figs. 194, 195, 198). The right suprarenal vein probably does not represent a persistent right subcardinal, but is a new vessel opening into the vena cava. The portion of each subcardinal caudal to the anastomosis probably disappears entirely, but this has not been definitely determined.

The observations on the development of the azygos veins in the human embryo are only fragmentary. In the rabbit the portions of the posterior cardinal veins immediately cranial to the anastomosis between the sub-cardinals and cardinals, that is, just cranial to the renal veins, disappear. The more cranial portion of the right cardinal persists as the azygos vein which receives the intercostal (segmental) branches and opens into the superior vena cava. An oblique anastomosis is formed, dorsal to the aorta, between the two cardinals (Fig. 195). This anastomosis and the portion of the left cardinal caudal to it together form the hemiazygos vein. The portion of the left cardinal cranial to the anastomosis loses its connection with the duct of Cuvier (or coronary sinus) and becomes the accessory hemiazygos vein (Fig. 196). The ascending lumbar veins, which join the azygos and hemiazygos, probably do not represent persistent parts of the caudal ends of the cardinals, but are formed by longitudinal anastomoses between the original segmental lumbar veins.

The changes which occur in the region of the liver are of much importance and result in conditions which bear no resemblance to the primary ones. As has already been noted, the omphalomesenteric veins enter the body at the umbilicus, pass cranially along the intestine and open into the caudal end of the heart. The umbilical veins, which appear soon after, enter the body at the umbilicus and pass cranially, one on each side, in the ventro-lateral part of the body wall; at the level of the heart they turn mesially through the septum transversum and join the corresponding omphalomesenteric veins to form a common trunk on each side, into which the duct of Cuvier then opens (Fig. 193). When the liver grows out as an evagination from the intestine, it comes in contact with the proximal ends of the omphalomesenteric veins and, as it enlarges, breaks them up into numerous smaller channels (Fig. 199).

The blood then, instead of having a direct channel, is forced to flow through these smaller channels which have been termed sinusoids. When the liver has attained a considerable size a more direct and definite channel is formed, which extends through the substance of the liver from the proximal end of the right omphalomesenteric vein obliquely caudally to the left omphalomesenteric vein. This newly formed channel is the ductus venosus (Figs. 199 and 200). In the meantime, three transverse anastomoses develop between the omphalomesenteric veins just caudal to the liver. The middle one is dorsal to the intestine, the other two ventral, so that the intestine is surrounded by two venous loops or rings (Figs. 199 and 200). At the same time a cross-anastomosis develops between the left umbilical vein, which is primarily the smaller, and the corresponding omphalomesenteric. This anastomosis joins the omphalomesenteric at about the point where the latter joins the ductus venosus, so that it seems to be a continuation of the ductus venosus. A similar cross-anastomosis also develops between the right umbilical and right omphalomesenteric (Figs. 199 and 200). Thus the blood that is brought in from the placenta by the umbilical veins may pass through the liver. Then the portion of each umbilical between the anastomosis and the duct of Cuvier atrophies and disappears (Fig. 200). The remaining portion of the left umbilical, which was originally the smaller, gradually increases in size and finally carries all the blood from the placenta. The right umbilical, on the other hand, loses its connection with the liver and persists only as a small vein in the body wall, which opens into the left umbilical vein near the umbilical cord (Fig. 201). Thus there is the peculiar phenomenon of a vessel carrying blood in different directions at different periods of its history. During the course of development of the septum transversum and diaphragm the left umbilical is withdrawn from the body wall and passes directly from the umbilicus to the ventral side of the liver. During fcetal life it conveys all the blood from the placenta to the liver. A part of the blood is distributed in the liver, a part is carried directly to the inferior vena cava by the ductus venosus (Fig. 202). After birth' the placental blood is cut off and the umbilical vein degenerates to form the round ligament of the liver.

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'''Fig. 200. Veins in the liver region of a human embryo of 4 mm.''' His, Kollmann's Atlas.

The venous rings around the intestine also undergo marked changes. The right side of the most caudal and the left side of the most cranial disappear; the remaining vessel finally loses its connection with the ductus venosus and becomes the portal vein (Figs. 199, 200, 201 and 202). The portal vein is thus a derivative of the omphalomesenterics. After birth, when the placental blood is cut off, blood is distributed in the liver by branches of the portal vein, which represent the advehent hepatic veins; it is collected again by branches which unite to form the revehent hepatic veins, or hepatic veins proper, and the latter open into the inferior vena cava. The advehent and revehent hepatic veins are formed by the enlargement of some of the original sinusoids (Figs. 199 and 201).

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Fig. 201. Veins in the liver region of a human embryo of 10 mm. Kollmann's Atlas.

++++++++++++++++++++++++++++++++++

Observations on the development of the veins in the extremities of human embryos are so fragmentary that it seems advisable to make use of the work that has been done on the rabbit. In the upper extremity the first vein to develop is the primary ulnar vein which begins in the radial (cranial) side of the extremity near its proximal end, extends distally along the radial border, thence proximally along the ulnar (caudal) border, and opens into the anterior cardinal vein (internal jugular) near the duct of Cuvier (Fig. 203). This condition is present in rabbit embryos of thirteen days. A little later a second vessel, the cephalic vein, appears as a branch of the external jugular, extends along the radial side of the extremity and becomes connected with the digital veins (Fig. 204). When the digital veins are taken up by the cephalic, the distal portion of the primitive ulnar undergoes regression. These changes have taken place in rabbit embryos of fifteen days, and for a short period the cephalic vein is the chief vessel of the extremity. The primitive ulnar vein, however, develops more rapidly than the cephalic and,

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Fig. 202. Veins of the liver (seen from below) of a human foetus at term Kollmann's Atlas.

++++++++++++++++++++++++++++++++++

with its branches, soon becomes the chief vessel; the portion in the forearm gives rise to either the ulnar or basilic vein; the portion in the arm becomes the brachial vein which then passes over into the axillary, and the latter in turn passes over into the subclavian. The cephalic vein of the embryo persists as the cephalic of the adult, and, during the period when it forms the chief vessel of the extremity, a branch arises from it which becomes the radial vein. Primarily the cephalic vein opens into the external jugular, but later a new connection is formed with the axillary, while the original connection persists as the j ugulocephalic (Fig. 205).

In a rabbit embryo of ten and one-half days a vein follows the border of the lower extremity all the way round, connecting on the cranial side with the umbilical and on the caudal side with the posterior cardinal. This is the primitive fibular vein, and from its course is homologous with the primitive ulnar vein of the upper extremity (Fig. 203). From this time on, however, the course of development in the lower extremity differs from that in the upper. The connection of the fibular vein with the umbilical is soon lost. In older embryos (fifteen days) two branches of the fibular vein have appeared; one of these, the anterior tibial vein, begins on the embryo of 14 days (n mm.), dorsum of the foot and extends diagonally proximally, to open into the fibular in the caudal border; the other, the so-called connecting branch, begins as twigs in the abdominal wall and tibial side of the extremity and opens into the fibular just proximal to the opening of the anterior tibial (Fig. 204). Later the distal part of the primitive fibular is broken up by the differentiation of the digits (toes) and disappears almost up to the point of junction with the anterior tibial. The latter enlarges and receives the digital branches, and appears as a continuation of the proximal part of the primitive fibular. The anterior tibial and primitive fibular together thus constitute the sciatic vein (Fig. 205). Another vessel appears in embryos of fifteen days, which represents the beginning of the femoral vein and opens into the cardinal, cranial to the opening of the sciatic (Fig. 205). From this time on the femoral, with its branches, enlarges at the expense of the other veins and becomes the principal vein of the lower extremity. In the human embryo the femoral anastomoses with the sciatic near the knee and the proximal portion of the sciatic then atrophies, the distal portion persisting as the small sephenous vein. The

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'''Fig. 203. Diagram of the veins in the extremities of a rabbit embryo of 14 days (11 mm).''' Modified from Lewis

{|
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| <div id="Fig204"></div>
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|-
| '''Fig. 204. Diagram of the veins in the extremities of a rabbit embryo of 14 days and 18 hours (14.5 mm.).''' Modified from Lewis.
| '''Fig. 205. Diagram of the veins in the extremities of a rabbit embryo of 17 days (21 mm.).''' Modified from Lewis.
|}

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'''Fig. 206. Diagram illustrating the foetal circulation.''' Compare with Fig. 207. Modified from Kollmann. The shading represents the relative impurity of the blood in different regions, the darkest shading representing the most impure blood large saphenous vein and the posterior tibial vein possibly are derivatives of the femoral, but this question has not been settled.

==Changes in the Circulation at Birth==

During fcetal life the course of the blood is adapted to the placental circulation, since the placenta is the only means by which the blood is purified and from which the foetus derives its nutriment. The pure blood from the placenta passes through the umbilical vein to the liver; there a part of it is distributed to the liver by some of the advehent veins, is collected again by the revehent veins and poured into the inferior vena cava; a part passes directly to the vena cava through the ductus venosus. At this point the blood acquires some impurity from the stream brought in by the vena cava itself and the portal vein. The slightly impure blood then flows into the right atrium, is directed by the Eustachian valve through the foramen ovale into the left atrium, thence flows into the left ventricle and is forced out into the aorta. A part of the blood flows on through the aorta, a part is carried to the upper extremities and head and neck regions by the subclavian and carotid arteries. The latter part, then becoming impure, is carried back to the right atrium by the subclavian and jugular veins and superior vena cava; from the right atrium the greater portion flows into the right ventricle and thence is forced out into the large pulmonary artery. But since the lungs are non-functional, this blood passes through the ductus arteriosus to join the stream in the aorta. The blood received by the more cranial portion of the foetus is but slightly impure, for the impure blood from the ductus arteriosus joins the aortic stream distal to the origin of tlie subclavian and carotid arteries. This accounts for the fact that the more cranial portion of the body generally is better developed than the more caudal portion. It is well to note here that the liver receives purer blood than any other part of the body, and this is undoubtedly correlated with the relatively enormous size of that organ in the foetus. The rather impure blood which starts through the dorsal aorta is in part distributed to the viscera, body walls, and lower extremities by the visceral and segmental arteries, and thence is collected by the branches of the portal vein and inferior vena cava to be returned as impure blood to the umbilical current at the liver; in part it is carried by the umbilical arteries to the placenta, there to be purified and collected by the branches of the umbilical vein (see Fig. 206).

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'''Fig. 207. Diagram illustrating the circulation in the adult.''' Compare with Fig; 206. The shading represents the relative impurity of the blood, the white being the purest blood.

At birth, when the placental circulation is cut off, the proximal end of the umbilical vein atrophies to form the round ligament of the liver; the ductus venosus also atrophies and becomes merely a connective-tissue cord in the liver. The hepatic portal circulation is still maintained by the portal vein. The foramen ovale is closed and the impure blood from the inferior vena cava as well as that from the superior, passes from the right atrium into the right ventricle and thence is forced out through the pulmonary artery to the lungs, which at this time become functional, and is returned to the left atrium by the pulmonary veins. The ductus arteriosus atrophies to form the ligamentum arteriosum. From the left atrium the pure blood flows into the left ventricle, thence is forced out through the aorta and its branches to all parts of the body. At the same time the more distal portions of the umbilical arteries in the embryo atrophy to form the lateral umbilical ligaments, their proximal portions persisting as the superior vesical arteries (see Fig. 207).

Haemopoiesis Histogenesis of the Blood Cells.

Two sharply contrasting views are held regarding the origin and genetic relationships of the different kinds of blood cells. The one view, expressed in the monophyletic theory, holds that there is differentiated out of the mesenchyme a certain type of cells the primitive blood cells, or haemoblasts and that from this single type all the cells of the blood arise through processes of development along divergent lines. The other view, expressed in the polyphyletic theory, holds that while the blood cells are of mesenchymal origin the red cells and white cells have a dual origin, each type arising from its own mother-cells; and further that perhaps each kind of white cells arises from a distinct parent-cell. The recent extensive studies of the problem have yielded evidence that turns the balance at present in favor of the monophyletic theory, and the following account is based in the main upon these studies, particularly those of Maximow on the rabbit and Dantschakoff on the chick.

The sites of blood formation, or haemopoiesis, are (i) the area opaca (yolk sac), (2) the body mesenchyme, including the endothelium of the early blood-vessels, (3) the liver and spleen, (4) bone marrow, and (5) the lymph glands. These various structures are functional at successive periods of development of the embryo, but overlap to a certain extent, the marrow and lymph glands being probably the only foci of origin of blood cells in the adult. In the area opaca blood-cell development is initiated in the formation of the blood islands. Some of the mesenchymal cells become less irregular in shape by retraction of their protoplasmic processes and isolation from the general syncytium. They assume amoeboid properties and the cytoplasm aquires a distinctly basophilic character (Fig. 208). These then represent primitive blood cells, or hcemoUasts. Maximow has given them the name primitive lymphocytes, or lymphoblasts , regarding them as the common ancestors of all the blood cells. Clusters of these cells constitute the blood islands which are involved in the development of the primitive blood spaces, the superficial cells being transformed into endothelium (see p. 186) and the central cells remaining as primitive lymphocytes. Other primitive lymphocytes also differentiate in the mesenchyme outside of the blood spaces, afterward probably entering the vessels by virtue of their amoeboid properties.

<div id="Fig208"></div>
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Fig. 208. Mesenchyme from a rabbit embryo at the time of beginning blood formation.

Maximow.

m, Ordinary mesenchyme cells; m', mesenchyme cell in mitosis; /, primitive Wood cell

(primitive lymphocyte).

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There is a view that both the blood cells and the endothelium of blood vessels arise from certain mesam&boid cells of entodermal origin, which are insinuated between the entoderm and mesoderm but are not in the strict sense constituents of the latter, and which collectively have been called the | angioUast. While the mesamceboid cells are probably identical with the j primitive lymphocytes, the idea that they constitute a set of specific rudiments of entodermal origin, from which both blood cells and endothelium arise, has not been generally accepted. The view, however, is not discordant with the monophyletic concept of the origin of blood cells.

<div id="Fig209"></div>
[[File:Bailey209.jpg|600px]]

Fig. 209. Portion of a blood vessel from the yolk sac of a rabbit embryo, showing various

stages in the formation of erythrocytes. Maximow. fl, megaloblasts; a', megaloblast in mitosis; b, normoblasts; b', normoblast in mitosis; c, erythro

blasts; d, erythrocyte, not yet discoid; en, endothelium; /, primitive lymphocytes;

k, normoblast recently divided; n, shrunken erythroblasts (?); n' ', extruded nucleus.

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The primitive lymphocytes (of Maximow), constituting the parent stem from which all the blood cells arise according to the monophyletic theory, specialize at first in two general directions. In one direction the specialization leads toward the erythrocytes, or red blood corpuscles, and in the other toward the leucocyte, or white blood cell, series including the myelocytes. In the former case the lymphocytes become modified in that the cytoplasm becomes less basophilic and acquires a trace of haemoglobin; the nuclei become somewhat eccentric, the chromatin network a little denser and the nucleoli less conspicuous. While these changes are in progress the cells multiply by mitosis. The resulting cells are termed megaloblasts (Fig. 209, a). These continue to multiply by mitosis, the cytoplasm acquiring more haemoglobin and the nuclei becoming more dense, the resulting cells being somewhat smaller and known as normoblasts (Fig. 209, b) . The normoblasts, still dividing by mitosis, acquire still more haemoglobin and become erythroblasts (Fig. 209, c). These lose their nuclei and thus become erythrocytes, the definitive red blood corpuscles. The manner in which the nuclei are lost is a matter of dispute. Some claim it is absorbed (karyolysis) ; others claim it is extruded (karyorrhexis) (Fig. 210); recently the observation has been made that the nucleus with a small amount of surrounding cytoplasm escapes from the cell in a manner resembling constriction.

In the specialization leading to the white blood cell series, the parent stem cell (primitive lymphocyte) proliferates by mitosis and undergoes certain divergent changes in its nucleus and cytoplasm which yield the characters of the various kinds of leucocytes. Some of the cells become polymorphonuclear and acquire neutrophile granules to become neutrophile leucocytes; others acquire acidophile granules as acidophiles; still others, basophile granules as basophiles. The large mononuclear leucocytes, with the transitional forms having the horseshoe-shaped nuclei, possibly represent but slightly modified primitive lymphocytes. The definitive lymphocytes are probably derived from the primitive by division and but slight changes in character. Thus the various forms of white blood cells would not represent different stages in a series but divergent lines of specialization from a parent stem.

As mentioned before, the various blood forming organs function as such at successive stages of development of the embryo. The mesenchyme generally, both in the yolk sac and in the body, gives rise to blood cells during the earlier stages and may continue to do so until relatively late in embryonic life as has been demonstrated in the chick. It is interesting to note in this connection that in certain regions endothelial cells may also be transformed into primitive blood cells. In the earlier stages of liver development active haemopoiesis is observed in the sinusoids, probably partly from cells carried in by the blood stream and partly from primitive blood cells derived from the neighboring mesenchyme (Fig. 211). This function ceases in the liver in later embryonic life. The formation of blood cells takes place in the developing spleen but erythrocyte formation ceases after birth, although following severe haemorrhage the function may be resumed even in adult life. The formation of lymphocytes, however, goes on throughout life in the splenic corpuscles.

<div id="Fig210"></div>
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Fig. 210. Showing the escape of the nuclei from nucleated red blood cells. Howell.

I, 2, 3, 4, represent stages of extrusion observed in living cells; a, from circulating blood of adult cat after bleeding four times; b, from young kitten after bleeding; c, from 90 mm. cat embryo; others from marrow of adult cat. ++++++++++++++++++++++++++++++++++

<div id="Fig211"></div>
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Fig. 211. From the liver of a rabbit embryo, showing formation of red blood cells. Maximow. a, Megaloblasts; a', megaloblast in mitosis; b, normoblasts; c. erythroblasts; en, en', en'', endotheHal cells; h, liver cells; /, primitive lymphocytes; /', primitive lymphocyte in mitosis; , nucleus being extruded from small erythroblast.

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The lymph glands are constant sources of lymphocytes, the parent cells being the large mononuclear cells found in the germinal centers. These cells are regarded as closely allied to the primitive lymphocytes, perhaps even identical, although here in this particular environment giving rise only to the lymphocyte line.

The bone marrow is an important source of blood cells in the embryo, and in the adult under normal conditions is regarded as the only source of red corpuscles. The parent stem cells, here called myeloblasts, are recognizable in the form of large mononuclear, non-granular cells, with the general characters of primitive lymphocytes, which give rise to the red blood cells through clearly distinguishable megaloblast and normoblast stages, and to the various forms of leucocytes and lymphocytes. In addition the parent cells also give rise to certain other cells which are normally confined to the marrow, viz., the myelocytes. These are large mononuclear cells, with vesicular nuclei, the cytoplasm containing neutrophile, acidophile, or basophile granules similar to those of the leucocyte series (Fig. 212). The genetic relationships of the "giant" cells, or myeloplaxes, in the marrow are not clear. The myeloplaxes are large masses (30 to 100 micra in diameter) of homogeneous or finely granular, slightly basophilic cytoplasm containing either a single lobulated, annular nucleus (megakaryocytes, Fig. 212, meg) or many nuclei (polykaryocytes). The polykaryocytes have been considered identical with the osteoclasts, which may represent fused osteoblasts, but this relationship has not been definitely established. Both kinds of cells have been considered as derivatives of the myeloblasts, the polykaryocytes being later stages of megakaryocytes.

<div id="Fig212"></div>
[[File:Bailey212.jpg|600px]]

Fig. 212. From a section of red marrow from the femur of a young rabbit. Schafer. e, Erythrocy tes ; e r , normoblasts; e", normoblast in mitosis; /, outlines of fat cells; ^, polymorphonuclear leucocytes; m, neutroohile myelocytes; m', myelocytes in mitosis; m", eosinophile myelocytes; m'". basophile myelocytes.

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The blood platelets are now regarded by some authors as derivatives of the megakaryocytes; pseudopodia of the latter breaking off and gaining access to the blood stream. By others they are not believed to be formed constituents of the circulating blood, but appear only after shed blood comes in contact with a foreign substance.

The accompanying table, which is a tentative graphic scheme of the monophyletic theory, will assist the student in tracing the lineage of the blood cells.

==The Lymph Vascular System==

A controversy has arisen over the origin of the lymph channels and their endothelium, similar to the one that arose over the genesis of the blood vessels. There are therefore two main views, viz.: (i) that the endothelium of the lymph vessels arises as sprouts from the endothelium of veins and continues to grow by proliferation and migration of its own cells, the lymphatics thus being direct derivatives of the venous channels; (2) that the lymph vessels arise in situ through enlargement and coalescence of intercellular tissue spaces, the mesenchymal cells bounding these spaces becoming flattened and rearranged to form the endothelial walls of the vessels, and, as a corollary, that the junction of the lymph vessels with the veins, which occurs at certain definite points, is a secondary matter.

<div id="Fig213"></div>
[[File:Bailey213.jpg|400px]]

'''Fig. 213. Diagram showing the arrangement of the lymphatic vessels in a pig embryo of 40 mm.''' Sabin.

<div id="Fig214"></div>
[[File:Bailey214.jpg|thumb|300px|'''Fig. 214.''' Diagram showing network of lymphatic vessels in skin of pig embryos. Sabin. Area marked A shows extent of network in an embryo of 18 mm.; B, in embryo of 20 mm.; C, in embryo of 30 mm.; D, in embryo of 40 mm.]]

Here again the scope of the work does not permit presentation in detail of the evidence adduced in favor of either of these views. The advocates of the first view have placed much dependence upon the method of injection, which, as in the case of the origin of blood vessels, has been met with the criticism that injection shows only those lymph channels with continuous lumina and leaves undetermined the field beyond the injected area (see page 194). To supplement their studies by the injection method, the investigators who maintain that lymphatic endothelium grows by sprouting of preexisting endothelium have added studies on living tissues in which the sprouting phenomena are claimed to be clearly observable. Those who maintain that the lymphatics and their endothelium arise in situ from intercellular tissue spaces and the bordering cells, argue that the same principles underlie the formation of lymphatics that determine blood-vessel development and that it has been shown experimentally that blood vessels develop in regions which have been entirely cut off from any source of endothelium except the mesenchymal cells in situ (see page 194).

According to the first view lymphatic development can be divided into two stages: (i) the formation of isolated lymph sacs, derived from veins, which become united into a system, and (2) the peripheral growth of lymph vessels which sprout from the endothelium of these sacs and spread through the body. (i) The first sacs appear, one on each side, along the jugular (anterior cardinal) veins. The branches of these veins at first form a plexus; a portion of the plexus becomes cut off from the parent stems and lies as a series of isolated spaces in the mesenchyme ; these spaces then enlarge and coalesce to form an endothelial-lined sac the jugular lymph sac or heart which afterward joins the jugular vein by a new opening (Fig. 213). A second pair of sacs the posterior lymph sacs or hearts develops in the same manner from the more caudal branches of the posterior cardinal veins (Fig. 213). Two other saclike structures develop the cisterna chyli and retroperitoneal sac the former in the region of the renal veins and the latter in the vicinity of the suprarenal bodies. Through the longitudinal fusion of the chain of sac-like structures, the axial lymphatic drainage line of the body is established (Fig. 213). The thoracic duct probably represents the fused cisterna chyli and jugular lymph hearts. The lymph hearts in the avian and mammalian embryo become relatively smaller as development proceeds until in the adult they are barely discernible as slight dilatations in the lymph vessels. The cisterna chyli, however, may persist as a clearly distinguishable dilatation at the caudal end of the thoracic duct.

(2) The peripheral lymph channels, which drain into the thoracic duct, represent outgrowths from the lymph sacs. From the jugular sacs sprouts invade the neck, head, shoulders, and finally the entire upper extremities and upper part of the body wall (Fig. 214). Similarly, from the posterior lymph hearts sprouts invade the lower extremities and lower portion of the body wall (Fig. 214). Outgrowths from the original axial drainage line invade the various visceral organs (Fig. 213). Thus the lymphatic drainage of the body is effected through outgrowths from a few primary centers which represent derivatives of the venous channels. The lymph glands are secondary foci of development along the lymph vessels (see page 249).

<div id="Fig215"></div>
[[File:Bailey215.jpg|600px]]

'''Fig. 215. From cross-sections of cat embryos in successive stages''' (<z, b, c, d) of development, in the region of the jugular lymph sac; diagrammatic but amply supported by studies of serial sections and reconstructions. Huntington.
: i, Anterior cardinal vein; 2, somatic tributary of same; 4, developing blood cells in the mesenchyme; 5, mesenchymal intercellular spaces rudiments of the jugular lymph sac; 6, rudimerits of brachio-cephalic venous anastomosis; 7, brachio-cephalic venous anastomosis; 8, haemophoric lymphatic plexus forerunner of jugular lymph sac; u, thoracic duct'approach' of jugular lymph sac; 12, rudiments of thoracic duct; 13, jugular lymph sac preparing to rejoin vein and to establish secondary connection with rudiments of thoracic duct (12) and of other systemic lymphatics (14); 15, jugular lymph sac, which has rejoined vein through permanent lymphatico-venous tap (16); 17, thoracic duct; 1 8, jugular and cephalic systemic lymphatics.

<div id="Fig216"></div>
[[File:Bailey216.jpg|600px]]

'''Fig. 216. From a photograph (X 600) of a cross-section through the caudal end of a chick embryo of 15 mm.''' Showing enlarged mesenchymal intercellular spaces as rudiments of the posterior lymph sac. West. 3, Coccygeal vein; 6, caudal muscle plate; 8, isolated enlarged intercellular spaces, the bounding cells becoming flattened; 9, lateral branch of coccygeal vein; 10, lymphatics containing collections of developing blood cells.

The view that lymphatics arise as enlarged isolated intercellular spaces in the mesenchymal tissue does not include any dispute as to the general disposition of the lymph channels in the body, but comprises a fundamentally different concept of the origin of these vessels. Upon a long and exhaustive series of observations on closely graded series of embryos of Fishes, Amphibia, Reptiles, Birds, and Mammals is based the conclusion that not only the lymph sacs but the peripheral lymphatics as well originate independently of the veins; and that the opening of the main lymphatic drainage lines into the jugular or subclavian veins near their junction, and into the inferior vena cava and renal veins (in some monkeys) , is second* arily established. The same hydrodynamic mechanical factors regarded as operative in the formation of blood vessels, viz.: pressure and friction incident to blood flow (see page 195), are considered as effective likewise in the development of lymphatics. Fundamentally, therefore, the lymph vascular system from the viewpoint of development differs in no wise from the blood vascular system.

<div id="Fig217"></div>
[[File:Bailey217.jpg|600px]]

'''Fig. 217. Diagrams showing three stages (a, b, c) in the development of the thoracic duct in the cat embryo''', in which the jugular lymph sac has established two permanent venous connections (8 and 9). Huntington.
: i, Anterior cardinal vein; 2, duct of Cuvier; 3, posterior cardinal vein; 4, external jugularcephalic vein; 5, subclavian vein; 6, jugular lymph sac; 7, thoracic duct 'approach' of lymph sac; 8, common jugular opening of lymph sac; 9, jugulo-subclavian opening of lymph sac; 10, rudiments of thoracic duct; n, thoracic duct.

The lymph sacs, both jugular and posterior, arise through enlargement and confluence of mesenchymal intercellular spaces, the cells bounding the spaces becoming flattened and rearranged to form endothelium. In the case of the mammalian (cat) jugular sac, intercellular spaces in the region dorso-lateral to the anterior cardinal vein unite into an intricate plexus of channels which then opens into the vein (Fig. 215, a and b). Following this the components of the plexus enlarge and coalesce to form the sac, which then temporarily severs connection with the vein (Fig. 21 5, c) . Finally the sac effects a permanent connection with the vein through one or more openings which represent the lymphatico-venous communications of the adult (Fig. 215, d). In the case of the posterior sac, intercellular spaces dorsal to the posterior cardinal vein (Fig. 216, 8) first form a plexus the components of which then unite into a large endothelial-lined space which opens into the dorsal tributaries of the vein.

The thoracic duct also arises as a chain of isolated endothelial-lined spaces along the line of the aorta. These unite longitudinally into a continuous channel which joins the jugular lymph sac, thus forming the axial lymphatic drainage line of the body (Fig. 217, a, b, c). In reptilian embryos the spaces first fuse into a distinct periaortic plexus out of which the thoracic duct is established. In the avian embryo the chain of spaces follows the general line of the aorta but does not become so intimately associated with the great arterial trunk as in reptiles. In the mammalian forms rudiments of the thoracic duct follow the same general plan of development, but are associated topographically with the ventro-medial tributaries of the azygos veins. These tributaries finally become detached from the larger venous trunks, atrophy and disappear, being replaced by the thoracic duct.

On the same principles laid down for the development of the lymph sacs and thoracic duct, the peripheral lymphatics also are developed. In all the regions of the body not immediately drained by the lymph sacs or thoracic duct, mesenchymal intercellular spaces enlarge and coalesce, the cells bounding the coalesced spaces being transformed directly into endothelium; the spaces unite to form a plexus of endothelial-lined channels, and in this plexus certain channels increase in size to form the larger lymphatics which converge and eventually join the main axial drainage line. Thus the lymphatic drainage of the entire body is established.

One of the most interesting and significant phases of lymphatic development, which has been brought out through recent studies of the problem, is the role played by certain early lymph channels in conveying blood cells to the general circulation. It has been found that, in the region subsequently occupied by the lymph sacs, extensive blood cell formation (haemopoiesis) occurs prior to the formation of lymphatic rudiments. As the lymph spaces appear and unite into a plexus the developing blood cells are included within them (Fig. 215, a and Fig. 216, 10). When the lymphatic plexus joins the veins the blood cells are carried into the general circulation (Fig. 215, b). This haemophoric function of the early lymph channels is especially prominent in the case of the thoracic duct in the chick. Here extensive collections of blood cells develop in the mesenchymal tissue along the line of the aorta and become included within the rudiments of the thoracic duct and eventually, when the latter unites with the jugular lymph sac, are carried into the veins and thus enter the general circulation. After these early lymphatics, which transport blood cells and which have been defined as haemophoric lymphatics, or veno-lymphatics, fulfil their haemophoric function they are retained as permanent lymph channels in the general lymphatic organization. In a broader interpretation, the haemophoric function of certain lymph vessels during ontogeny is particularly significant in that it indicates essential and fundamental similarity of lymphatic vascular development to haemal vascular development.

==The Lymph Glands==

The lymph glands do not begin to develop for some time after the lymphatic vessels, since there are no indications of them in the human foetus until the latter part of the third month and none in pig embryos until thev

<div id="Fig218"></div>
[[File:Bailey218.jpg|600px]]

Fig. 218. From a section through the axilla of a human embryo of 125 mm. (4-5 months), showing an early stage of a lymph gland. Kling.

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have reached a length of 30 mm. While it is definitely settled that lymph glands originate in very close relation with the lymphatic vessels, certain points in their later development need further study. In the axilla and groin, for example, the lymphatic vessels form a dense network in the meshes of which are masses of connective tissue. These masses become more cellular and with the surrounding vessels constitute the anlagen of lymph glands (Fig. 218). The new cells which appear in the masses are lymphocytes which may pass through the walls of the neighboring blood vessels and lodge here or may be derived directly from connective tissue (mesenchymal) cells in situ. Whatever the origin of the lymphocytes may be, they have the opportunity here to divide freely. The mass becomes still more cellular and enlarges at the expense of the lymphatic vessels which then come to form a network around the mass. This network is the marginal plexus, and it communicates freely with the neighboring lymphatic channels. Within the mass of cells blood vessels are present from the beginning, and these are destined to be the blood vessels of the lymph gland, and the point of their entrance and exit marks the hilus. Outside of the marginal plexus the connective tissue condenses to form the capsule. The gland at this stage thus consists of a central compact cellular mass, made up of connective tissue and lymphocytes, in which blood vessels ramify; a plexus of lymphatic channels around the mass which communicate with the neighboring channels; and around the whole structure a capsule of connective tissue (Fig. 218). Further development consists of the breaking up of the cell mass by

<div id="Fig219"></div>
[[File:Bailey219.jpg|600px]]

Fig. 219. Diagram illustrating a stage (later than Fig. 218) in the development of a lymph gland. Stohr.

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iymj hatic channels and the formation of the follicles. It seems probable that branches from the marginal plexus invade the cell mass principally from an area around the hilus, thus breaking it up into smaller irregular masses or cords. At the side opposite the hilus the invading channels are less numerous, leaving larger parts of the mass which become the follicles (nodules) of the cortex. On all sides the invading channels communicate with the marginal plexus and form the so-called intermediary plexus. The gland as a whole enlarges and its peripheral part pushes outward into the surrounding tissue. Over the follicles the capsule is pushed outward, while between them it remains in place and comes to dip into the gland as the trabeculcz. The blood vessels tend to lie in the trabeculae, but a small branch probably passes to each follicle. In the follicles themselves the lymphocytes proliferate and the central part of each follicle becomes a germinal center. The connective tissue among the lymphatic vessels composing the marginal plexus becomes proportionately less as the vessels enlarge and finally exists only as strands of reticular tissue which, naturally, are covered by the endothelium ; thus the marginal plexus becomes the marginal sinus. The intermediary sinus is formed by the channels which originally invaded the cell mass. The reticular tissue is probably composed of remnants of the original connective tissue. All the channels converge at the hilus to form the efferent lymphatic vessels (Figs. 219 and 220).

<div id="Fig220"></div>
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Fig. 220. Diagram illustrating a late stage in the development of a lymph gland. Compare with Fig. 219. Stohr.

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The haemolymph glands are probably developed in much the same manner as the lymph glands except that in the former the sinuses are filled with red blood cells.

The first lymph glands to develop are those in the axilla, in the inguinal region, in the neck, and in the base of the mesentery. These are the so-called primary glands and develop during fcetal life. They are of constant occurrence in these regions, but vary in number in different individuals. The secondary lymph glands are those in the bend of the elbow, in the popliteal space, in the mesentery, and around the aorta. Some of these develop during foetal life and some later. While lymph glands are of constant occurrence in some regions throughout life, the number may vary at different times in any region; and there may also be variations in different individuals. Glands may be called into existence at any time during life, in almost any region, as the result of exceptional activity of some organ, or in pathological conditions. Such structures are known as tertiary lymph glands.

The origin of the lymph (plasma) itself is probably extremely complex. At one time it was considered as the result of nitration from the blood plasma through the capillary walls. If lymph originates in this way the nitration is selective, for the chemical composition of the lymph differs from that of the blood plasma. In all probability the lymph plasma consists of blood plasma which has escaped through the vessel walls plus the products of cell activity in the tissues.

==The Spleen==

Since the spleen is generally considered as a lymphatic organ and since recent researches have shown that its structure is quite comparable to that of the lymph glands, it seems advisable to consider it under the head of lymphatic organs. Its ultimate origin is not yet settled and the details of its later development are still obscure. The same difficulties are met with as in the case of the origin and development of blood cells, for it is known that the spleen plays a part in the formation of the blood cells. Its structure differs from that of the lymph glands chiefly in that it possesses no distinct lymphatic sinuses; but it does possess lymph follicles (splenic corpuscles) and densely cellular cords (pulp cords) which are separated by cavernous blood vessels (cavernous veins).

For some time the spleen was considered as a derivative primarily of the mesenchyme in the region of the dorsal mesogastrium. More recently, however, investigators have taken the view that it arises partly, or possibly entirely, from the mesothelium (coelomic epithelium) of the dorsal mesogastrium. In human embryos during the fifth week the anlage of the spleen appears as an elevation on the left (dorsal) side of the mesogastrium (Fig. 221). This elevation is produced by a local thickening and vascularization of the mesenchyme, accompanied by a thickening of the mesothelium which covers it; and, furthermore, the mesothelium is not so distinctly marked off from the mesenchyme as in other regions. Cells from the mesothelium then migrate into the subjacent mesenchyme and the latter becomes much more cellular (Fig. 222). The migration is brief, and in embryos of about forty-two days has ceased, and the mesothelium is again 1 reduced to a single layer of cells. The elevation becomes larger and projects ; into the body cavity. At first it is attached to the mesentery (mesogastrium) by a broad, thick base, but as development proceeds the attachment if becomes relatively smaller and finally forms only a narrow band of tissue 'j through which the blood vessels (splenic artery and vein) pass.

Further development of the substance of the spleen consists of the breaking up of the cellular mesenchymal tissue by blood vessels and the formation of the splenic corpuscles. The connective tissue trabeculce, as well as the jfj capsule of the spleen are derived from the original mesenchymal tissue. The blood vessels become dilated in parts of their course to form the cavernous vessels (cavernous veins) which are separated by the pulp cords. The connective (reticular) tissue of the pulp cords is a derivative of the mesenchyme, as are also the various types of cells in the cords. The adventitia of the walls of some of the small arteries becomes infiltrated with lymphocytes to form the splenic corpuscles (lymph follicles).

<div id="Fig221"></div>
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'''Fig. 221. From transverse section through stomach region of a 14 pig embryo.''' Photograph.

It is generally recognized that during foetal life the spleen is a hematopoietic organ, that is, both leucocytes and nucleated red blood cells ai.e produced within it. Normally, the formation of erythrocytes stops at or soon after birth. In severe anaemia or in pernicious anaemia in postnatal life, however, the presence of dividing nucleated red blood cells suggests a return to embryonic conditions. The reticular tissue constitutes the source of these nucleated forms (erythroblasts) . It has also been suggested that the spleen acts as a destroyer of worn-out erythrocytes, for in many cases apparent remnants of the latter have been observed within the cytoplasm of the "spleen cells." The lymphocytes proliferate to a certain extent in the splenic corpuscles, and in that way, at least, the spleen serves as a base of supply for leucocytes. There is a possible suggestion that the first leucocytes of the spleen have their origin in the mesenchymal cells of the spleen anlage. This would be in accord with the observations which indicate that leucocytes are derived from indifferent mesenchyme cells.

<div id="Fig222"></div>
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Fig. 222. From section through dorsal mesogastrium (anlage of spleen) of a chick embryo of 3 days and 21 hours incubation. Tonkofl.

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Glomus Coccygeum.

The coccygeal skein (coccygeal gland) was originally considered as belonging to the same category as the suprarenal glands, but the latest researches have indicated that its cells do not possess the characteristic chromamn reaction and that it belongs rather to the category of lymph glands. It develops ventral to the apex of the coccyx in relation with branches of the middle sacral artery.

Although the thymus gland becomes a lymphatic structure it is primarily derived from the epithelium (entoderm) of the branchial grooves and will be considered in connection with the development of the alimentary tract (Chap. XII). The tonsils also will be considered in the same connection.

==Anomalies==

===Anomalies of the Heart===

====Acardia====

The malformation known as acardia occurs in the case of twins that have but one chorion. The so-called acardiac condition does not necessarily imply the absence of the heart in the affected twin, for the latter may develop to a considerable degree and possess a functionating heart. On the other hand, the affected twin may be only an amorphous mass of tissue which derives its total blood supply through the agency of the stronger twin's heart. Or there may be any intermediate form between these two extremes. The point is that the acardiac monster (acardiacus) derives its blood wholly or in part through the agency of the stronger heart. A further discussion of acardiac monsters and their possible explanation will be found in Chap. XX.

====Double Heart====
But one or two cases of a double heart in a single human foetus have been recorded. In some of the lower forms (chick) it occurs more frequently. The explanation is probably to be found in the double origin of the heart in Amniotes (p. 196).

====Anomalous Position of the Heart====

Congenital anomalies in the position of the heart are rare. Dextrocardia (heart on the right side) is almost invariably associated with changes in the position of the viscera (see transposition of the viscera, page 304) . In the condition known as ectopia cordis, the heart, with the pericardium, protrudes through a cleft in the ventral wall of the thorax, the cleft being probably due to an imperfect fusion of the two sides of the body wall in that particular region.

====Anomalies of the Septa====
The most frequent anomaly in the atrial septum is the persistence of the foramen ovale. The entire foramen may remain patent, or, as is more frequently the case, a smaller opening may persist between the ventral (anterior) border of the foramen and the valve of the latter (p. 203).

The atrial septum may be wholly lacking, but this always occurs in conjunction with other defects. It sometimes happens that the primary atrial septum (septum superius), which grows from the cephalic side of the common chamber, fails to fuse with the septum of the atrio-ventricular aperture (p. 203 and Fig. 171).

Defects in the ventricular septum occur less frequently than in the atrial septum. It may happen that the cephalic (upper) border of the ventricular septum fails to fuse with the septum which divides the aortic trunk and bulb into the aorta and pulmonary artery. This affects the cephalic (upper) part of the septum sometimes called the pars membranacea (p. 204 and Fig. 174); and since the defect is situated near the opening of the aorta it brings about the so-called "origin of the aorta from both ventricles." Stenosis of the pulmonary artery usually accompanies this condition. Rarely is there a deficiency in the caudal (lower) part of the ventricular septum. Complete absence of the ventricular septum may occur, and along with it also an absence of the atrial septum, so that the heart is simply two-chambered; or the single ventricle may open into two atria. The causes of these defects ] are obscure.

====Anomalies of the Valves====
There may be congenital variations in the j size and number of the atrio-ventricular valves, depending upon abnormal position, fusion, or division of the pad-like masses from which the valves ! develop (p. 206).

There may be also a greater or lesser number of semilunar valves in the | aorta and pulmonary artery. This irregularity can probably be referred back to an atypical division of the aortic trunk and bulb, and a corresponding \ atypical division of the protuberances which give rise to the valves (p.. 206). Variations in the valves may or may not be accompanied by functional dis- i turbances. The congenital diminution in the number of valves should be distinguished from the acquired, where chronic endocarditis may cause a fusion.

===Anomalies of the Large Vascular Trunks===

====Anomalies of the Arteries====

There may be a transposition of the aorta \ and pulmonary artery. This results from an anomalous division of the aortic trunk and bulb. The partition develops in such a way as to put the aorta in communication with the right ventricle, and the pulmonary artery with 1 the j left ventricle (p. 204). Or the aorta and pulmonary artery may remain in \ direct communication on account of an imperfect development of the partition. Rarely the two vessels remain as a common stem.

Congenital stenosis (constriction) of the pulmonary artery may occur, j accompanied by an increase in the size of the aorta, possibly due to an unequal j division of the aortic trunk and bulb. After birth little or no blood can pass \ to the lungs, and the result is a general damming (stasis) of the venous blood ! with marked cyanosis. This is at least one explanation of the so-called "blue babies." Less frequently there is a stenosis of the proximal end of the aorta, with excessive size of the pulmonary artery, also due to an unequal division of the aortic trunk and bulb (p. 204) . These stenoses are usually, though not always, accompanied by defects in the ventricular septum.

Persistence of the ductus arteriosus may occur without any other defect; ;i but usually the persistence is associated with anomalous conditions of the aorta and pulmonary artery.

Occasionally the arch of the aorta is found on the right side. This condition is due to the persistence of the fourth aortic arch on the right side instead of the corresponding arch on the left side; this is the normal condition in Birds. Rarely both fourth aortic arches persist, which results in a double arch of the aorta the normal condition in Reptiles. (Compare Figs. 181 and 182.)

The dorsal aorta, particularly the abdominal part, is occasionally found to consist of two parallel, imperfectly separated vessels a condition known as double aorta. This anomaly is due to an imperfect fusion of the two primitive aortae (p. 187 and Fig. 165).

Numerous variations are met with in the larger branches of the aorta,, many of which are explained by referring them to embryonic conditions. Especially noteworthy are the branches from the arch of the aorta, since their development is so closely associated with the changes in the aortic arches. The normal arrangement passing from the heart, is innominate artery, left common carotid artery, left subclavin artery (see Fig. 182).

1. All these branches may be collected into a single trunk a condition characteristic of the horse.

2. Two branches may arise from the arch, (a) The left common carotid unites with the innominate, and the left subclavian arises separately. This is the normal arrangement among the apes, and is probably the most common variation in man. (b) Very rarely there are two innominate arteries, each formed by the union of a common carotid and subclavian a condition characteristic of Birds.

3. Three branches may arise from the arch but in a manner differing from the normal. Each subclavian arises separately and the two common carotids are united into a single vessel. This arrangement is found in some of the Cetacea.

4. Four vessels may arise from the arch, (a) These are, in order, innominate, left common carotid, left vertebral, left subclavian. (b) Or the order may be right common carotid, left common carotid, left subclavian, right subclavian. In this case the proximal part of the right subclavian represents the portion of the right dorsal aortic root just cranial to the bifurcation; the fourth arch on the right side disappears, (c) Or very rarely the order may be right subclavian, right common carotid, left common carotid, left subclavian.

5. Five branches of the arch are rare. In order they are right subclavian, right vertebral, right common carotid, left common carotid, left subclavian.

6. Very rarely there are six branches of the arch; right subclavian, right vertebral, right .common carotid, left common carotid, left vertebral, left subclavian.

====Anomalies of the Veins====

The two pulmonary veins on each side, more frequently those on the left side, many unite into a common trunk before opening into the atrium. This variation is probably due to the fact that the absorption of the originally single pulmonary trunk into the wall of the atrium does not proceed far enough to cause all four of the pulmonary veins to open separately (see p. 205) . The upper (more cephalic) vein on the right side may open into the superior vena cava; or the upper vein on the left side may open into the left innominate vein. A possible explanation for this is that the pulmonary veins are formed after the heart and other vessels have developed to a considerable degree, and some of them may unite with the other vessels instead of with the atrium.

Occasionally two superior vena cava are met with. In this case the right opens into the right atrium in the normal position; the left opens into the right atrium through the coronary sinus which naturally is much enlarged. This condition represents a persistence of the proximal end of the left anterior cardinal vein and the left duct of Cuvier, and is the normal arrangement in many of the lower Vertebrates. Even with two venae cavae there may be a small anastomosing branch in the position of the left innominate vein, which represents the normal structure in the Marsupials (see Figs. 194 and 195 and p. 223). There are a few cases on record of a single left superior vena cava.

The inferior vena cava is also subject to variations which represent the abnormal persistence of certain embryonic vessels. Perhaps the most striking of these variations is the condition known as double inferior vena cava. There may be two parallel vessels, of equal or unequal size, which unite at or above the level of the renal veins. This condition is to be explained by the persistence of parts of both posterior cardinal veins. It is met with not infrequently among the lower Mammals, especially the Marsupials (see Figs. 195 and 198).

Rarely the inferior vena cava opens into the superior, and in this case the hepatic veins open directly into the right atrium. This anomaly probably represents a failure of the absorption of the sinus venosus into the wall of the atrium (p. 205).

A left renal vein may open into the left common iliac, which condition represents a persistence of the more caudal part of the left posterior cardinal (Fig. 198). This anomaly is rare.

The azygos vein occasionally presents variations which are due to anomalous development. All the intercostal veins on the left side may be collected into a vessel which opens into the left innominate vein. There may be a single median azygos vein; or there may be a transposition of the azygos vein. It may be on the left side and open into the coronary sinus (normal conditions in the sheep and a few other Mammals). The latter condition represents a persistence of the more cephalic part of the left posterior cardinal vein (see Figs. 195 and 106).

Space does not permit a discussion of the great number of congenital variations that occur in the smaller blood vessels, both arteries and veins. The student is referred, however, to the more extensive text-books of anatomy.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_11|Muscular]]

==References for Further Study==

BORN, G.: Beitrage zur Entwicklungsgeschichte des Saugetierherzens. Archiv f. mik. Anat. Bd. XXXIII, 1899.

{{Ref-Bremer1915}}

CLARK, E. R.: Further Observations on Living Growing Lymphatics; their Relation to Mesenchymal Cells. Am. Jour, of Anat., Vol. XIII 1911.

CLARKE, W. C.: Experimental Mesothelium. Anat. Record, Vol. VIII, 1914.

DANTSCHAKOFF, W.: Untersuchungen iiber die Entwicklung des Blutes und Bindegewebes bei den Vogeln. Anat. Hefte, Bd. XXXVII, 1908.

DANCHAKOFF, V.: Origin of the Blood Cells. Development of the Haematopoietic Organs and Regeneration of the Blood Cells from the Standpoint of the Monophyletic School. Anat. Record, Vol. X, No. 5, 1916.

DANCHAKOFF, VERA: Cell Potentialities and Differential Factors in Relation to Erythropoiesis. Am. Jour, of Anat., Vol. XXIV, 1918.

ETERNOD, A. C. F.: Premiers stades de la circulation sanguine dans 1'ceuf et embryon humain. Anat. Anz., Bd. XV, 1899.

EVANS, H. M.: On the Earliest Blood Vessels in the Anterior Limb Buds of Birds and their Relation to the Primary Subclavian Artery. Am. Jour, of Anat., Vol. IX, 1909.

His, W.: Anatomic menschlicher Embryonen. Leipzig, 1880-1885. With Atlas.

HOCHSTETTER, F.: Die Entwickelung des Blutgefasssystems. In Hertwig's Handbuch der vergleich. und experiment. Entwickelungslehre. Bd. Ill, Teil II, 1901. Contains also extensive bibliography.

HOWELL, W. H.: The Life History of the Formed Elements of the Blood, Especially the Red Blood-corpuscles. Journal of Morph., Vol. IV, 1890.

HUNTINGTON, G. S., and McCLURE, C. F. W.: Development of Postcava and Tributaries in the Domestic Cat. Am. Jour, of Anat., Vol. VI, 1907.

J HUNTINGTON, G. S.: The Phylogenetic Relations of the Lymphatic and Blood Vascular Systems in Vetebrates. Anat. Record, Vol. IV, 1910.

HUNTINGTON, G. S.: The Genetic Principles of the Development of the Systemic Lymphatic Vessels in the Mammalian Embryo. Anat. Record, Vol. IV, 1910.

HUNTINGTON, G. S.: The Development of the Lymphatic System in Reptiles. Anat. Record, Vol. V, 1911.

HUNTINGTON, G. S.: The Anatomy and Development of the Systemic Lymphatic Vessels in the Domestic Cat. Memoirs of the Wistar Institute of Anatomy and Biology, No. i, 1911.

HUNTINGTON, G. S.: The Development of the Mammalian Jugular Lymph Sac, of the Tributary Primitive Ulnar Lymphatic and the Thoracic Ducts from the Viewpoint of recent Investigations of Lymphatic Ontogeny, Am. Jour, of Anat., Vol. XVI, No. 3, 1914.

HUNTINGTON, GEORGE S.: The Morphology of the Pulmonary Artery in the Mammalia. Anat. Record, Vol. XVII, 1919.

KLING, C. A.: Studien iiber die Entwicklung der Lymphdriisen beim Menschen. Archvo f. mik. Anat., Ed. LXIII, 1904.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen, Bd. II, 1907.

LEHMAN, H.: On the Embryonic History of the Aortic Arches in Mammals. Anat. Am., Bd. XXVI, 1905.

LEWIS, F. T.: The Development of the Vena Cava Inferior. Am. Jour, of Anat., Vol. I, 1902.

LEWIS, F. T.: The Development of the Veins in the Limbs of Rabbit Embryos. Am. Jour, of Anat. Vol. V, 1906.

MALL, F. P.: Development of the Internal Mammary and Deep Epigastric Arteries in Man. Johns Hopkins Hosp. Bull., 1898.

{{Ref-Mall1905}}

{{Ref-Mall1912}}

MAXIMOW, A.: Die Friihesten Entwicklungsstadien der Blut- und Bindegewebszellen beim Saugetierembryo, bis zum Anfang der Blutbildung in der Leber. Arch. f. mik. Anat., Bd. LXXIII, 1909.

MAXIMOW, A.: Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leber der Saugetiere. Folia Hdmatolog., Bd. VIII, 1909.

MAXIMOW, A.: Die embryonale Histogenese des Knochenmarks der Saugetiere. Arch.f. mik. Anat., Bd. LXXVI, 1910.

McCLURE, C. F. W.: The Development of the Lymphatic System in Fishes with Especial Reference to its Development in the Trout. Memoirs of the Wistar Institute of Anatomy and Biology, No. 4, 1915.

McCLURE, C. F. W., and SILVESTER, C. F.: A Comparative Study of theLymphatico- Venous Communications in Adult Mammals. Anat. Record, Vol. Ill, 1909.

MILLER, A. M.: Histogenesis and Morphogenesis of the Thoracic Duct in the Chick; Development of Blood Cells and their Passage to the Blood Stream via the Thoracic Duct. Am. Jour, of Anat., Vol. XV, 1913.

MINOT, C. S.: On a Hitherto Unrecognized Form of Blood Circulation without Capillaries in the Organs of Vertebrata. Proc. Boston Soc. Nat. Hist., Vol. XXIX, 1900.

REAGAN, F. P.: Experimental Studies on the Origin of Vascular Endothelium and of Erythrocytes. Am. Jour, of Anat., Vol. XXI, 1917.

ROSE, C.: Zur Entwickelungsgeschichte des Saugetierherzens. Morph. Jahrbuch, Bd. XV, 1889.

RUCKERT, J., and MOLLIER, S.: Die erste Entstehung der Gefasse und des Blutes bei Wirbeltiere. In Hertwig's Handbuch der vergleich und experiment. Entwickelungslehre, Bd. I, Teil I, 1906. Contains also extensive bibliography.

SABIN, F. R. : On the Origin of the Lymphatic System from the Veins and the Development of the Lymph Hearts and Thoracic Duct in the Pig. Am. Jour, of Anat., Vol. I, 1902.

SABIN, F. R.: The Origin and Development of the Lymphatic System. The Johns Hopkins Hospital Reports Monographs, New Series, No. 5, 1913.

SALA, L.: Svilluppo dei cuori linfatici e dei dotti toracici nelP embrione di polio. Ricerche fatte nel laboratorio de anatomia normale della R. Universita di Roma, Vol. VII, 1900.

SCAMMON, R. E., and NORRIS, E. H.: On the Time of the Post-natal Obliteration- of the Foetal Blood-passages (Foramen ovale, Ductus arteriosus, Ductus Venosus). Anat. Record, Vol. XV, 1918.

SCHULTE, H. VON W.: Early Stages of Vasculogenesis in the Cat (Felis domestica) with Especial Reference to the Mesenchymal Origin of Endothelium. Memoirs of the Wistar Institute of Anatomy and Biology, No. 3, 1914.

SCHULTE, H. VON W.: The Fusion of the Cardiac Anlages and the Formation of the Cardiac Loop in the Cat (Felis domestica). Am. Jour, of Anat., Vol. XX, 1916.

{{Ref-Senior1919}}

STOCKARD, CHAS. R.: The Origin of Blood and Vascular Endothelium in Embryos without a Circulation of the Blood and in the Normal Embryo. Am. Jour.] of Anat. t Vol. XVIII, No. 2, 1915.

STOERK, O.: Uber die Chromreaktion der Glandula coccygea und die Beziehung dieser Druse zum Nervus sympthathicus. Arch. f. mik. Anat., Bd. LXIX, 1906.

STOHR, P.: Uber die Entwicklung der Darmlymphknotchen und uber die Riickbildung von Darmdriisen. Arch. f. mik. Anat., Bd. LI, 1898.

{{Ref-Senior1915}}

TANDLER, J.: Zur Entwickelungsgeschichte der menschlichen Darmarterien. Anat. Heft, Bd. XXIII, 1903.

TONKOFF, W.: Die Entwickelung der Milz bei den Amnioten. Archil), f. mik. Anat., Bd. LVI, 1900.

WEIDENREICH, F.: Die Morphologic der Blutzellen und ihre Beziehungen zu einander. Anat. Record, Vol. IV, 1910.

WEST, R.: The Origin and Early Development of the Posterior Lymph Heart in the Chick. Am. Jour, of Anpt., Vol. XVII, 1915.

WRIGHT, J. H.: The Origin and Nature of the Blood Plates. Boston Med. and Surg. Jour., Vol. CLIV, 1906.

{{Bailey_1921_Footer}}

Book - Text-Book of Embryology 9

2024-01-25T00:26:13Z

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=The Development of Connective Tissues and the Skeletal System=
<div id="Fig100"></div>
[[File:Bailey100.jpg|thumb|'''Fig. 100. Transverse section of chick embryo of 27 hours' incubation.''' Photograph.]]

All the connective or supporting tissues of the body, except neuroglia, are derived from the mesoderm. This Goes not imply, however, that all the mesoderm is transformed into connective tissues; for such structures as the endothelium of the blood vessels and lymphatic vessels, probably blood itself, the epithelium lining the serous cavities, smooth and striated muscle, and a part of the epithelium of the urogenital system are derived from mesoderm.

The origin of the mesoderm itself has been discussed elsewhere (p. 93). In this connection it is sufficient to recall that it is situated between the ectoderm and entoderm and consists of several layers of closely packed cells (Fig. ioo). The axial portion in the neck and body regions becomes differentiated into the mesodermic somites. At the same time a cleft (the coelom) separates the more peripheral portion into a parietal and a visceral layer (Figs. 101 and 103). In the head region where, in the higher animals, there is little or no indication of somites and ccelom, the mesoderm simply fills in the space between the ectoderm and entoderm (Fig. 102). Portions of the mesoderm in all these regions are destined to give rise to connective tissues. Each mesodermic somite! soon becomes differentiated into three parts the sclerotome, cutis plate and ( myotome (Fig. 104). Of these, only the sclero tome and cutis plate are directly concerned in the formation of connective tissues, the myotomes giving rise to striated voluntary muscle. The sclerotomes are destined to give rise to the vertebrae and other forms of connective tissue in their neighborhood, the cutis plates to a part, at least, of the corium of the skin. The parietal and visceral layers of the mesoderm (excepFthe mesothelium lining the ccelom) and the mesoderm of the head region are destined to give rise to the various types of connective tissue forming parts of the other organs of the body.

<div id="Fig101"></div>
[[File:Bailey101.jpg|600px]]

'''Fig. 101. Transverse section of chick embryo (2 days' incubation).''' Photograph. The parietal mesoderm (lying above the coelom) is not labeled. The two large vessels under the primitive segments are the primitive aortae. Spaces separating germ layers are clue to shrinkage.

<div id="Fig102"></div>
[[File:Bailey102.jpg|600px]]

'''Fig. 102. Transverse section through head region of chick embryo of 42 hours' incubation.''' Photograph.

<div id="Fig103"></div>
[[File:Bailey103.jpg|600px]]

'''Fig. 103. Transverse section of human embryo with 13 primitive segments.''' Section taken through the 6th segment. Kollmann.

==Histogenesis==

The sclerotomes and cutis plates at first constitute parts of the mesoorermic somites, and are composed of epithelial-like cells with little intercellular substance. The intercellular substance gradually increases in amount so that the cells become more widely separated from one another, at the same time assuming oval or spindle shapes and then irregular branching forms (Fig. 106). The rest of the mesoderm, except the mesothelium, also undergoes a similar transformation so that structurally its cells are indistinguishable from those derived from the sclerotomes and cutis plates.

<div id="Fig104"></div>
[[File:Bailey104.jpg|600px]]

'''Fig. 104. Transverse section of human embryo of the 3rd week.''' Scl. 1 , Break in myotome at point where sclerotome is closely attached. Kollmann.

<div id="Fig105"></div>
[[File:Bailey105.jpg|400px]]

'''Fig. 105. Three primitive segments from sagittal section of human embryo of the 3rd week'''. Kollmann.

Thus the mesoderm at this stage is composed of irregular, branching cells, with a relatively large amount of homogeneous intercellular substance filling the interstices. The branches, or protoplasmic processes, of each cell anastomose freely with those of other cells in the immediate vicinity.

<div id="Fig106"></div>
[[File:Bailey106.jpg|400px]]

'''Fig. 106. Mesenchymal tissue from somatopleure of a 5 mm human embryo'''. Mesothelium is shown along lower border of figure.

In this manner a syncytium is formed to which the term mesenchyme is applied (Fig. 106). The mesenchyme itself lacks specialization, being what is known as an indifferent tissue, but it constitutes the structural basis upon which all the connective tissues of the adult body are built; all the forms of connective tissue (except neuroglia) develop from it.

That intercellular substance is derived originally from the cell can scarcely be denied. All the cells of the organism are derived from the fertilized ovum. As soon as two or more cells are formed by segmentation of the ovum, they are either simply in apposition or else they are united by something in the nature of a "cement" substance which must have been derived from the cells themselves. In the mesenchymal tissue this intercellular ground substance is a prominent feature, and probably represents in part nutritive materials and in part the products of cell activity.

==Fibrils and Fibers==
<div id="Fig107"></div>
[[File:Bailey107.jpg|thumb|'''Fig. 107. Fibril forming cells from fresh subcutaneous tissue of head of chick embryo.''' Boll.]]

The least differentiated and perhaps the least specialized tissue derived from mesenchyme is ''reticular tissue'', such as that found in the lymph nodes and spleen. In the peripheral part of the cytoplasm, or exoplasm, of the mesenchymal cells and their processes there arise delicate fibrils, often extending from one cell to another, which probably represent specialized parts of the spongioplasm. These fibrils maintain their intracellular position instead of becoming separated from the parent cytoplasm, so that the reticular tissue retains a marked resemblance in form to the original mesenchyme.
<div id="Fig109"></div>
[[File:Bailey109.jpg|thumb|'''Fig. 109. Longitudinal section of developing ligament from finger of human foetus of 6 months.''' Photograph.]]

<div id="Fig108"></div>
[[File:Bailey108.jpg|600px]]

Fig. 108. Connective tissue (mesenchymal) cells from larval salamander. Flemming.

The first step in the development of the true fibrillar forms of connective tissue from mesenchyme is the formation of fibrils and fibers. While it has been held by some investigators that the fibrils arise in and from the homogeneous intercellular substance, the best substantiated view is that they arise within and from the cytoplasm of the mesenchymal cells (Figs. 107 and 108). They then become separated from the cytoplasm and lie free in the " ground" substance in bundles (fibers). These fibrillated fibers are collaginous in character. Elastic fibers, while not fibrillated, probably have a similar origin. This first step in development gives rise to a loose, delicate tissue in the embryo, known as embryonal connective tissue, from which all the adult forms, except reticular tissue, develop.

The areolar tissue of the adult retains many of the general characters of embryonal connective tissue. The fibers, both collaginous and elastic, are loosely arranged and extend in all directions. The cells (fibroblasts) are fewer, however, and while they are characterized by irregular, branching forms it is not known whether their processes anastomose.

In any fibrous tissue, such as areolar, or the denser forms (fascia, tendons, ligaments), the structure depends upon the secondary arrangement of the fibers and not upon any peculiarity of origin. In all these forms the fibers have the same origin, but in the denser fascia, tendons and ligaments they become arranged in parallel lines (Fig. 109).

Adipose Tissue. Adipose tissue is a form of connective tissue in which the fatty element replaces to a great extent the cytoplasm in many of the embryonic connective tissue cells. It always develops in close relation to blood vessels, and first appears in the axilla and groin about the thirteenth week. It is formed in other places at later periods, even during adult life, but the mode of development is always the same. In some of the cells in the neighborhood of small blood vessels minute droplets of fat are deposited. The origin of the fat is not known. The droplets become larger, other smaller ones appear, and finally all of them coalesce to form a single large drop which practically fills the cell. The result of this is that the remaining cytoplasm is pushed outward and forms a sort of pellicle around the fat. The nucleus also is crowded outward and comes to lie flattened in the pellicle of cytoplasm (Fig. 111). At the same time the whole fat cell increases in size and forms a relatively large structure.

<div id="Fig110"></div>
[[File:Bailey110.jpg|400px]]

'''Fig. 110. Developing fat from subcutaneous tissue of pig embryo 5 inches long.''' Small artery breaking up into capillary network' groups of fat cells developing in embryonic connective tissue.

Fat cells usually develop in groups or masses around blood vessels (Fig. no). The neighboring groups gradually enlarge and approach each other, but do not fuse, thus leaving more or less fibrous connective tissue between them, which constitutes the interlobular tissue seen in adult adipose tissue. Among the individual cells in a lobule there is also a small amount of fibrous tissue present. From the mode of development a small artery usually affords the blood supply for each lobule.

==Cartilage==

In the different kinds of cartilage the matrix probably represents a modification of tne "ground substance" of the original embryonic tissue. The fibers in the matrix are probably derived from the cells in the same manner as the fibers in the fibrillar forms of connective tissue (Fig. 112).

==Osseous Tissue==

Here again the basis for development is embryonic connective tissue, although in one type of development cartilage precedes the bone. Two types of ossification are recognized intramembranous and intracartilaginous or endochondral. Intramembranous ossification calcium salts are deposited in ordinary embryonic connective tissue. In intracartilaginous ossification hyalin cartilage first develops in the same general shape as the future bone and the calcium salts are afterward deposited within the mass of cartilage. It is customary to speak also of another type of ossification subperiosteal in which the calcium salts are deposited under the periosteum.

<div id="Fig111"></div>
[[File:Bailey111.jpg|600px]]

'''Fig. 111. Developing fat from subcutaneous tissue of pig embryo 5 inches long.''' Fat (stained black) developing in embryonic connective tissue cells. At the right are five individual cells showing stages of development from an embryonic cell to an adult fat cell.

==Intramembranous Ossification==
<div id="Fig112"></div>
[[File:Bailey112.jpg|thumb|'''Fig. 112. Connective tissue cells from intervertebral disk of calf embryo.''' Showing origin of "white" and elastic fibers in protoplasm of cells. Ectoplasm represents a modified part of the protoplasm. Hansen.]]
This is the type of ossification by which many of the flat bones of the skull and face are formed. The region in which these bones are to develop consists of embryonic connective tissue. At certain points in this region bundles of connective tissue fibers become impregnated with calcium salts. Such areas are known as calcification centers. In each of these areas the cells increase in number, the tissue becomes very vascular and some of the cells, becoming more or less round or oval, with distinct nuclei and a considerable amount of cytoplasm, arrange themselves in single, fairly regular rows along the bundles of calcined fibers. The differentiated cells are known as osteoblasts (bone formers) , and the whole tissue is now known as osteo genetic tissue. Under the influence of the osteoblasts a thin layer of calcium salts is deposited between the osteoblasts and the calcified fibers. In this way the first true bone is formed, and the calcification center becomes an ossification center. Successive layers or lamellae of calcium salts are laid down and some of the osteoblasts become enclosed between the lamellae to form the bone cells (Figs. 113 and 1 14). The spaces in which the bone cells lie are the lacuna. At the same time the fibers also are enclosed within the bone and give it its characteristic fibrous structure (Fig. 114).

<div id="Fig113"></div>
[[File:Bailey113.jpg|600px]]

'''Fig. 113. Vertical section through frontal bone of human foetus of 4 months.''' (Intramembranous ossification.) Photograph.

Such a process results in the formation of irregular, anastomosing trabeculae of bone. The spaces among the trabeculae are known as primary marrow spaces- and contain osteogenetic tissue (Fig. 113). This type of bone, consisting of irregular, anastomosing trabeculae and enclosed marrow spaces, is known as spongy bone. The spongy bone thus formed is covered on-ats outer side by a layer of connective tissue which from its position is called the periosteum (Fig. 113), and which represents a part of the original embryonic connective tissue membrane in which the bone was laid down. During its development the periosteum becomes an exceedingly dense fibrous membrane which is closely applied to the surface of the bone.

<div id="Fig114"></div>
[[File:Bailey114.jpg|600px]]

'''Fig. 114. From vertical section through parietal bone of human foetus of 4 months.''' Bone cells not shown in lacunae, (Intramenibranous ossification.)

In a growing embryo, provision must be made for increase in the size of the cranial cavity to accommodate the growing brain. This is accomplished in the following manner : On the inner surface of the newly formed bone, large multinuclear cells appear, which are known as osteoclasts (bone destroyers). The osteoclasts are unusually large cells with a large number of nuclei and abundant cytoplasm, and in sections can be seen lying in depressions in the bone Howslip's lacuna (Fig. 114). Whether they are the specific agents in dissolution of bone has been questioned (Arey). While the destruction of bone is going on on the inner surface, new bone is being formed on the outer surface, especially under the periosteum where the osteoblasts are most numerous. Thus the layer of bone gradually comes to lie farther and farther out and the cranial cavity is enlarged. So long as the cranial cavity continues to enlarge the new bone is of the spongy variety, but toward the end of development the trabeculae become thicker and finally come together to form the compact bone characteristic of the roof of the skull. The fact that the new bone laid down during the enlargement of the cranial cavity is laid down under the periosteum has led to the term subperiosteal ossification. The process is essentially the same as in the original intramembranous ossification.

<div id="Fig115"></div>
[[File:Bailey115.jpg|600px]]

'''Fig. 115. Longitudinal section of one of the metatarsal bones of a sheep embryo.''' (Intracartilaginous ossification.)

==Intracartilaginous Ossification==
(''The modern term is endochondral ossification'')

In this type of ossification hyalin cartilage is first formed in a shape which corresponds very closely to the shape of the future bone. For example, the femur is first represented by a piece of hyalin cartilage which develops from the original embryonic connective tissue. On the surface of the cartilage a membrane of dense fibrous connective tissue, known as the perichondrium, develops (Fig. 115). In most cases, ossification begins about the middle of the piece of cartilage, corresponding to the middle of the shaft of a long bone (Fig. 115). The cell spaces enlarge and in some cases the septa of matrix between the enlarged spaces break down, so that several cells may lie in one space. The cell spaces radiate from a common center, but a little later they come to lie in rows parallel with the long axis of the mass of cartilage. During these early changes lime salts are deposited in the matrix of the cartilage in this region, and the portion so involved is known as a calcification center.

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'''Fig. 116. From section of one of the tarsal bones of a pig embryo.''' Showing periosteal bud pushing into the cartilage at the ossification center. (Intracartilaginous ossification.)

So far the process is preparatory to actual bone formation. Then small blood vessels from the perichondrium (periosteum) grow into the cartilage, carrying with them some of the embryonic connective tissue. These little ingrowths of connective tissue and blood vessels are known as periosteal buds (Fig. 1 1 6). The septa between the enlarged cartilage cell spaces break down still further, forming still larger spaces into which the periosteal buds grow. Many of the connective tissue cells are transformed into osteoblasts oval or round cells with distinct nuclei and a considerable amount of cytoplasm and with the fibers and blood vessels constitute osteogenetic tissue (Fig. 117). The cartilage cells in this region disintegrate and disappear, and the cavity formed by the coalescence of the cell spaces constitutes the primary marrow cavity (Fig. 117). From the primary marrow cavity osteogenetic tissue pushes in both directions toward the ends of the cartilage. The transverse septa between the enlarged cartilage cell spaces break down, leaving a few longitudinal septa which form the walls of long anastomosing channels which are continuous with the primary marrow cavity. The osteoblasts arrange themselves in rows along the septa of calcined cartilage and a thin layer or lamella of calcium salts is deposited between them and the cartilage. Successive lamellae are deposited in the same manner and some of the osteoblasts become enclosed to form bone cells (Fig. 118). The cartilage in the center gradually disappears. This region where bone formation is going on is known as an ossification center (Fig. 115) and the irregular anastomosing trabeculae of bone with the enclosed marrow spaces constitute primary spongy bone.

From this time on, ossification gradually progresses toward each end of the cartilage, and at the same time a special modification of the cartilage precedes it. Nearest the ossification center the cartilage cell spaces become enlarged and arranged in rows and contain cartilage cells in various stages of disintegration. Some of the septa break down, leaving larger, irregular spaces; the remaining septa become calcified (Fig. 115). Passing away from the center of ossification, there is less enlargement of the cell spaces and they have a tendency to be arranged in rows transverse to the long axis of the cartilage; there is also a lesser degree of calcification. The region of modified cartilage at each end of the ossification center passes over gradually into ordinary hyalin cartilage and is known as the calcification zone. It always precedes the formation of bone as the latter process moves toward the end of the cartilage (Fig. 115).

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[[File:Bailey117.jpg|thumb|'''Fig. 117.''' From same section as Fig. 115. Showing osteogenetic tissue pushing into the cartilage and breaking it up into trabeculae. (Intracartilaginous ossification.)]]

Along with the type of ossification just described subperiosteal ossification also occurs (Fig. 115). Beneath the periosteum (perichondrium) is a layer of connective tissue the cells of which are transformed into osteoblasts. They deposit layers of calcium salts on the surface of the cartilage in the same manner as around the trabeculae inside the cartilage.

The transformation of the spongy bone into compact bone is peculiar in that the former is dissolved and then replaced by new bone. Whether this dissolution occurs through the agency of the large multinucleated cells known as osteoclasts is not certain. By the process of dissolution the marrow spaces are increased in size and are known as Haversian spaces. Within these spaces new bone is then deposited layer upon layer, under the influence of the osteoblasts, until the Haversian spaces are reduced to narrow channels, the Haversian canals. The layers of bone are the Haversian lamella. The interstitial lamella in compact bone have two possible origins. They may be the remnants of certain lamellae of the original spongy bone which were not removed in the enlargement of the primary marrow spaces, or they may be parts of early formed Haversian lamellae which were later more or less replaced by other Haversian lamellae.

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'''Fig. 118. From same section as Fig. 115''' Showing bone deposited around one of the trabeculae of cartilage. (Intracartilaginous ossification.)

Carey, in his recent studies on certain mechanical phases of development, concludes " that cartilage and bone are not self -differentia ted, nor are they self-crystallized products," but represent " cellular responses to the varying intensity of the stresses and strains produced by resistance (pressure) counteracting the growth" of the skeleton in its blastemal stage, that is, while the cells are closely compacted prior to the appearance of the specific tissue. In his analysis of the femur, Koch has concluded that the "normal external form and internal architecture of the human femur results from an adaptation of form to the normal static demands, or normal function of the bone." It would appear therefore that in the development of bone mechanical factors play an essential part not only in the formation of the bone itself but also in the establishment of its form and internal structure.

GROWTH OF BONES. The way in which the cranial cavity enlarges has been described on page 139. While the process of enlargement is going on, the individual bones increase in size principally by the addition of new bone along their edges.

Intracartilaginous bones grow both in diameter and in length. It has already been stated that the primary spongy bone formed in cartilage is dissolved and that new bone is deposited under the periosteum. This naturally brings about an enlargement of the primary marrow cavity and at the same time an increase in the diameter of the bone as a whole. From this it is obvious that the compact bone of the shaft of a long bone is of subperiosteal origin, the intracartilaginous bone having been completely absorbed.

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'''Fig. 119. Diagram representing growth in diameter of a long bone.''' from Flour ens.

The fact that the osseous tissue bordering the marrow cavity is absorbed and that new bone is deposited under the periosteum can be quite clearly demonstrated. A young growing animal is fed for a few weeks on madder, which colors all the bone formed during that time a distinct red. If the animal is then killed and sections made of the long bones, the outer part of the latter will appear a distinct red. Another growing animal is fed on madder for a few weeks, then allowed to live a few weeks longer without madder. Then if it is killed and sections made of the bones, the red bone is found to be covered with a layer of uncolored bone which was deposited after the madder feeding had been stopped. If a young growing animal is fed on madder for a time and then allowed to live long enough without madder, the red bone will be found lining the marrow cavity. (See Fig. 119.)

Growth in length of the long bones takes place in a different manner. The primary center of ossification is situated near the middle of the piece of cartilage, and ossification proceeds in both directions toward the ends of the cartilage to produce the diaphysis or shaft of the bone. In each end of the cartilage there appears a secondary center from which ossification proceeds in all directions to produce the epiphysis. Between the shaft and epiphysis a disk of cartilage remains, and here, so long as the bone is growing, new cartilage continues to be formed. At the same time new bone is being formed in the new cartilage, principally in the part next the shaft. This produces an elongation of the shaft, the two epiphyses being carried farther and farther apart, and consequently a lengthening of the bone as a whole. When the bone reaches the required length, the cartilage disk diminishes and finally is wholly replaced by bone, being represented in the adult only by the epiphyseal line. (See Fig. 120.) MARROW. The forerunner of marrow is the osteogenetic tissue in the primary marrow spaces, which in turn is derived from embryonic connective tissue (Fig. 117). During the development of bone, great numbers of osteoblasts are constantly being differentiated from the connective tissue cells and many of these ultimately become bone cells. When development ceases, osteoblasts cease to become differentiated. Marrow is one of the chief centers of blood cell formation in later foetal life, and in the adult is normally probably the only source of erythrocytes. An account of blood cell formation will be found in the section on "Haemopoiesis." The myeloblasts, which are probably identical with or at least closely allied to the primitive blood cells (haemoblasts), by acquiring certain types of granules in the cytoplasm become neutrophilic, acidophilic or basophilic myelocytes. During development two types of giant-cells (myeloplaxes) appear in the marrow. According to Jordan one of these is haemogenic and the other osteolytic. The former originates from enlarged hasmoblasts and may be regarded as representing centers of intense haemopoiesis, giving rise to erythrocytes. The osteolytic giant-cells (osteoclasts) arise more frequently from fused portions of the marrow reticulum, less often from fused osteoblasts, and are always multinucleated. Arey maintains in his more recent work that the so-called osteoclasts usually arise by fusion of old and basophilic osteoblasts, the cytoplasm of the syncytial mass becoming acidophilic. Arey also holds that this type of giant-cell is not a specific agent in bone resorption. In young marrow there is little or no fat present, but in later life many of the connective tissue cells are transformed into fat cells (p. 136), so that these form the greater part of the marrow. Such a process occurs most extensively in the shaft of the long bones and gives rise to "yellow" marrow. In the heads of the long bones, in the ribs, and in the short bones the marrow retains its earlier character and is known as "red" marrow.

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'''Fig. 120. Longitudinal section from head of femur of young dog'''. Photograph. The head of the femur is shown in the upper part of the figure, the end of the shaft in the lower part. Between the two the lighter line represents the cartilage between the primary center of ossification (shaft) and the secondary center (epiphysis, head), and marks the site of the epiphyseal line. The lighter portion covering the head represents the cartilage bordering the joint cavity.

==The Development of the Skeletal System==

===The Axial Skeleton===

===The Notochord===
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[[File:Bailey121.jpg|thumb|'''Fig. 121.''' From transverse section of human embryo with 8 pairs of primitive segments (2.69 mm.). Kollmann. ]]

The notochord (chorda dorsalis) constitutes the primitive axial skeleton of all Vertebrates, yet it differs from the other skeletal elements in that it is a derivative of the entoderm. In man it is merely a transient structure and disappears early in foetal life, leaving but a slight trace of itself in the intervertebral disks. In embryos of 2-3 mm. the cells of the entoderm just ventral to the neural groove become slightly differentiated (Fig. 121) and then form a groove with a ventral concavity. The groove closes in, becomes constricted from the parent tissue (entoderm) and lies just ventral to the neural tube, where it soon becomes surrounded by mesodermal tissue. This structure is the notochord and constitutes a solid, cylindrical cord of cells extending from a point just caudal to the hypophysis to the caudal extremity of the embryonic body. In embryos of 17-20 mm. the mesodermal tissue around the notochord becomes modified to form the chorda! sheath. On account of its position the notochord naturally becomes embedded in the developing vertebral column, extending through the bodies of the vertebrae and the intervertebral disks. The cells are at first of an epithelial nature (Fig. 121), but those within the vertebral bodies become vacuolated and broken up into irregular, multinuclear masses which then disappear. The cord is thus first interrupted in the vertebrae, leaving only the segments within the intervertebral disks. Later these segments also undergo degenerative changes, but persist as the so-called pulpy nuclei.

While the notochord is morphologically the forerunner of the axial skeleton, and persists as a whole in Amphioxus, and in part in Fishes and Amphibia, in the higher forms it is almost exclusively an embryonic structure with little or no functional significance. It differs in origin from the true skeletal elements and becomes involved with them only to disappear as they develop.

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'''Fig. 122. Five myotomes and sclerotomes from sagittal section of human embryo of 5 mm.''' Bardeen.
:Each sclerotome is differentiated into a looser cephalic part and a denser caudal part, the two being separated by a cleft (fissure of von Ebner).

===The Vertebrae===

The changes which occur in the ventro-medial parts of the primitive segments to form the sclerotomes have already been described. At the same time it was stated that the vertebrae, with the other types of connective tissue around them, were derived from the mesenchymal tissue of the sclerotomes (p. 131; see also Fig. 104). The segmentally arranged masses forming the sclerotomes are separated by looser tissue in which the intersegmental arteries develop. The arteries mark the boundaries between the sclerotomes (Fig. 122). About the third week of development the caudal part of each sclerotome condenses to form a more compact mass of tissue, and a little later becomes separated from the cephalic part by a small cleft (Fig. 123). From the denser caudal part a secondary mass of tissue grows medially and meets and fuses with its fellow of the opposite side, thus enclosing the notochord. The medial mass thus formed may be considered as the anlage of the body of a vertebra. Another secondary mass also grows dorsally between the myotome and the spinal cord, forming the anlage of the -vertebral arch. A third mass grows ventro-laterally to form the costal process (Figs. 124 and 125). The looser tissue of the cephalic part of each sclerotome also sends an extension medially to surround the notochord, and fills up the intervals between the succeeding denser (caudal) parts. The looser part also forms a sort of membrane between the succeeding vertebral arches. The tissue between the denser caudal part and the looser cephalic part of each sclerotome is destined to give rise to an intervertebral fibrocartilage. While the denser tissue forming the caudal part of each sclerotome probably gives rise to the greater part of a vertebra, the looser tissue of the cephalic part is also involved in the formation of the cartilaginous body, as will be noted again in the following paragraph. The peculiar feature of the process is that the denser caudal part of a sclerotome becomes associated with the looser cephalic part of the next succeeding sclerotome, so that each vertebra is derived from parts of two adjacent sclerotomes and not from a single sclerotome. This naturally brings about an alternation of vertebra and myotomes (Fig. 123).

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'''Fig. 123. Six myotomes and sclerotomes from sagittal section of human embryo of 6 mm.''' Bardeen. Compare with Fig. 160.

So far the anlagen of the vertebrae are in the so-called blastemal stage.

Following the blastemal stage and beginning in human embryos of about 15 mm., comes the cartilaginous stage in which the mesenchymal anlagen of the vertebrae are converted into embryonic hyalin cartilage. In the body of each vertebra a center of chondrification appears in the looser tissue of the caudal part and gradually enlarges and involves the denser cephalic part. It is to be noted that the denser tissue of the cephalic part of a vertebral body corresponds to the caudal part of a sclerotome. Two chondrification centers appear, one on (Fig. 126). All these centers then enlarge and unite to form a single mass of cartilage which corresponds quite accurately in shape to the future bony vertebra. Processes then grow out from the vertebral arch. These represent the transverse and articular processes (Fig. 127). Each half of a vertebral arch meets its fellow of the opposite side dorsal to the spinal cord, and from the point of meeting the spinous process grows out. The costal processes do each side of the medial line, but the two soon fuse around the notochord to form a single center. In addition to the center in the body of the vertebra, one also appears in each half of the vertebral arch, and one in each costal process not retain their connection with the body of the vertebra, but break away and become the rib cartilages, as will be noted again in connection with the development of the ribs.

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'''Fig. 124. Transverse section (dorsal part) of pig embryo of 14 mm.''' Photograph.

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'''Fig. 125. Models of three vertebrae in the blastemal stage from an embryo of 11 mm.''' Bardeen.

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Fig. 126. Transverse section (dorsal part) of pig embryo of 35 mm. Photograph.

Following the cartilaginous stage is the stage of ossification in which the vertebrae become ossified and acquire the adult condition. Ossification begins during the third month of foetal life and extends over a long period, even up to the age of twenty-five years. A single center of ossification appears in the body of each vertebra, and following this a center in each half of the vertebral arch (Fig. 128). Osseous tissue then gradually replaces the cartilage. The two halves of an arch fuse dorsal to the spinal cord during the first year of postnatal life, thus completing the bony arch. The arch fuses with the body of the vertebra between the third and eighth years. Thus it is seen that the process of ossification is a slow one, and this is even more striking when one considers the formation of the secondary centers. For at about the age of puberty a secondary center appears in each of the cartilages that cover the ends of the vertebrae, producing disks of bone the epiphyses. A secondary center also appears in the cartilage on the tip of each spinous process and transverse process, and in the lumbar vertebrae one appears also on the tip of each articular process (Fig. 120). The epiphyses unite with the vertebrae any time between sixteen and twenty-five years. About the twenty-fifth year the sacral vertebrae unite to form a single mass of bone, and a similar union also takes place between the more or less rudimentary coccygeal vertebrae.

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'''Fig. 127. Models of the 6th, 7th and 8th thoracic vertebrae of an embryo of 33 mm.''' (dorsal view). Bardeen. On the right the cartilage is shown, on the left the surrounding fibrous tissue.

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'''Fig. 128. Thoracic vertebra and ribs of human embryo of 55 mm.''' (middle of 3rd month). Kollmann's Atlas. Cartilage indicated by stippled areas, ossification centers by irregular black lines.

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'''Fig. 129. Lumbar vertebra (lateral view) showing secondary centers of ossification.''' Sappey.

While the general plan of development is practically the same in all the vertebrae, there are a few noteworthy modifications. The greatest modification is in the atlas and epistropheus (axis). The entire atlas is formed from the denser caudal part of a sclerotome. The lateral mass and the posterior (dorsal) arch represent the vertebral arch. The anterior (ventral) arch represents the hypochordal bar, a plate of cartilage which develops in all vertebrae ventral to the notochord but disappears in all except the atlas. A body also develops but instead of forming part of the atlas it unites with the body of the epistropheus to form the dens (odontoid process) of the latter.

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'''Fig. 130. Ventral view of developing sternum of human embryo of 30 mm.''' (beginning of 3rd month). Ruge, Kollmann's Atlas.

The various ligaments of the vertebral column are derived from the embryonic connective tissue surrounding the vertebras. The embryonic connective tissue in the clefts separating the developing vertebrae is transformed into the intervertebral fibrocartilages.

===The Ribs===

It has been stated in a previous paragraph that the costal processes arise as outgrowths from the denser caudal parts of the sclero tomes; that they grow in a ventro-lateral direction and consequently are at first connected with and are parts of the bodies of the vertebrae (Figs. 124 and 126). These costal processes are the anlagen of the ribs, and they continue to grow ventrally until they practically encircle the body, the ventral ends of a number of them fusing in the medial line to form the sternum. The primary junctions between the costal processes and vertebrae are dissolved, and the embryonic connective tissue in this region gives rise to the costo-vertebral ligaments. The dissolution of the junctions leaves the ribs simply articulating with the vertebrae.

A chondrification center appears in each costal process, shortly after that in the body of the vertebra, and from this point the formation of cartilage gradually extends throughout the entire rib.

Ossification begins during the third month at a center which is situated near the angle of the rib (Fig. 128). At the age of eight to fourteen years a secondary center appears in each capitulum and tuberculum and subsequently fuses with the rest of the rib at the age of fourteen to twenty-five years. As the tuberculum develops, the transverse process of the corresponding vertebra grows ventrally and caudally to meet it and form the articulation.

The ribs reach the highest degree of development in the thoracic region where one develops on each side, corresponding to each vertebra. The first seven or eight thoracic ribs extend almost to the midventral line and are attached to the sternum; the last four or five become successively shorter and are only indirectly or not at all attached to the sternum. In the cervical region the ribs do not reach a high degree of development. Their tips simply fuse with the transverse processes of the vertebrae and their heads with the bodies of the vertebrae, leaving a space the foramen transversarium through which the vertebral vessels pass. The seventh cervical rib may, however, reach a fairly high degree of development. In the lumbar region also the ribs are reduced to small pieces of bone which are firmly united with the transverse processes and form the accessory processes. In the sacral region the rudimentary ribs unite to form the lateral part (pars lateralis) of the sacral bone. After the blastemal stage there are no indications of ribs in the coccygeal region. In the blastemal stage, however, there is a small bit of tissue Fig. 131. Sternum of which probably represents the anlage of a rib, but soon fuses with the transverse process.

===The Sternum===
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[[File:Bailey131.jpg|thumb|'''Fig. 131.''' 12 year old child, showing centers of ossification. Seven ribs are attached on the right side, 8 on the left. Markowski, Kollmann's Atlas.]]
The sternum, according to Hanson's recent contribution, originates independently of the ribs. On each side, some distance from the midventral line, the sternal band or bar arises as a mesenchymal condensation in the body wall. These bars then approach the midventral line and fuse with each other to form a single cartilaginous structure. Meanwhile the ventral ends of the first seven ribs extend far enough to come into contact with and join the sternal bar (Fig. 130). Before the two bars have united a medial unpaired rudiment appears opposite their anterior ends to form the presternum with which the paired rudiments subsequently unite. The presternal component, with which the clavicles articulate, probably represents the ventral part of the primitive vertebrate shoulder girdle.

Ossification begins in the sternum about the end of the fifth month of foetal life. In the cephalic portion two unpaired centers appear; caudal to these is a series of paired centers which subsequently fuse across the midventral line. (See Fig. 131.) The paired centers perhaps reflect the paired character of the sternal bars. Sometimes, however, the centers appear as a single series, that is, with no indication of a paired character. The ossification of the most cephalic segment, along with the episternal cartilages, produces the manubrium sterni. Ossification of the following six or seven segments and their union produce the corpus sterni. The xyphoid process appears to be a caudal extension of the corpus sterni. This process remains cartilaginous for a long period, and may be single, perforated, or bifurcated, depending upon the degree of fusion between the two primary bars.

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'''Fig. 132.''' Diagram of first stage in the development of the cartilaginous primordial cranium. Wiedersheim.

'''Fig. 133.''' Diagram of later stage of same. Wiedersheim.

===The Head Skeleton===

Topographically the skeleton of the head appears as the cephalic part of the axial skeleton. Structurally it is decidedly different, for it is adapted to different conditions. The neural tube here becomes differentiated into the brain with its many and dissimilar parts. In connection with the brain the complicated sense organs (nose, eye and ear) arise. A part of the alimentary tract and portions of the visceral arches are also inclosed within the head. The head skeleton is specially modified to accommodate these highly developed organs, and becomes extremely complicated. In general the skeleton in any part of the body adapts itself to the other structures and not the other structures to the skeleton.

The anlage of the skull is a mass of embryonic connective tissue which surrounds the cephalic end of the notochord, extends from there into the nasal region and also extends around the sides and dorsal part of the neural tube (brain). Unlike the anlage of the vertebral column, the anlage of the skull shows no distinct division into primitive segments. The only indications of a segmental character are referred to in a succeeding paragraph (small print,

The next step in the development of the skull is the appearance of cartilage in certain regions of the embryonic connective tissue. On account of the complicated arrangement of the cartilage in the human skull, it is best to consider first its more simple arrangement in the lower Vertebrates. In these there appear in the embryonic connective tissue around the cephalic end of the notochord two bilaterally symmetrical pieces of cartilage, which extend as far as the hypophysis. Then two other bilaterally symmetrical pieces appear, extending from the hypophysis to the nasal region. Subsequently all these pieces fuse into a single mass which extends from the cephalic end of the vertebral column to the tip of the nose, enclosing the end of the notochord and, to a certain extent, the ear, eye and olfactory apparatus. There is left, however, an opening for the hypophysis. From this mass of cartilage, chondrification extends into the embryonic connective tissue along the sides and roof of the cranial cavity, so that the brain and sense organs are practically enclosed. To this capsule the term cartilaginous primordial cranium has been applied. (See Figs. 132, 133, 134.)

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'''Fig. 134. Primordial cranium of Salmo (salmon) embryo of 25 mm.''' Dorsal view. Gaupp Compare with Fig. 133 and note further elaboration of parts surrounding the sense organs.

In the higher Vertebrates, chondrification is limited to the basal region of the skull, while the side walls and roof are formed later by intramembranous bone.

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'''Fig. 135. Dorsal view of primordial cranium of human embryo of 80 mm.''' (3rd month). Gaupp. Hertwig. The membrane bones of the roof of the skull have been removed. Through the large occipital foramen can be seen the first three cervical vertebrae.

In the human embryo chondrification occurs first in the occipital and sphenoidal regions, and then gradually extends into the nasal (ethmoidal) region. A little later it spreads somewhat dorsally in the occipital and sphenoidal regions to form part of the squamous portion of the occipital and the wings of the sphenoid. At the same time cartilage develops in the embryonic connective tissue surrounding the internal ear to form the periotic capsule whicn subsequent!} unites with the occipital and sphenoidal cartilages. The pieces of cartilage thus formed constitute the chondrocranium.

In connection with the development of the caudal part of the occipital cartilage there is an interesting feature which is at least indicative of a segmental character. In some of the lower Mammals there are four fairly distinct condensations of embryonic connective tissue just cranial to the first cervical vertebra, corresponding to the first cervical nerve and the three roots of the hypo glossal. These condensations bear a general resemblance to the primitive segments and indicate the existence of four vertebrae which are later taken up into the chondrocranium. In the human embryo the condensations are less distinct, but the existence of a first cervical and a three-rooted hypoglossal nerve in this region suggests an original segmental character. If this is true, then the base of the human skull is formed from the unsegmented chondrocranium plus four vertebrae which become incorporated in the occipital region.

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Fig. 136. Lateral view of primordial cranium of human embryo of 80 mm. (3rd month). Gaupp, Hertwig. The membrane bones of the roof of the skull have been removed. Compare with Fig. 135. The maxilla, vomer, palate, and mandible are membrane bones.

In addition to the chondrocranium, other cartilaginous elements enter into the formation of the skull, all of which are derived from the visceral arches. Not all the arches, however, produce cartilage; for in the maxillary process of the first arch, which forms the upper boundary of the mouth, cartilage does not appear, and the bones which later develop in it are of the membranous type. The mandibular process of the first arch produces a rod of cartilage Meckel's cartilage. This gives rise, at its proximal end, to a part of the auditory ossicles, but the cartilage in the jaw proper soon wholly or almost wholly disappears. The cartilage of the second arch becomes connected with the skull in the region of the periotic capsule. The cartilages of the other three arches are only indirectly connected with the skull and will be considered later.

Figs. 135 and 136 show the condition of the chondrocranium in a human embryo of 80 mm. (third month) . Although at first glance it seems exceedingly complicated, a careful study and comparison of the various parts will aid the student in his comprehension of the cartilaginous foundation upon which the skull is built.

===Ossification of the Chondrocranium===

In the human foetus ossification begins in the occipital region during the third month. Four centers appear which correspond to the four parts of the adult occipital bone (Fig. 137). (i) An unpaired center situated ventral to the foramen magnum. From this center ossification proceeds in all directions to form the pars basilaris (basioccipital). (2 and 3) Two lateral centers, one on each side. From these, ossification proceeds to produce the partes laterales (exoccipital) which bear the condyles. (4) A center dorsal to the foramen magnum. This produces the pars squamosa (supraoccipital) as far as the superior nuchal line. Beyond this line the pars squamosa is of intramembranous origin. (See p. 160.) At birth the four parts are still separated by plates of cartilage. During the first or second year after birth the partes laterales unite with the pars squamosa, and about the seventh year the pars basilaris unites with the rest of the bone.

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'''Fig. 137. Occipital bone of human embryo of 21.5 cm.''' Kollmann's Atlas.

In the sphenoidal region ossification begins at a number of centers which, as in the occipital region, correspond generally to the parts of the adult sphenoid bone (Fig. 138). (i and 2) About the ninth week an ossification center appears on each side in the cartilage which corresponds to the ala magna (alisphenoid). (3 and 4) About the twelfth week a center appears on each side which corresponds to the ala parva (orbitosphenoid) . (5 and 6) A short time after this a center appears on each side of the medial line in the basal part of the cartilage, and the two centers subsequently fuse to produce the corpus (basisphenoid) . (7 and 8) Lateral to each basal center, another center appears which represents the beginning of the lingula. (9 and 10) Finally two centers appear in the basal part of the cartilage, in front of the other basal centers, and then fuse to form the presphenoid. As in the case of the occipital bone, not all of the adult sphenoid is of intracartilaginous origin; for the upper anterior angle of each ala magna is of intramembranous origin, as are also the medial and lateral laminae of the pterygoid process. The pterygoid hamulus, however, is formed by the ossification of a small piece of cartilage which develops on the tip of the medial lamina. The fusion of these various parts occurs at different times. The lateral pterygoid lamina unites with the alisphenoid before the sixth month of foetal life; about the sixth month the lingula fuses with the basisphenoid, and the presphenoid with the orbitosphenoid. The alisphenoid and medial pterygoid lamina fuse with the rest of the bone during the first year after birth. The union of the basisphenoid and basioccipital usually occurs when the growth of the individual ceases, though the two bones may remain separate throughout life.

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'''Fig. 138. Sphenoid bone of embryo of 3-4 months.''' Sappey. The parts that are still cartilaginous are represented in black.

In the region of the periotic capsule, several centers of ossification appear in the cartilage during the fifth month. During the sixth month these centers unite to form a single center which then gradually increases to form the pars petrosa and pars mastoidea of the adult temporal bone. The mastoid process is formed after birth by an evagination from the pars petrosa, and is lined by an evaginated portion of the mucosa of the middle ear. The other parts of the temporal bone are of intramembranous origin, except the styloid process which represents the proximal end of the second branchial arch.

In the ethmoidal region, conditions become more complicated on account of the peculiarities of the nasal cavities, and on account of the fact that the cartilage is never entirely replaced by bone, and that "membrane" bones also enter into more intimate relations with the "cartilage" bones. The ethmoidal cartilage at first consists of a medial mass, which extends from the presphenoid region to the end of the nasal process, and of a lateral mass on each side, which is situated lateral to the nasal pit (Fig. 136). Ossification in the lateral mass on each side produces the ethmoidal labyrinth (lateral mass of ethmoid). It is perhaps not quite correct to say that ossification produces the ethmoidal labyrinth, for at first there is only a mass of spongy bone with no indication of the honey-combed structure characteristic of the adult. The latter condition is produced by at certain amount of dissolution of the bone and the growth of the nasal mucosa into the cavities so formed. By the same process of dissolution and ingrowth of nasal mucosa the superior, middle and inferior concha (turbinated bones) are formed. The medial mass of cartilage begins to ossify after birth and then only in its upper (superior) edge. It forms the lamina perpendicular is and crista galli and extends into the nose as the nasal septum. The lower (inferior) edge remains as cartilage until the vomer, which is a membrane bone (p. 194), develops, after which it is partly dissolved. The lamina cribrosa (cribriform plate) is formed by bony trabeculae which extend across between the medial mass and the lateral masses and surround the bundles of fibers of the olfactory nerve.

==Membrane Bones of the Skull==

Under this head we shall consider only those bones which develop a from the visceral arches, those which involve the arches being considered later. It has been seen that by far the greater parts of the bones forming the base of th skull are of intracartilaginous origin. On the other hand, those forming the sides and roof of the skull are largely of intramembranous origin. In the case of the occipital bone, two centers of ossification appear in the membrane dorsal to the supraoccipital, and the bone so formed begins to unite with the supraoccipital during the third month of foetal life. At birth the union is usually complete, though for a time an open suture may persist on each side. The bone derived from the two centers forms that part of the occipital squama which is situated above the superior nuchal line; the part below the line is of intracartilaginous origin (p. 190). The adult occipital is thus a composite bone, partly of intramembranous, partly of intracartilaginous origin.

The temporal is also a composite bone, the petrous and mastoid parts and the styloid process being of intracartilaginous origin, while the temporal squama and the tympanic part are of intramembranous origin. During the eighth week of foetal life a center of ossification appears in the membrane in the temporal region, and the bone formed from this center subsequently unites with the petrous part and becomes the temporal squama. Another center appears in the membrane to the outer side of the periotic capsule and produces a ring of bone around the external auditory meatus, which fuses with the petrous part and forms the tympanic part of the adult bone. It gives attachment at its inner border to the tympanic membrane. While the union of the different parts begins during foetal life, it is usually completed after birth.

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'''Fig. 139. Diagram of skull of new-born child.''' Combined from McMurrich and Kollmann. White areas represent bones of intramembranous origin; dotted areas represent bones (not derived from branchial arches) of intracartilaginous origin; black areas represent derivatives of branchial arches.

The sphenoid bone is also composed of parts which have different origins. The body, small wings and large wings are of intracartilaginous origin, the pterygoid process of intramembranous origin. About the eighth week of development a center of ossification appears in the mesenchyme in the lateral wall of the posterior part of the nasal cavity and gives rise to the medial pterygoid lamina. On the tip of the latter a small piece of cartilage appears in which ossification later takes place to form the pterygoid hamulus (p. 159). The lateral pterygoid lamina is also of intramembranous origin and fuses with the medial lamina, the two laminae forming the pterygoid process which subsequently unites with the body of the sphenoid. (See Fig. 138.)

In the ethmoidal region, only the vomer is of intramembranous origin. An ossification center appears in the embryonic connective tissue on each side of the perpendicular plate (lamina perpendicularis) and these two centers produce two thin plates of bone which unite at their lower borders and invest the lower part of the perpendicular plate. The portion of the latter thus invested undergoes resorption.

The frontal and parietal bones are purely of intramembranous origin. About the eighth week two centers of ossification, one on each side, appear for the frontal. The bones produced by these centers unite in the medial line to form the single adult bone. In the event of an incomplete union an open suture remains the metopic suture. A single center of ossification appears for each parietal bone at about the same time as those for the frontal. The union of the bones which form the roof and the greater part of the sides of the skull does not occur till after birth. The spaces between them constitute the sutures and fontanelles so obvious in new-born children (Fig. 139).

A single center of ossification appears in the embryonic connective tissue for each zygomatic, lachrymal and nasal bone, all of which are of intramembranous origin.

==Bones Derived from the Branchial Arches==

The first branchial arch becomes divided into two portions. One of these, the maxillary process, is destined to give rise to the upper jaw and much of the upper lip and face region. The other, the mandibular process, is destined to give rise to the lower jaw, the lower lip and chin region, and two of the auditory ossicles. The angle between the two processes corresponds to the angle of the mouth, and the cavity enclosed by the processes is the forerunner of the mouth and nasal cavities. (See Fig. 96, also p. 119.) So far as the skeletal elements are concerned, cartilage develops only in the mandibular process where it forms a slender bar or rod known as MeckeVs cartilage. Only a small part of this becomes ossified, the greater portion of the mandible being of intramembranous origin. No cartilage develops in the maxillary process. This probably indicates a condensation of development in man and the higher animals, for among the lower animals cartilage precedes the bone. In man the maxilla and palate bone also are of intramembranous origin.

The palate bone develops from a single center of ossification which appears at the side of the nasal cavity in embryos of about 18 mm. This center represents the perpendicular part, the horizontal part appearing in embryos of about 24 mm. as an outgrowth from the perpendicular and not as a separate center of ossification. The orbital and sphenoidal processes also represent outgrowths from the primary center and appear much later.

Opinions regarding the development of the maxilla are at variance. One view is that it arises from five centers of ossification. One of these centers gives rise to that part of the alveolar border which bears the molar and premolar teeth; a second center forms the nasal process and that part of the alveolar border which bears the canine tooth; a third produces the part which bears the incisor teeth; and the two remaining centers give rise to the rest of the bone. All these parts effect a firm union at an early stage, with the exception of the part bearing the incisor teeth which remains more or less distinct as the incisive bone (premaxilla, intermaxilla) . Another view arising from recent work on human embryos is that there are primarily only two ossification centers; one of these gives rise to the incisive bone, the other to the rest of the maxilla (Mall). These centers appear at the end of the sixth week (embryos of 18 mm.).

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'''Fig. 140. Head of human embryo of 7 weeks.''' His. Ventral aspect of upper jaw region. Lower jaw and tongue have been removed.

A very important feature in the development of the maxilla is its agency in separating the nasal cavity from the mouth cavity. The palatine process of the bone grows medially and meets and fuses with its fellow of the opposite side in the medial line, the two processes together thus constituting about the anterior three-fourths of the bony part of the hard palate. It should be observed, however, that the palatine processes do not meet at their anterior borders, for the incisive bone is insinuated between them (see Figs. 140, 141).

The incisive bone is probably not derived from the maxillary process of the first visceral arch, but from the fronto-nasal process. The question thus arises as to whether it is derived from both the middle and lateral nasal processes or only from the middle. According to Kolliker's view, the lateral nasal process takes no part in the formation of the incisive bone. It is derived from the middle process, hence genetically it is a single bone on each side. According to Albrecht's view the incisive bone is genetically composed of two parts, one derived from the lateral, the other from the middle nasal process. While the matter is not one of great importance merely from the standpoint of development, it has an important bearing on the question of certain congenital malformations, e.g., hare lip, and will be discussed further under that head (p. 180).

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'''Fig. 141. Ventral aspect of hard palate of human embryo of 80 mm.''' Kollmann's Atlas.

In the mandibular process of the first visceral arch, the mandible develops as a bone which is partly of intramembranous and partly of intracartilaginous origin. In the first place a rod of cartilage, known as Meckel's cartilage, forms the core of the mandibular process and extends from the distal end of the process to the temporal region of the skull, where it passes between the tympanic bone and the periotic capsule and ends in the tympanic cavity of the ear (Fig. 136). During the sixth week of foetal life, intramembranous bone begins to develop in the mandibular process. In the region of the body of the mandible the bone encloses the cartilage, but in the region of the ramus and coronoid process the cartilage lies to the inner side of the bone. Development is further complicated by the appearance of cartilage in the region of the middle incisor teeth and on the coronoid and condyloid processes. These pieces of cartilage form independently of Meckel's cartilage and subsequently are replaced by the bone which constitutes the corresponding parts of the mandible. The part of Meckel's cartilage enclosed in the bone disappears; the part to the inner side of the ramus is transformed into the sphenomandibular ligament. (See Fig. 142.) In each half of the second branchial arch a rod of cartilage develops, which extends from the ventro-medial line to the region of the periotic capsule. The proximal end of this rod is then replaced by bone which fuses with the temporal bone and forms the styloid process. The distal (ventral) end is replaced by bone which forms the lesser horn of the hyoid bone. Between the styloid process and the lesser horn, the cartilage is transformed into the stylohyoid ligament (see Figs. 139 and 142).

In each half of the third branchial arch a piece of cartilage develops and subsequently is replaced by bone to form the greater horn of the hyoid bone. The two horns become connected at their ventral ends by the body of the hyoid bone which is also a derivative of the third arch. Later the lesser horn fuses with the greater horn to bring about the adult condition (Fig. 142).

In the ventral parts of the fourth and fifth arches pieces of cartilage develop and form the skeletal elements, of the larynx. A more detailed account of these will be found under the head of the larynx.

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'''Fig. 142. Lateral dissection of head of human foetus'''. Showing derivatives of branchial arches in natural position. Kollmann's Atlas.

The auditory ossicles are also derived largely from the branchial arches, the incus and malleus being derived from the proximal end of Meckel's cartilage (first arch) , the stapes having a double origin from the second arch and the embryonic connective tissue surrounding the periotic capsule. But since they form integral parts of the organ of hearing, a discussion of their formation is best included in the development of the ear.

The accompanying table indicates the types of development in the different bones of the head skeleton.

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==The Appendicular Skeleton==

The growth of the limb buds and their differentiation into arm, forearm and hand, thigh, leg and foot, along with the rotation which they undergo during development, have been discussed in the chapter on the external form of the body (p. 121). The metameric origin of the muscles of the extremities is discussed in the chapter on the muscular system (Chap. XI). It has been seen that the greater part of the axial skeleton is derived from the sclerotomes, is preformed in cartilage, and maintains its segmental character throughout life. It has also been seen that the head skeleton is in part preformed in cartilage, is in part of intramembranous origin, and shows but a trace of segmental character, and that only in the occipital region at a very early stage. The appendicular skeleton is derived wholly from the embryonic connective tissue which forms the cores of the developing extremities, and shows no trace of a segmental character. Here also, as in the axial skeleton, three stages may be recognized a blastemal, a cartilaginous (Fig. 143), and a final osseous,

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'''Fig. 143. Cartilages of left upper extremity of a human embryo of 17 mm.''' Hagen.

In the region of the shoulder girdle a plate of cartilage appears in the embryonic connective tissue which lies among the developing muscles dorso-lateral to the thorax. This plate of cartilage is the forerunner of the scapula, and in general resembles it in shape. During the eighth week of foetal life a single center of ossification appears and gives rise to the body and spine of the scapula. After birth certain accessory centers appear and produce the coracoid process, the supraglenoidal tuberosity, the acromion process, and the inferior angle and vertebral margin (Fig. 144). Later the supraglenoidal fuses with the coracoid and forms part of the wall of the glenoid cavity. About the seventeenth year the single center formed by the union of these two fuses with the rest of the scapula.

At the age of twenty to twenty-five years all the other accessory centers unite with the rest of the scapula to form the adult bone.

There are two views concerning the development of the clavicle: one that it is of intracartilaginous origin, the other that it is of intramembranous origin. Ossification begins during the sixth week, possibly from two centers. It is true that the cartilage that appears around the centers is of a looser character than the ordinary embryonic cartilage, but whether the centers appear in cartilage seems not to have been determined. At the age of fifteen to twenty years a sort of secondary center appears at the sternal end of clavicle and fuses with the body about the twenty-fifth year.

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'''Fig. 144. Scapula of new-born child.''' Showing primary center of ossification, and cartilage (lighter shading) in which secondary centers appear. Bonnet.

The humerus, radius and ulna are preformed in cartilage (Fig. 143) and develop as typical long bones. Ossification begins in each during the seventh week at a single center and proceeds in both directions to form the shaft. During the first four years after birth epiphyseal centers appear for the head, greater and smaller tubercles, trochlea and epicondyles. All these secondary centers unite with the shaft of the humerus when the growth of the individual ceases. In the case of the radius and ulna a secondary center appears at each end of each bone to form the epiphysis; and in the ulna another secondary center appears to form the olecranon. (For the growth of bones, see page 144) . The carpal bones are all preformed in cartilage (Fig. 143) but their development is somewhat complicated owing to the fact that pieces of cartilage appear which subsequently may disappear, or ossify and become incorporated in other bones. Primarily seven distinct pieces of cartilage develop and become arranged transversely in two rows; these represent seven of the carpal bones. The proximal row consists of three large pieces which are the forerunners of the navicular (radial, scaphoid), lunate (intermediate, semilunar) and triquetral (ulnar, pyramidal, cuneiform) . The distal row is composed of four elements which are the forerunners of the large multangular (trapezium), small multangular (trapezoid), capitate (os magnum), and hamatate or hooked (unciform). In addition to the cartilages mentioned, several others also appear in an inconstant way in different individuals. Two of these are important. One appears on the ulnar side of the proximal row and is the forerunner of the pisiform; the other is situated between the two rows and may either disappear entirely or fuse with the navicular. Ossification does not begin in the carpal cartilages until after birth; it begins in the hamatate and capitate during the third year, in the others at later periods, and is completed only when the growth of the individual ceases. The fact that the hamatate ossifies from two centers indicates that it is probably derived phylogenetically from two bones. Comparative anatomy teaches that the accessory cartilages in the human wrist are representatives of structures which are normally present in the lower forms.

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'''Fig. 145. Diagram of right hand of 5 year old girl.''' (Courtesy of Dr. Edward Learning). The ossification centers are indicated by the darker areas.

The metacarpals and phalanges are preformed in cartilages which correspond in shape to the adult bones. A center of ossification appears in each cartilage and produces the shaft of the bone. Only one epiphysis develops on each metacarpal and phalanx. In each metacarpal it develops at the distal end, except in the thumb where it appears at the proximal end. In each phalanx it develops at the proximal end (Fig. 145).

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'''Fig. 146. Cartilage of right side of pelvic girdle of a human embryo of 13.6 mm.''' (5 weeks). Petersen. The numerals indicate the vertebrae; the first sacral being opposite the ilium.

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'''Fig. 147. Cartilage of right side of pelvic girdle of a human embryo of 18.5 mm.''' (8 weeks). Petersen. The numerals indicate the vertebras; the first and second sacral being opposite the ilium. Compare with Fig. 146.

The skeletal elements of the lower extremities, including the pelvic girdle, are of intracartilaginous origin. Each hip bone (os coxae, innominate bone) is preformed in cartilage which, in a general way, resembles in shape the adult bone. The ventral part of the pubic cartilage does not at first join the ischial; but by the eighth week the junction is complete, leaving dorsal to it the obturator foramen. In the earliest stages the long axis of the cartilage is nearly at right angles to the ; vertebral column, and the ilium lies close to the fifth lumbar and first sacral | vertebrae; later (eighth week) the long axis lies nearly parallel with the vertebral l column and the whole cartilage has shifted so that the ilium is associated with I the first three sacral vertebrae (Figs. 146 and 147).

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'''Fig. 148 Right os coxae (innominate bone) of new-born child.''' Bonnet. Bone is indicated by darker areas/ cartilage by lighter areas.

Ossification begins at three centers which correspond to the ilium, ischium and pubis; the center for the ilium appears during the eighth week, the centers j for the ischium and pubis several weeks later (Fig. 148). The process of ossifi: cation is slow, and is far from complete at the time of birth, for at that time the entire crest of the ilium, the bottom of the acetabulum and all the region ventral to the obturator foramen are cartilaginous. During the eighth or ninth year the ventral parts of the pubis and ischium become partly ossified, but up to the time of puberty the pubis, ischium and ilium remain separated by plates of cartilage which radiate from a common center at the bottom of the acetabulum. Soon after this, the three bones unite to form the single os coxae, leaving only the crest of the ilium, the pubic tubercle and the sciatic tuber (tuberosity of the ; ischium) cartilaginous. In each of these regions an accessory ossification center appears and finally fuses with the corresponding bone about the twentyfourth year.

The femur, tibia and fibula are preformed in cartilage. In the femur a center of ossification appears about the end of the sixth week and gives rise to the shaft; similar centers appear in the tibia and fibula during the seventh and eighth week, respectively. In the femur a distal epiphyseal center appears shortly before birth, and during the first year after birth a proximal center appears for the head. These centers do not unite with the shaft until the individual ceases to grow. The great and lesser trochanters also have accessory ossification centers. In the tibia the center of ossification for the proximal epiphysis appears about the time of birth, the one for the distal during the second year. In the fibula the epiphyseal centers appear during the second and sixth years after birth. The cartilage of the patella appears during the third or fourth month of foetal life, and ossification begins two or three years after birth.

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'''Fig. 149. Diagram of cartilages of left leg and foot of human embryo of 17 mm'''. Hagen.

The bones of the tarsus, like those of the carpus, are preformed in pieces of cartilage which are arranged in two transverse rows. The proximal row consists of three pieces, one at the end of the tibia (tibial), one at the end of the fibula (fibular), and the third between the two (intermedial) . At an early stage the tibial and intermedial fuse to form a single piece of cartilage which corresponds to the talus (astragalus) bone. The fibular cartilage corresponds to the calcaneus (os calcis). The distal row is composed of four pieces of cartilage which correspond to the first cuneiform (internal), second cuneiform (middle), third cuneiform (external), and cuboid (Fig. 149). Between the two rows is a piece of cartilage which corresponds to the navicular (scaphoid). Ossification begins relatively late in the metatarsals. A center for the calcaneus appears during the sixth month of foetal life, and one for the talus shortly before birth. Centers appear in the cuboid and third cuneiform during the first year after birth, and in the first cuneiform, navicular and second cuneiform in order during the third and fourth years (Figs. 150 and 151). At the age of puberty ossification is nearly complete in all the metatarsals. In the talus two centers, corresponding to the tibial and intermedial, appear, but soon fuse into a single center. Occasionally the intermedial remains separate and forms the trigonum.

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'''Fig. 150. Ossification centers in foot of a child 9 months old.''' Hasselwander. An accessory center appears in the calcaneus at the insertion of the tendon of Achilles.

The metatarsals and phalanges develop in a manner corresponding to the metacarpals and phalanges (of fingers). Ossification begins in the metatarsals about the ninth week, in the first row of (proximal) phalanges about the thirteenth week, in the second row about the sixteenth week and in the third row (distal) about the beginning of the ninth week. Epiphyseal centers appear from the second to the eighth year after birth.

==Development of Joints==

The embryonic connective tissue from which the connective tissues, including cartilage and bone, are developed, at first forms a continuous mass. When cartilage appears it may form a continuous mass, as in the chondrocranium, or it may form a number of distinct and separate pieces, as in the vertebral column, the pieces being united by a certain amount of the undifferentiated embryonic connective tissue.

===Synarthrosis===

====Syndesmosis====

When ossification begins at one or more centers, either in cartilage or in embryonic connective tissue, the centers gradually enlarge and approach each other, and the bone so formed comes in contact with the bone formed in neighboring centers, (a) In a case where more than one center appears for any single adult bone, they may come in contact and fuse so completely that the line of fusion becomes indistinguishable, (b) In the case of adjacent bones the fusion may not be so complete; that is, the two bones may simply articulate, leaving a visible line of junction or suture. Such joints are immovable and are represented in the sutures of the skull.

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'''Fig. 151. Skeleton of right foot of a boy 3 years old, showing ossification centers.''' Toldt.

====Synchondrosis====

In some cases a small amount of embryonic connective tissue remains between adjacent bones, (a) In time, this embryonic connective tissue gives rise to cartilage which unites the bones quite firmly, thus producing a practically immovable joint, as in the case of the sacro-iliac joint, (b) Or the cells in the center of the cartilage disintegrate or become liquefied so that a small cavity is produced (articular cavity). This type of joint makes possible a slight degree of mobility and is exemplified by the symphysis of the pubic bones. Such a type is also represented by the joints of the vertebral column. In place of cavities, however, are the pulpy nuclei which are remnants of the notochord.

===Diarthrosis===

Where a great degree of mobility is necessary, the arrangement of the joint is different. The cells in the central part of the embryonic connective tissue between the ends of adjacent bones (or cartilages) (Fig. 152) liquefy so that a relatively large cavity, the joint cavity, is formed (Fig. 153). The liquefaction of the connective tissue cells may also extend for a short distance along the sides of the bones so that the joint cavity surrounds the ends of the bones (Figs. 154 and 155). The origin of the synovial fluid is not known with certainty, but it is probably in part the product of liquefaction of the connective tissue cells. The more peripheral part of the connective tissue which encloses the joint cavity is transformed into a dense fibrous tissue, the joint capsule. The cells lining the cavity become differentiated into oval or irregular cells, among which is a considerable amount of intercellular substance. By some it is held that these cells form a continuous single layer like endothelium, but the most recent researches tend to disprove this. The cells lining the cavity are the most highly differentiated, the cell bodies being large and apparently swollen, and there is gradually less differentiation as the distance from the surface increases, until finally they merge with the ordinary type of connective tissue cells of the joint capsule (Clarke). The more mobile joints of the body are all representatives of this type.

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'''Fig. 152. Section through axilla and arm of a human embryo of 26 mm.''' (2 months). Photograph. Note the mesenchymal tissue between the humerus and the radius the site of the elbow joint.

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'''Fig. 153. Longitudinal section of finger of human embryo of 26 mm.''' (2 months), showing beginning of joint cavity between adjacent ends of phalanges. (Photograph from preparation by Dr. W. C. Clarke.)

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'''Fig. 154. From longitudinal section of finger of child at birth, showing developing joint cavity between adjacent ends of phalanges.''' The darker portion at each end of the figure indicates the ossification center in the phalanx, the end of the latter (lighter area) being yet cartilaginous. The dark bands at each side of the joint indicate developing ligaments. Photograph.

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'''Fig. 155. From longitudinal section of finger of child at birth, showing joint cavity and synovial membrane between adjacent ends of the first metacarpal and proximal phalanx.''' Other description same as in Fig. 154. Photograph.

==Anomalies==

===The Axial Skeleton===

====The Vertebrae====

The number of cervical vertebrae in man is remarkably constant. Cases where the number is but six are extremely rare. The thoracic vertebrae may vary in number in different individuals from eleven to thirteen, twelve being the usual number. The lumbar vertebrae may vary from four to six, five being the usual number. The sacral vertebrae, fused in the adult to form the sacrum, are usually five in number, sometimes four, sometimes six. Occasionally a vertebra between the lumbar region and sacral region lumbo-sacral vertebra possesses both lumbar and sacral characters, one side being fused with the sacrum, the other side having a free transverse process. Variation occurs frequently in the coccygeal vertebrae; four and five are present with about equal frequency, more rarely there are only three.

The total number of true (presacral) vertebrae may be diminished by one or increased by one. In the former case the first sacral is the twenty-fourth vertebra, and, if the number of ribs remains normal, there are only four lumbar vertebrae. In case the total number is increased by one, the first sacral is the twenty-sixth vertebra, and there are twelve thoracic and six lumbar or thirteen thoracic and five lumbar.

From these facts it is seen that variation occurs most frequently in the more caudal portion of the vertebral column in the lumbar, sacral and coccygeal regions. According to a hypothesis advanced by Rosenberg, the sacrum in the earlier embryonic stages is composed of a more caudal set of vertebrae than those which belong to it in the adult, and during development lumbar vertebrae are converted into sacral and sacral vertebrae into coccygeal. In other words, the hip bone moves headward during development and finally becomes attached to vertebrae which are situated more cranially than those with which it was primarily associated. This change in the position of the pelvic attachment, and the corresponding reduction in the total number of vertebrae, during the development of the individual (i.e., during ontogenetic development) is believed to correspond to a similar change in position during the evolution of the race (i.e., during phylogenetic development).

According to Rosenberg, variation in the adult is due largely to a failure during ontogeny to carry the processes of reduction in the number of vertebrae as far as they are usually carried in the race, or to their being carried beyond this point.

The coccygeal vertebrae apparently represent remnants of the more extensively developed caudal vertebrae in lower forms. In human embryos of 8 to 16 mm., when the caudal appendage is at the height of its development, there are usually seven anlagen of coccygeal vertebrae. During later development this number becomes reduced by fusion of the more distally situated anlagen to the smaller number in the adult. This process of reduction varies in different individuals, so that five or four, rarely three, coccygeal vertebrae may be the result. In cases where children are born with distinct caudal appendages there is no good evidence that the number of coccygeal vertebrae is increased, although the coccyx may extend into the appendage.

====The Ribs====

Occasionally in the adult a rib is present on one side or on each side in connection with the seventh cervical vertebra (cervical rib), or in connection with the first lumbar vertebra (lumbar rib) . There seems to be no case on record where cervical and lumbar ribs are present in the same individual. The cervical rib may vary between a small piece of bone connected with the transverse process of the vertebra and a well developed structure long enough to reach the sternum. There are also great variations in the size of the lumbar rib. In case the number of ribs is normal, the last (twelfth) may be rudimentary.

The eighth costal cartilage not infrequently unites with the sternum. Occasionally the seventh costal cartilage fails to fuse with the sternum, owing to the shortening of the latter, but meets and fuses with its fellow of the opposite side in the midventral line.

The above mentioned anomalies can be referred back to aberrant development. Primarily costal processes appear in connection with the cervical, lumbar and sacral vertebrae. Normally these processes fuse with and finally form parts of the vertebrae (p. 153). In some cases, however, the seventh cervical or the first lumbar processes develop more fully and form more or less distinct ribs.

As an explanation of these variations in the number of ribs, it has been suggested that there is a tendency toward reduction in the total number of ribs, and that supernumerary ribs represent the result of a failure to carry the reduction as far as the normal number. In case the twelfth rib is rudimentary, the reduction has been carried beyond the normal limit. This hypothesis is a corollary to the hypothesis regarding the variations in the number of vertebrae. (See under "The Vertebrae.")

====The Sternum====

Certain anomalous conditions of the sternum can also be explained by reference to development. The condition known as cleft sternum, in which the sternum is partially or wholly divided into two longitudinal bars by a medial fissure, represents the result of a failure of the two bars to unite in the midventral line (p. 153, see also Fig. 130). This is sometimes associated with ectopia cordis (p. 255). The xyphoid process may also be bifurcated or perforated, according to the degree of fusion between the two primary bars

(P- I54)

Suprasternal bones may be present. They represent the ossified episternal cartilages which have failed to unite with the manubrium (p. 154). Morphologically the suprasternal bones possibly represent the omosternum, a bone situated cranially to the manubrium in some of the lower Mammals.

===The Head Skeleton===

The skull is sometimes decidedly asymmetrical. Probably no skull is perfectly symmetrical. The condition which most frequently accompanies the irregular forms of skulls is premature synosteosis or premature closure of certain sutures. The cranial bones increase in size principally at their margins, and when a suture is prematurely closed the growth of the skull in a direction at right angles to the line of suture is interfered with. Consequently compensatory growth must take place in other directions. Thus if the sagittal suture is prematurely closed and transverse growth prevented, increase occurs in the vertical and longitudinal directions. This results in the vault of the skull becoming heightened and elongated, like an inverted skiff, a condition known as scaphocephaly. After premature closure of the coronal suture, growth takes place principally upward and gives rise to acrocephaly. In case only one-half the coronal or lambdoidal suture is closed, the growth is oblique and results in plagiocephaly.

A suture the metopic suture sometimes exists in the medial line between the two halves of the frontal bone, a condition known as metopism. This is due to an imperfect union of the two plates of bone produced by the two centers of ossification in the frontal region (p. 162).

Certain malformations in the face region and in the roof of the mouth are brought about by defective fusion or complete absence of fusion between certain structures during the earlier embryonic stages. The maxillary process of the first branchial arch sometimes fails to unite with the middle nasal process (Kolliker's view, p. 164; see also Fig. 98). The result is a fissure in the upper lip, a condition known as hare lip, which may or may not be accompanied by a cleft in the alveolar process of the maxilla, extending as far as the incisive (palatine) foramen. The same result may be produced by a defective fusion between the middle nasal process and the lateral nasal process (Albrecht's view, p. 164; see also Fig. 98). Hare lip may be either unilateral (single) or bilateral (double), accordingly as defective fusion occurs on one or both sides, but never medial.

Occasionally the palatine process of the maxillary process fails to meet not only its fellow of the opposite side, but also the vomer (see Fig. 141) . The result is a cleft in the hard palate, a condition known as cleft palate. This malformation may be unilateral or bilateral, but not medial. Sometimes the cleft extends into the soft palate where it occupies, however, a medial position.

Cleft palate may accompany hare lip, or either may exist without the other, depending upon the degree of fusion between the processes mentioned above. In bilateral hare lip, with or without cleft palate, the incisive (intermaxillary) bone is sometimes pushed forward by the vomer and projects beyond the surface of the face, a condition known as "wolf's snout."

The causes underlying the origin of harelip and cleft palate are obscure.

===The Appendicular Skeleton===

====The Humerus====

On the medial side of the humerus, just proximal to the medial condyle, there is not infrequently a small hook-like process directed distally the supracondyloid process. This process represents a portion of bone which in some of the lower mammals (cat, for example) joins the internal condyle and completes the supracondyloid foramen, through which the median nerve and brachial artery pass.

====The Carpal Bones====

Occasionally an os centrale is present in addition to the usual carpal bones. It is situated on the dorsal side of the wrist between the navicular, capitate and small multangulum. In the embryo an additional piece of cartilage is of constant occurrence in this location, but usually disappears during later development; in cases where it persists, ossification takes place to form the os centrale. In some of the apes the os centrale is of constant occurrence in the adult.

====The Femur====

The gluteal tuberosity (ridge) sometimes projects like a comb, forming the so-called third trochanter, a structure homologous with the third trochanter in the horse and some other mammals.

====The Tarsal Bones====

Cases have been recorded in which the total number of tarsal bones was reduced, owing to congenital synosteosis (fusion) of the calcaneus (os calcis) and scaphoid (navicular), of the talus (astragalus) and calcaneus, or of the talus and scaphoid. Occasionally an additional bone the trigonum is present at the back of the talus. In the embryo, the talus ossifies from two centers which normally fuse at an early stage into a single center. The trigonum probably represents a bone produced by one of the centers which has remained separate.

====Polydactyly====

This anomaly consists of an increase in the number of fingers or toes, or both. Any degree of variation may exist from a supernumerary finger or toe to a double complement of fingers or toes. The causes underlying the origin of such anomalies are not clear. Some assign the supernumerary digits to the category of pathological growths or neoplasms, linking them with partial duplicate formations. Others explain the extra digits on the ground of atavism or reversion to an ancestral type. The latter explanation assumes an ancestral type with more than five digits. But neither zoology nor paleontology has found any vertebrate form, above the Fishes, which normally possesses more than five digits on each extremity. Consequently one must refer to the Fishes for some ancestral type to explain the existence of more than five digits. Going back so far in phylogenetic history, no certainty whatever can be attached to the origin of supernumerary digits, for it is not even known from what fins the extremities of the higher forms are derived. Still another view regarding the origin of supernumerary digits is that they are due to certain external influences among which the most important is the mechanical impression of amniotic folds or bands. This, however, could not be the sole cause of polydactylism, since such malformations are common in amphibian embryos where no amnion is present.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_10|Vascular]]

==References for Further Study==

ADOLPHI, H. : Ueber die Variationen des Brustkorbes und der Wirbelsaule des Menschen. Morph. Jahrbuch, Bd. XXIII, 1905.

BADE, P. : Die Entwickelung des menschlichen Skeletts bis zur Geburt. Arch. f. mik. Anat., Bd. LV, 1900.

AREY, LESLIE B.: The Origin, Growth and Fate of Osteoclasts and their Relation to Bone Resorption. American Jour, of Anat., Vol. XXVI, No. 3, 1920.

BARDEEN, C. R.: Numerical Vertebral Variations in the Human Adult and Embryo. Anat. Anz., Bd. XXV, 1904.

{{Ref-Bardeen1905}}

{{Ref-Bardeen1905a}}

BARTELS, M.: Ueber Menschenschwanze. Arch. f. Anthropol., Bd. XII.

BELL, E. T.: II. On the Histogenesis of the Adipose Tissue of the Ox. American Jour. of. Anat., Vol. IX, 1909.

BOLL, F.: Die Entwickelung des fibrillaren Bindegewebes. Arch. /. mik. Anat., Bd. VIII, 1872.

BOLK, L. : Beziehungen zwischen Skelett, Muskulatur und Nerven der Extremitaten, etc. Morph. Jahrbuch, Bd. XXI, 1894.

BONNET, R.rLehrbuch der Entwickelungsgeschichte. Berlin, 1907.

BRAUS, H.: Die Entwickelung der Form der Extremitaten und des Extremitatenskeletts. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1904.

BROWN, ALFRED J.: The Development of the Vertebral Column in the Domestic Cat. Anat. Record, Vol. X, No. 3, 1916.

CAREY, EBEN J.: Studies in the Dynamics of Histogenesis. American Jour, of Anat., Vol. XXIX, No. i, 1921.

FAWCETT E.: On the Early Stages in the Ossification of the Pterygoid Plates of the Sphenoid Bone of Man. Anat. Anz., Bd. XXVI, 1905.

FAWCETT, E.: Ossification of the Lower Jaw in Man. Jour. Amer. Med. Assoc., Bd. XLV, 1905.

FAWCETT, E.: On the Development, Ossification and Growth of the Palate Bone. Jour, of Anat. and Physiol., Bd. XL, 1906.

FERGUSON, JEREMIAH S.: The Behavior and Relations of Living Connective Tissue Cells in the Fins of Fish Embryos with Special Reference, to the Histogenesis of the Collaginous or White Fibers. American Jour, of Anat., Vol. XIII, No. 2, 1912.

FLEMMING, W.: Die Histogenese der Stiitzsubstanzen der Bindesubstanzgruppe. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1901.

FLEMMING, W.: Morphologic der Zelle. Ergebnisse der Anat. u. Entwick., Bd. VII, 1897.

GAUPP, E.: Alte Probleme und neuere Arbeiten iiber den Wirbeltierschadel. Ergebnisse der Anat. u. Entwick., Bd. X, 1901.

GAUPP, E.: Die Entwickelung des Kopfskeletts. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1905.

GEGENBAUR, C.: Die Metamerie des Kopfes und die Wirbeltheorie des Kopfskeletts. Morph. Jahrbuch, Bd. XIII, 1887.

GR^FENBERG, E.: Die Entwickelung der Knochen, Muskeln und Nerven der Hand und der fur die Bewegungen der Hand bestimmten Muskeln des Unterarms. Anat. Hefte, Heft XC, 1905.

HAGEN, W. : Die Bildung des Knorpelskeletts beim menschlichen Embryonen. Arch. f. Anat. u. PhysioL, Anal. Abth., 1900.

HANSEN, C.: Ueber die Genese einiger Bindegewebsgrundsubstanzen. Anat. Anz., Ed. XVI, 1899.

HANSON, FRANK BLAIR: The Ontogeny and Phylogeny of the Sternum. American Jour, of Anat., Vol. XXVI, No. i, 1919.

HASSELWANDER, A.: Untersuchungen iiber die Ossification des menschlichen Fussskeletts. Zeitschr. f. Morphol. u. AnthropoL, Bd. V, 1903.

HERTWIG, O.:Lehrbuch der Entwickelungsgeschichte des Menschen u. der Wirbeltiere. Jena, 1906.

HUNTINGTON, G. S.: Modern Problems of Evolution, Variation, and Inheritance in the Anatomical Part of the Medical Curriculum. Anat. Record, Vol. XIV, No. 6, 1918.

JAKOBY, M.: Beitrag zur Kenntniss des menschlichen Primordialcraniums. Arch. f. mik. Anat., Ed. XLIV, 1894.

JORDAN, H. E.: A Contribution to the Problems Concerning the Origin, Genetic Relationship and Function of the Giant-cells of Hemopoietic and Osteolytic Foci. American Jour, of Anat., Vol. XXIV, No. 2, 1918.

KEIBEL, F. : Ueber den Schwanz des menschlichen Embryo. Arch.f. Anat. u. PhysioL, Anat. Abth., 1891.

KEIBEL, F.: Zur Entwickelungsgeschichte der Chorda bei Saugern. Arch.f. Anat. u. PhysioL, Anat. Abth., 1889.

{{Ref-KeibelMall1910}} [[Book - Manual of Human Embryology 11|Chap. XI.]]

KJELLBERG, K.: Beitrage zur Entwickelungsgeschichte des Kiefergelenks. Morph. Jahrbuch, Bd. XXXII, 1904.

KOCH, JOHN C.: The Laws of Bone Architecture. American Jour, of Anat., Vol. XXI, No. 2, 1917.

KOLLMANN, J.: Entwickelung der Chorda dorsalis bei dem Menschen. Anat. Anz., Bd. V, 1890.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

{{Ref-Mall1902ct}}

{{Ref-Mall1906bone}}

{{Ref-McMurrich1914}}

{{Ref-Paterson1900}}

PETERSEN, H.: Untersuchungen zur Entwickelung des menschlichen Beckens. Arch, f. Anat. u. PhysioL, Anat. Abth., 1893.

RABL, C.: Theorie des Mesoderms. Morph. Jahrbuch, Bd. XV, 1889.

ROSENBERG, E.: Ueber die Entwickelung der Wirbelsaule und das Centrale carpi des Menschen. Morph. Jahrbuch, Bd. I, 1876.

SCHAUINSLAND, H.: Die Entwickelung der Wirbelsaule nebst Rippen und Brustbein. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1905.

SPULER, A.: Beitrage zur Histologie und Histogenese der Binde- und Stutzsubstanz. Anat. Hefte, Heft XXI, 1896.

THILENIUS, G.: Untersuchungen iiber die morphologische Bedeutung accessorischer Elemente am menschlichen Carpus (und Tarsus). Morph. Arbeiten, Bd. V, 1896.

{{Ref-Thomson1899}}

TORNIER, G.: Das Entstehen der Gelenkformen. Arch. f. Entw.-Mechanik, Bd. I, 1895.

WALDEYER, W.: Kittsubstanz und Grundsubstanz, Epithel und.Endothel. Arch. f. mik. Anat., Bd. LVII, 1900.

WEISS, A.: Die Entwickelung der Wirbelsaule der weissen Ratte, besonders der vordersten Halswirbel. Zeitschr. f. wissensch. Zool., Bd. LXIX, 1901.

ZIMMERMANN, K.: Ueber Kopfhohlenrudimente beim Menschen. Arch./, mik. Anat., Bd. LIII, 1899.

{{Bailey_1921_Footer}}

Book - Text-Book of Embryology 9

2024-01-25T00:23:36Z

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{{Template:Bailey 1921}}

=The Development of Connective Tissues and the Skeletal System=
<div id="Fig100"></div>
[[File:Bailey100.jpg|thumb|'''Fig. 100. Transverse section of chick embryo of 27 hours' incubation.''' Photograph.]]

All the connective or supporting tissues of the body, except neuroglia, are derived from the mesoderm. This Goes not imply, however, that all the mesoderm is transformed into connective tissues; for such structures as the endothelium of the blood vessels and lymphatic vessels, probably blood itself, the epithelium lining the serous cavities, smooth and striated muscle, and a part of the epithelium of the urogenital system are derived from mesoderm.

The origin of the mesoderm itself has been discussed elsewhere (p. 93). In this connection it is sufficient to recall that it is situated between the ectoderm and entoderm and consists of several layers of closely packed cells (Fig. ioo). The axial portion in the neck and body regions becomes differentiated into the mesodermic somites. At the same time a cleft (the coelom) separates the more peripheral portion into a parietal and a visceral layer (Figs. 101 and 103). In the head region where, in the higher animals, there is little or no indication of somites and ccelom, the mesoderm simply fills in the space between the ectoderm and entoderm (Fig. 102). Portions of the mesoderm in all these regions are destined to give rise to connective tissues. Each mesodermic somite! soon becomes differentiated into three parts the sclerotome, cutis plate and ( myotome (Fig. 104). Of these, only the sclero tome and cutis plate are directly concerned in the formation of connective tissues, the myotomes giving rise to striated voluntary muscle. The sclerotomes are destined to give rise to the vertebrae and other forms of connective tissue in their neighborhood, the cutis plates to a part, at least, of the corium of the skin. The parietal and visceral layers of the mesoderm (excepFthe mesothelium lining the ccelom) and the mesoderm of the head region are destined to give rise to the various types of connective tissue forming parts of the other organs of the body.

<div id="Fig101"></div>
[[File:Bailey101.jpg|600px]]

'''Fig. 101. Transverse section of chick embryo (2 days' incubation).''' Photograph. The parietal mesoderm (lying above the coelom) is not labeled. The two large vessels under the primitive segments are the primitive aortae. Spaces separating germ layers are clue to shrinkage.

<div id="Fig102"></div>
[[File:Bailey102.jpg|600px]]

'''Fig. 102. Transverse section through head region of chick embryo of 42 hours' incubation.''' Photograph.

<div id="Fig103"></div>
[[File:Bailey103.jpg|600px]]

'''Fig. 103. Transverse section of human embryo with 13 primitive segments.''' Section taken through the 6th segment. Kollmann.

==Histogenesis==

The sclerotomes and cutis plates at first constitute parts of the mesoorermic somites, and are composed of epithelial-like cells with little intercellular substance. The intercellular substance gradually increases in amount so that the cells become more widely separated from one another, at the same time assuming oval or spindle shapes and then irregular branching forms (Fig. 106). The rest of the mesoderm, except the mesothelium, also undergoes a similar transformation so that structurally its cells are indistinguishable from those derived from the sclerotomes and cutis plates.

<div id="Fig104"></div>
[[File:Bailey104.jpg|600px]]

'''Fig. 104. Transverse section of human embryo of the 3rd week.''' Scl. 1 , Break in myotome at point where sclerotome is closely attached. Kollmann.

<div id="Fig105"></div>
[[File:Bailey105.jpg|400px]]

'''Fig. 105. Three primitive segments from sagittal section of human embryo of the 3rd week'''. Kollmann.

Thus the mesoderm at this stage is composed of irregular, branching cells, with a relatively large amount of homogeneous intercellular substance filling the interstices. The branches, or protoplasmic processes, of each cell anastomose freely with those of other cells in the immediate vicinity.

<div id="Fig106"></div>
[[File:Bailey106.jpg|400px]]

'''Fig. 106. Mesenchymal tissue from somatopleure of a 5 mm human embryo'''. Mesothelium is shown along lower border of figure.

In this manner a syncytium is formed to which the term mesenchyme is applied (Fig. 106). The mesenchyme itself lacks specialization, being what is known as an indifferent tissue, but it constitutes the structural basis upon which all the connective tissues of the adult body are built; all the forms of connective tissue (except neuroglia) develop from it.

That intercellular substance is derived originally from the cell can scarcely be denied. All the cells of the organism are derived from the fertilized ovum. As soon as two or more cells are formed by segmentation of the ovum, they are either simply in apposition or else they are united by something in the nature of a "cement" substance which must have been derived from the cells themselves. In the mesenchymal tissue this intercellular ground substance is a prominent feature, and probably represents in part nutritive materials and in part the products of cell activity.

==Fibrils and Fibers==
<div id="Fig107"></div>
[[File:Bailey107.jpg|thumb|'''Fig. 107. Fibril forming cells from fresh subcutaneous tissue of head of chick embryo.''' Boll.]]

The least differentiated and perhaps the least specialized tissue derived from mesenchyme is ''reticular tissue'', such as that found in the lymph nodes and spleen. In the peripheral part of the cytoplasm, or exoplasm, of the mesenchymal cells and their processes there arise delicate fibrils, often extending from one cell to another, which probably represent specialized parts of the spongioplasm. These fibrils maintain their intracellular position instead of becoming separated from the parent cytoplasm, so that the reticular tissue retains a marked resemblance in form to the original mesenchyme.
<div id="Fig109"></div>
[[File:Bailey109.jpg|thumb|'''Fig. 109. Longitudinal section of developing ligament from finger of human foetus of 6 months.''' Photograph.]]

<div id="Fig108"></div>
[[File:Bailey108.jpg|600px]]

Fig. 108. Connective tissue (mesenchymal) cells from larval salamander. Flemming.

The first step in the development of the true fibrillar forms of connective tissue from mesenchyme is the formation of fibrils and fibers. While it has been held by some investigators that the fibrils arise in and from the homogeneous intercellular substance, the best substantiated view is that they arise within and from the cytoplasm of the mesenchymal cells (Figs. 107 and 108). They then become separated from the cytoplasm and lie free in the " ground" substance in bundles (fibers). These fibrillated fibers are collaginous in character. Elastic fibers, while not fibrillated, probably have a similar origin. This first step in development gives rise to a loose, delicate tissue in the embryo, known as embryonal connective tissue, from which all the adult forms, except reticular tissue, develop.

The areolar tissue of the adult retains many of the general characters of embryonal connective tissue. The fibers, both collaginous and elastic, are loosely arranged and extend in all directions. The cells (fibroblasts) are fewer, however, and while they are characterized by irregular, branching forms it is not known whether their processes anastomose.

In any fibrous tissue, such as areolar, or the denser forms (fascia, tendons, ligaments), the structure depends upon the secondary arrangement of the fibers and not upon any peculiarity of origin. In all these forms the fibers have the same origin, but in the denser fascia, tendons and ligaments they become arranged in parallel lines (Fig. 109).

Adipose Tissue. Adipose tissue is a form of connective tissue in which the fatty element replaces to a great extent the cytoplasm in many of the embryonic connective tissue cells. It always develops in close relation to blood vessels, and first appears in the axilla and groin about the thirteenth week. It is formed in other places at later periods, even during adult life, but the mode of development is always the same. In some of the cells in the neighborhood of small blood vessels minute droplets of fat are deposited. The origin of the fat is not known. The droplets become larger, other smaller ones appear, and finally all of them coalesce to form a single large drop which practically fills the cell. The result of this is that the remaining cytoplasm is pushed outward and forms a sort of pellicle around the fat. The nucleus also is crowded outward and comes to lie flattened in the pellicle of cytoplasm (Fig. 111). At the same time the whole fat cell increases in size and forms a relatively large structure.

<div id="Fig110"></div>
[[File:Bailey110.jpg|400px]]

'''Fig. 110. Developing fat from subcutaneous tissue of pig embryo 5 inches long.''' Small artery breaking up into capillary network' groups of fat cells developing in embryonic connective tissue.

Fat cells usually develop in groups or masses around blood vessels (Fig. no). The neighboring groups gradually enlarge and approach each other, but do not fuse, thus leaving more or less fibrous connective tissue between them, which constitutes the interlobular tissue seen in adult adipose tissue. Among the individual cells in a lobule there is also a small amount of fibrous tissue present. From the mode of development a small artery usually affords the blood supply for each lobule.

==Cartilage==

In the different kinds of cartilage the matrix probably represents a modification of tne "ground substance" of the original embryonic tissue. The fibers in the matrix are probably derived from the cells in the same manner as the fibers in the fibrillar forms of connective tissue (Fig. 112).

==Osseous Tissue==

Here again the basis for development is embryonic connective tissue, although in one type of development cartilage precedes the bone. Two types of ossification are recognized intramembranous and intracartilaginous or endochondral. Intramembranous ossification calcium salts are deposited in ordinary embryonic connective tissue. In intracartilaginous ossification hyalin cartilage first develops in the same general shape as the future bone and the calcium salts are afterward deposited within the mass of cartilage. It is customary to speak also of another type of ossification subperiosteal in which the calcium salts are deposited under the periosteum.

<div id="Fig111"></div>
[[File:Bailey111.jpg|600px]]

'''Fig. 111. Developing fat from subcutaneous tissue of pig embryo 5 inches long.''' Fat (stained black) developing in embryonic connective tissue cells. At the right are five individual cells showing stages of development from an embryonic cell to an adult fat cell.

==Intramembranous Ossification==
<div id="Fig112"></div>
[[File:Bailey112.jpg|thumb|'''Fig. 112. Connective tissue cells from intervertebral disk of calf embryo.''' Showing origin of "white" and elastic fibers in protoplasm of cells. Ectoplasm represents a modified part of the protoplasm. Hansen.]]
This is the type of ossification by which many of the flat bones of the skull and face are formed. The region in which these bones are to develop consists of embryonic connective tissue. At certain points in this region bundles of connective tissue fibers become impregnated with calcium salts. Such areas are known as calcification centers. In each of these areas the cells increase in number, the tissue becomes very vascular and some of the cells, becoming more or less round or oval, with distinct nuclei and a considerable amount of cytoplasm, arrange themselves in single, fairly regular rows along the bundles of calcined fibers. The differentiated cells are known as osteoblasts (bone formers) , and the whole tissue is now known as osteo genetic tissue. Under the influence of the osteoblasts a thin layer of calcium salts is deposited between the osteoblasts and the calcified fibers. In this way the first true bone is formed, and the calcification center becomes an ossification center. Successive layers or lamellae of calcium salts are laid down and some of the osteoblasts become enclosed between the lamellae to form the bone cells (Figs. 113 and 1 14). The spaces in which the bone cells lie are the lacuna. At the same time the fibers also are enclosed within the bone and give it its characteristic fibrous structure (Fig. 114).

<div id="Fig113"></div>
[[File:Bailey113.jpg|600px]]

'''Fig. 113. Vertical section through frontal bone of human foetus of 4 months.''' (Intramembranous ossification.) Photograph.

Such a process results in the formation of irregular, anastomosing trabeculae of bone. The spaces among the trabeculae are known as primary marrow spaces- and contain osteogenetic tissue (Fig. 113). This type of bone, consisting of irregular, anastomosing trabeculae and enclosed marrow spaces, is known as spongy bone. The spongy bone thus formed is covered on-ats outer side by a layer of connective tissue which from its position is called the periosteum (Fig. 113), and which represents a part of the original embryonic connective tissue membrane in which the bone was laid down. During its development the periosteum becomes an exceedingly dense fibrous membrane which is closely applied to the surface of the bone.

<div id="Fig114"></div>
[[File:Bailey114.jpg|600px]]

'''Fig. 114. From vertical section through parietal bone of human foetus of 4 months.''' Bone cells not shown in lacunae, (Intramenibranous ossification.)

In a growing embryo, provision must be made for increase in the size of the cranial cavity to accommodate the growing brain. This is accomplished in the following manner : On the inner surface of the newly formed bone, large multinuclear cells appear, which are known as osteoclasts (bone destroyers). The osteoclasts are unusually large cells with a large number of nuclei and abundant cytoplasm, and in sections can be seen lying in depressions in the bone Howslip's lacuna (Fig. 114). Whether they are the specific agents in dissolution of bone has been questioned (Arey). While the destruction of bone is going on on the inner surface, new bone is being formed on the outer surface, especially under the periosteum where the osteoblasts are most numerous. Thus the layer of bone gradually comes to lie farther and farther out and the cranial cavity is enlarged. So long as the cranial cavity continues to enlarge the new bone is of the spongy variety, but toward the end of development the trabeculae become thicker and finally come together to form the compact bone characteristic of the roof of the skull. The fact that the new bone laid down during the enlargement of the cranial cavity is laid down under the periosteum has led to the term subperiosteal ossification. The process is essentially the same as in the original intramembranous ossification.

<div id="Fig115"></div>
[[File:Bailey115.jpg|600px]]

'''Fig. 115. Longitudinal section of one of the metatarsal bones of a sheep embryo.''' (Intracartilaginous ossification.)

==Intracartilaginous Ossification==
(''The modern term is endochondral ossification'')

In this type of ossification hyalin cartilage is first formed in a shape which corresponds very closely to the shape of the future bone. For example, the femur is first represented by a piece of hyalin cartilage which develops from the original embryonic connective tissue. On the surface of the cartilage a membrane of dense fibrous connective tissue, known as the perichondrium, develops (Fig. 115). In most cases, ossification begins about the middle of the piece of cartilage, corresponding to the middle of the shaft of a long bone (Fig. 115). The cell spaces enlarge and in some cases the septa of matrix between the enlarged spaces break down, so that several cells may lie in one space. The cell spaces radiate from a common center, but a little later they come to lie in rows parallel with the long axis of the mass of cartilage. During these early changes lime salts are deposited in the matrix of the cartilage in this region, and the portion so involved is known as a calcification center.

<div id="Fig116"></div>
[[File:Bailey116.jpg|600px]]

'''Fig. 116. From section of one of the tarsal bones of a pig embryo.''' Showing periosteal bud pushing into the cartilage at the ossification center. (Intracartilaginous ossification.)

So far the process is preparatory to actual bone formation. Then small blood vessels from the perichondrium (periosteum) grow into the cartilage, carrying with them some of the embryonic connective tissue. These little ingrowths of connective tissue and blood vessels are known as periosteal buds (Fig. 1 1 6). The septa between the enlarged cartilage cell spaces break down still further, forming still larger spaces into which the periosteal buds grow. Many of the connective tissue cells are transformed into osteoblasts oval or round cells with distinct nuclei and a considerable amount of cytoplasm and with the fibers and blood vessels constitute osteogenetic tissue (Fig. 117). The cartilage cells in this region disintegrate and disappear, and the cavity formed by the coalescence of the cell spaces constitutes the primary marrow cavity (Fig. 117). From the primary marrow cavity osteogenetic tissue pushes in both directions toward the ends of the cartilage. The transverse septa between the enlarged cartilage cell spaces break down, leaving a few longitudinal septa which form the walls of long anastomosing channels which are continuous with the primary marrow cavity. The osteoblasts arrange themselves in rows along the septa of calcined cartilage and a thin layer or lamella of calcium salts is deposited between them and the cartilage. Successive lamellae are deposited in the same manner and some of the osteoblasts become enclosed to form bone cells (Fig. 118). The cartilage in the center gradually disappears. This region where bone formation is going on is known as an ossification center (Fig. 115) and the irregular anastomosing trabeculae of bone with the enclosed marrow spaces constitute primary spongy bone.

From this time on, ossification gradually progresses toward each end of the cartilage, and at the same time a special modification of the cartilage precedes it. Nearest the ossification center the cartilage cell spaces become enlarged and arranged in rows and contain cartilage cells in various stages of disintegration. Some of the septa break down, leaving larger, irregular spaces; the remaining septa become calcified (Fig. 115). Passing away from the center of ossification, there is less enlargement of the cell spaces and they have a tendency to be arranged in rows transverse to the long axis of the cartilage; there is also a lesser degree of calcification. The region of modified cartilage at each end of the ossification center passes over gradually into ordinary hyalin cartilage and is known as the calcification zone. It always precedes the formation of bone as the latter process moves toward the end of the cartilage (Fig. 115).

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[[File:Bailey117.jpg|thumb|'''Fig. 117.''' From same section as Fig. 115. Showing osteogenetic tissue pushing into the cartilage and breaking it up into trabeculae. (Intracartilaginous ossification.)]]

Along with the type of ossification just described subperiosteal ossification also occurs (Fig. 115). Beneath the periosteum (perichondrium) is a layer of connective tissue the cells of which are transformed into osteoblasts. They deposit layers of calcium salts on the surface of the cartilage in the same manner as around the trabeculae inside the cartilage.

The transformation of the spongy bone into compact bone is peculiar in that the former is dissolved and then replaced by new bone. Whether this dissolution occurs through the agency of the large multinucleated cells known as osteoclasts is not certain. By the process of dissolution the marrow spaces are increased in size and are known as Haversian spaces. Within these spaces new bone is then deposited layer upon layer, under the influence of the osteoblasts, until the Haversian spaces are reduced to narrow channels, the Haversian canals. The layers of bone are the Haversian lamella. The interstitial lamella in compact bone have two possible origins. They may be the remnants of certain lamellae of the original spongy bone which were not removed in the enlargement of the primary marrow spaces, or they may be parts of early formed Haversian lamellae which were later more or less replaced by other Haversian lamellae.

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'''Fig. 118. From same section as Fig. 115''' Showing bone deposited around one of the trabeculae of cartilage. (Intracartilaginous ossification.)

Carey, in his recent studies on certain mechanical phases of development, concludes " that cartilage and bone are not self -differentia ted, nor are they self-crystallized products," but represent " cellular responses to the varying intensity of the stresses and strains produced by resistance (pressure) counteracting the growth" of the skeleton in its blastemal stage, that is, while the cells are closely compacted prior to the appearance of the specific tissue. In his analysis of the femur, Koch has concluded that the "normal external form and internal architecture of the human femur results from an adaptation of form to the normal static demands, or normal function of the bone." It would appear therefore that in the development of bone mechanical factors play an essential part not only in the formation of the bone itself but also in the establishment of its form and internal structure.

GROWTH OF BONES. The way in which the cranial cavity enlarges has been described on page 139. While the process of enlargement is going on, the individual bones increase in size principally by the addition of new bone along their edges.

Intracartilaginous bones grow both in diameter and in length. It has already been stated that the primary spongy bone formed in cartilage is dissolved and that new bone is deposited under the periosteum. This naturally brings about an enlargement of the primary marrow cavity and at the same time an increase in the diameter of the bone as a whole. From this it is obvious that the compact bone of the shaft of a long bone is of subperiosteal origin, the intracartilaginous bone having been completely absorbed.

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'''Fig. 119. Diagram representing growth in diameter of a long bone.''' from Flour ens.

The fact that the osseous tissue bordering the marrow cavity is absorbed and that new bone is deposited under the periosteum can be quite clearly demonstrated. A young growing animal is fed for a few weeks on madder, which colors all the bone formed during that time a distinct red. If the animal is then killed and sections made of the long bones, the outer part of the latter will appear a distinct red. Another growing animal is fed on madder for a few weeks, then allowed to live a few weeks longer without madder. Then if it is killed and sections made of the bones, the red bone is found to be covered with a layer of uncolored bone which was deposited after the madder feeding had been stopped. If a young growing animal is fed on madder for a time and then allowed to live long enough without madder, the red bone will be found lining the marrow cavity. (See Fig. 119.)

Growth in length of the long bones takes place in a different manner. The primary center of ossification is situated near the middle of the piece of cartilage, and ossification proceeds in both directions toward the ends of the cartilage to produce the diaphysis or shaft of the bone. In each end of the cartilage there appears a secondary center from which ossification proceeds in all directions to produce the epiphysis. Between the shaft and epiphysis a disk of cartilage remains, and here, so long as the bone is growing, new cartilage continues to be formed. At the same time new bone is being formed in the new cartilage, principally in the part next the shaft. This produces an elongation of the shaft, the two epiphyses being carried farther and farther apart, and consequently a lengthening of the bone as a whole. When the bone reaches the required length, the cartilage disk diminishes and finally is wholly replaced by bone, being represented in the adult only by the epiphyseal line. (See Fig. 120.) MARROW. The forerunner of marrow is the osteogenetic tissue in the primary marrow spaces, which in turn is derived from embryonic connective tissue (Fig. 117). During the development of bone, great numbers of osteoblasts are constantly being differentiated from the connective tissue cells and many of these ultimately become bone cells. When development ceases, osteoblasts cease to become differentiated. Marrow is one of the chief centers of blood cell formation in later foetal life, and in the adult is normally probably the only source of erythrocytes. An account of blood cell formation will be found in the section on "Haemopoiesis." The myeloblasts, which are probably identical with or at least closely allied to the primitive blood cells (haemoblasts), by acquiring certain types of granules in the cytoplasm become neutrophilic, acidophilic or basophilic myelocytes. During development two types of giant-cells (myeloplaxes) appear in the marrow. According to Jordan one of these is haemogenic and the other osteolytic. The former originates from enlarged hasmoblasts and may be regarded as representing centers of intense haemopoiesis, giving rise to erythrocytes. The osteolytic giant-cells (osteoclasts) arise more frequently from fused portions of the marrow reticulum, less often from fused osteoblasts, and are always multinucleated. Arey maintains in his more recent work that the so-called osteoclasts usually arise by fusion of old and basophilic osteoblasts, the cytoplasm of the syncytial mass becoming acidophilic. Arey also holds that this type of giant-cell is not a specific agent in bone resorption. In young marrow there is little or no fat present, but in later life many of the connective tissue cells are transformed into fat cells (p. 136), so that these form the greater part of the marrow. Such a process occurs most extensively in the shaft of the long bones and gives rise to "yellow" marrow. In the heads of the long bones, in the ribs, and in the short bones the marrow retains its earlier character and is known as "red" marrow.

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'''Fig. 120. Longitudinal section from head of femur of young dog'''. Photograph. The head of the femur is shown in the upper part of the figure, the end of the shaft in the lower part. Between the two the lighter line represents the cartilage between the primary center of ossification (shaft) and the secondary center (epiphysis, head), and marks the site of the epiphyseal line. The lighter portion covering the head represents the cartilage bordering the joint cavity.

==The Development of the Skeletal System==

===The Axial Skeleton===

===The Notochord===
<div id="Fig121"></div>
[[File:Bailey121.jpg|thumb|'''Fig. 121.''' From transverse section of human embryo with 8 pairs of primitive segments (2.69 mm.). Kollmann. ]]

The notochord (chorda dorsalis) constitutes the primitive axial skeleton of all Vertebrates, yet it differs from the other skeletal elements in that it is a derivative of the entoderm. In man it is merely a transient structure and disappears early in foetal life, leaving but a slight trace of itself in the intervertebral disks. In embryos of 2-3 mm. the cells of the entoderm just ventral to the neural groove become slightly differentiated (Fig. 121) and then form a groove with a ventral concavity. The groove closes in, becomes constricted from the parent tissue (entoderm) and lies just ventral to the neural tube, where it soon becomes surrounded by mesodermal tissue. This structure is the notochord and constitutes a solid, cylindrical cord of cells extending from a point just caudal to the hypophysis to the caudal extremity of the embryonic body. In embryos of 17-20 mm. the mesodermal tissue around the notochord becomes modified to form the chorda! sheath. On account of its position the notochord naturally becomes embedded in the developing vertebral column, extending through the bodies of the vertebrae and the intervertebral disks. The cells are at first of an epithelial nature (Fig. 121), but those within the vertebral bodies become vacuolated and broken up into irregular, multinuclear masses which then disappear. The cord is thus first interrupted in the vertebrae, leaving only the segments within the intervertebral disks. Later these segments also undergo degenerative changes, but persist as the so-called pulpy nuclei.

While the notochord is morphologically the forerunner of the axial skeleton, and persists as a whole in Amphioxus, and in part in Fishes and Amphibia, in the higher forms it is almost exclusively an embryonic structure with little or no functional significance. It differs in origin from the true skeletal elements and becomes involved with them only to disappear as they develop.

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'''Fig. 122. Five myotomes and sclerotomes from sagittal section of human embryo of 5 mm.''' Bardeen.
:Each sclerotome is differentiated into a looser cephalic part and a denser caudal part, the two being separated by a cleft (fissure of von Ebner).

===The Vertebrae===

The changes which occur in the ventro-medial parts of the primitive segments to form the sclerotomes have already been described. At the same time it was stated that the vertebrae, with the other types of connective tissue around them, were derived from the mesenchymal tissue of the sclerotomes (p. 131; see also Fig. 104). The segmentally arranged masses forming the sclerotomes are separated by looser tissue in which the intersegmental arteries develop. The arteries mark the boundaries between the sclerotomes (Fig. 122). About the third week of development the caudal part of each sclerotome condenses to form a more compact mass of tissue, and a little later becomes separated from the cephalic part by a small cleft (Fig. 123). From the denser caudal part a secondary mass of tissue grows medially and meets and fuses with its fellow of the opposite side, thus enclosing the notochord. The medial mass thus formed may be considered as the anlage of the body of a vertebra. Another secondary mass also grows dorsally between the myotome and the spinal cord, forming the anlage of the -vertebral arch. A third mass grows ventro-laterally to form the costal process (Figs. 124 and 125). The looser tissue of the cephalic part of each sclerotome also sends an extension medially to surround the notochord, and fills up the intervals between the succeeding denser (caudal) parts. The looser part also forms a sort of membrane between the succeeding vertebral arches. The tissue between the denser caudal part and the looser cephalic part of each sclerotome is destined to give rise to an intervertebral fibrocartilage. While the denser tissue forming the caudal part of each sclerotome probably gives rise to the greater part of a vertebra, the looser tissue of the cephalic part is also involved in the formation of the cartilaginous body, as will be noted again in the following paragraph. The peculiar feature of the process is that the denser caudal part of a sclerotome becomes associated with the looser cephalic part of the next succeeding sclerotome, so that each vertebra is derived from parts of two adjacent sclerotomes and not from a single sclerotome. This naturally brings about an alternation of vertebra and myotomes (Fig. 123).

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[[File:Bailey123.jpg|600px]]

'''Fig. 123. Six myotomes and sclerotomes from sagittal section of human embryo of 6 mm.''' Bardeen. Compare with Fig. 160.

So far the anlagen of the vertebrae are in the so-called blastemal stage.

Following the blastemal stage and beginning in human embryos of about 15 mm., comes the cartilaginous stage in which the mesenchymal anlagen of the vertebrae are converted into embryonic hyalin cartilage. In the body of each vertebra a center of chondrification appears in the looser tissue of the caudal part and gradually enlarges and involves the denser cephalic part. It is to be noted that the denser tissue of the cephalic part of a vertebral body corresponds to the caudal part of a sclerotome. Two chondrification centers appear, one on (Fig. 126). All these centers then enlarge and unite to form a single mass of cartilage which corresponds quite accurately in shape to the future bony vertebra. Processes then grow out from the vertebral arch. These represent the transverse and articular processes (Fig. 127). Each half of a vertebral arch meets its fellow of the opposite side dorsal to the spinal cord, and from the point of meeting the spinous process grows out. The costal processes do each side of the medial line, but the two soon fuse around the notochord to form a single center. In addition to the center in the body of the vertebra, one also appears in each half of the vertebral arch, and one in each costal process not retain their connection with the body of the vertebra, but break away and become the rib cartilages, as will be noted again in connection with the development of the ribs.

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'''Fig. 124. Transverse section (dorsal part) of pig embryo of 14 mm.''' Photograph.

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'''Fig. 125. Models of three vertebrae in the blastemal stage from an embryo of 11 mm.''' Bardeen.

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Fig. 126. Transverse section (dorsal part) of pig embryo of 35 mm. Photograph.

Following the cartilaginous stage is the stage of ossification in which the vertebrae become ossified and acquire the adult condition. Ossification begins during the third month of foetal life and extends over a long period, even up to the age of twenty-five years. A single center of ossification appears in the body of each vertebra, and following this a center in each half of the vertebral arch (Fig. 128). Osseous tissue then gradually replaces the cartilage. The two halves of an arch fuse dorsal to the spinal cord during the first year of postnatal life, thus completing the bony arch. The arch fuses with the body of the vertebra between the third and eighth years. Thus it is seen that the process of ossification is a slow one, and this is even more striking when one considers the formation of the secondary centers. For at about the age of puberty a secondary center appears in each of the cartilages that cover the ends of the vertebrae, producing disks of bone the epiphyses. A secondary center also appears in the cartilage on the tip of each spinous process and transverse process, and in the lumbar vertebrae one appears also on the tip of each articular process (Fig. 120). The epiphyses unite with the vertebrae any time between sixteen and twenty-five years. About the twenty-fifth year the sacral vertebrae unite to form a single mass of bone, and a similar union also takes place between the more or less rudimentary coccygeal vertebrae.

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'''Fig. 127. Models of the 6th, 7th and 8th thoracic vertebrae of an embryo of 33 mm.''' (dorsal view). Bardeen. On the right the cartilage is shown, on the left the surrounding fibrous tissue.

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'''Fig. 128. Thoracic vertebra and ribs of human embryo of 55 mm.''' (middle of 3rd month). Kollmann's Atlas. Cartilage indicated by stippled areas, ossification centers by irregular black lines.

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'''Fig. 129. Lumbar vertebra (lateral view) showing secondary centers of ossification.''' Sappey.

While the general plan of development is practically the same in all the vertebrae, there are a few noteworthy modifications. The greatest modification is in the atlas and epistropheus (axis). The entire atlas is formed from the denser caudal part of a sclerotome. The lateral mass and the posterior (dorsal) arch represent the vertebral arch. The anterior (ventral) arch represents the hypochordal bar, a plate of cartilage which develops in all vertebrae ventral to the notochord but disappears in all except the atlas. A body also develops but instead of forming part of the atlas it unites with the body of the epistropheus to form the dens (odontoid process) of the latter.

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'''Fig. 130. Ventral view of developing sternum of human embryo of 30 mm.''' (beginning of 3rd month). Ruge, Kollmann's Atlas.

The various ligaments of the vertebral column are derived from the embryonic connective tissue surrounding the vertebras. The embryonic connective tissue in the clefts separating the developing vertebrae is transformed into the intervertebral fibrocartilages.

===The Ribs===

It has been stated in a previous paragraph that the costal processes arise as outgrowths from the denser caudal parts of the sclero tomes; that they grow in a ventro-lateral direction and consequently are at first connected with and are parts of the bodies of the vertebrae (Figs. 124 and 126). These costal processes are the anlagen of the ribs, and they continue to grow ventrally until they practically encircle the body, the ventral ends of a number of them fusing in the medial line to form the sternum. The primary junctions between the costal processes and vertebrae are dissolved, and the embryonic connective tissue in this region gives rise to the costo-vertebral ligaments. The dissolution of the junctions leaves the ribs simply articulating with the vertebrae.

A chondrification center appears in each costal process, shortly after that in the body of the vertebra, and from this point the formation of cartilage gradually extends throughout the entire rib.

Ossification begins during the third month at a center which is situated near the angle of the rib (Fig. 128). At the age of eight to fourteen years a secondary center appears in each capitulum and tuberculum and subsequently fuses with the rest of the rib at the age of fourteen to twenty-five years. As the tuberculum develops, the transverse process of the corresponding vertebra grows ventrally and caudally to meet it and form the articulation.

The ribs reach the highest degree of development in the thoracic region where one develops on each side, corresponding to each vertebra. The first seven or eight thoracic ribs extend almost to the midventral line and are attached to the sternum; the last four or five become successively shorter and are only indirectly or not at all attached to the sternum. In the cervical region the ribs do not reach a high degree of development. Their tips simply fuse with the transverse processes of the vertebrae and their heads with the bodies of the vertebrae, leaving a space the foramen transversarium through which the vertebral vessels pass. The seventh cervical rib may, however, reach a fairly high degree of development. In the lumbar region also the ribs are reduced to small pieces of bone which are firmly united with the transverse processes and form the accessory processes. In the sacral region the rudimentary ribs unite to form the lateral part (pars lateralis) of the sacral bone. After the blastemal stage there are no indications of ribs in the coccygeal region. In the blastemal stage, however, there is a small bit of tissue Fig. 131. Sternum of which probably represents the anlage of a rib, but soon fuses with the transverse process.

===The Sternum===
<div id="Fig131"></div>
[[File:Bailey131.jpg|thumb|'''Fig. 131.''' 12 year old child, showing centers of ossification. Seven ribs are attached on the right side, 8 on the left. Markowski, Kollmann's Atlas.]]
The sternum, according to Hanson's recent contribution, originates independently of the ribs. On each side, some distance from the midventral line, the sternal band or bar arises as a mesenchymal condensation in the body wall. These bars then approach the midventral line and fuse with each other to form a single cartilaginous structure. Meanwhile the ventral ends of the first seven ribs extend far enough to come into contact with and join the sternal bar (Fig. 130). Before the two bars have united a medial unpaired rudiment appears opposite their anterior ends to form the presternum with which the paired rudiments subsequently unite. The presternal component, with which the clavicles articulate, probably represents the ventral part of the primitive vertebrate shoulder girdle.

Ossification begins in the sternum about the end of the fifth month of foetal life. In the cephalic portion two unpaired centers appear; caudal to these is a series of paired centers which subsequently fuse across the midventral line. (See Fig. 131.) The paired centers perhaps reflect the paired character of the sternal bars. Sometimes, however, the centers appear as a single series, that is, with no indication of a paired character. The ossification of the most cephalic segment, along with the episternal cartilages, produces the manubrium sterni. Ossification of the following six or seven segments and their union produce the corpus sterni. The xyphoid process appears to be a caudal extension of the corpus sterni. This process remains cartilaginous for a long period, and may be single, perforated, or bifurcated, depending upon the degree of fusion between the two primary bars.

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'''Fig. 132.''' Diagram of first stage in the development of the cartilaginous primordial cranium. Wiedersheim.

'''Fig. 133.''' Diagram of later stage of same. Wiedersheim.

===The Head Skeleton===

Topographically the skeleton of the head appears as the cephalic part of the axial skeleton. Structurally it is decidedly different, for it is adapted to different conditions. The neural tube here becomes differentiated into the brain with its many and dissimilar parts. In connection with the brain the complicated sense organs (nose, eye and ear) arise. A part of the alimentary tract and portions of the visceral arches are also inclosed within the head. The head skeleton is specially modified to accommodate these highly developed organs, and becomes extremely complicated. In general the skeleton in any part of the body adapts itself to the other structures and not the other structures to the skeleton.

The anlage of the skull is a mass of embryonic connective tissue which surrounds the cephalic end of the notochord, extends from there into the nasal region and also extends around the sides and dorsal part of the neural tube (brain). Unlike the anlage of the vertebral column, the anlage of the skull shows no distinct division into primitive segments. The only indications of a segmental character are referred to in a succeeding paragraph (small print,

The next step in the development of the skull is the appearance of cartilage in certain regions of the embryonic connective tissue. On account of the complicated arrangement of the cartilage in the human skull, it is best to consider first its more simple arrangement in the lower Vertebrates. In these there appear in the embryonic connective tissue around the cephalic end of the notochord two bilaterally symmetrical pieces of cartilage, which extend as far as the hypophysis. Then two other bilaterally symmetrical pieces appear, extending from the hypophysis to the nasal region. Subsequently all these pieces fuse into a single mass which extends from the cephalic end of the vertebral column to the tip of the nose, enclosing the end of the notochord and, to a certain extent, the ear, eye and olfactory apparatus. There is left, however, an opening for the hypophysis. From this mass of cartilage, chondrification extends into the embryonic connective tissue along the sides and roof of the cranial cavity, so that the brain and sense organs are practically enclosed. To this capsule the term cartilaginous primordial cranium has been applied. (See Figs. 132, 133, 134.)

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'''Fig. 134. Primordial cranium of Salmo (salmon) embryo of 25 mm.''' Dorsal view. Gaupp Compare with Fig. 133 and note further elaboration of parts surrounding the sense organs.

In the higher Vertebrates, chondrification is limited to the basal region of the skull, while the side walls and roof are formed later by intramembranous bone.

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'''Fig. 135. Dorsal view of primordial cranium of human embryo of 80 mm.''' (3rd month). Gaupp. Hertwig. The membrane bones of the roof of the skull have been removed. Through the large occipital foramen can be seen the first three cervical vertebrae.

In the human embryo chondrification occurs first in the occipital and sphenoidal regions, and then gradually extends into the nasal (ethmoidal) region. A little later it spreads somewhat dorsally in the occipital and sphenoidal regions to form part of the squamous portion of the occipital and the wings of the sphenoid. At the same time cartilage develops in the embryonic connective tissue surrounding the internal ear to form the periotic capsule whicn subsequent!} unites with the occipital and sphenoidal cartilages. The pieces of cartilage thus formed constitute the chondrocranium.

In connection with the development of the caudal part of the occipital cartilage there is an interesting feature which is at least indicative of a segmental character. In some of the lower Mammals there are four fairly distinct condensations of embryonic connective tissue just cranial to the first cervical vertebra, corresponding to the first cervical nerve and the three roots of the hypo glossal. These condensations bear a general resemblance to the primitive segments and indicate the existence of four vertebrae which are later taken up into the chondrocranium. In the human embryo the condensations are less distinct, but the existence of a first cervical and a three-rooted hypoglossal nerve in this region suggests an original segmental character. If this is true, then the base of the human skull is formed from the unsegmented chondrocranium plus four vertebrae which become incorporated in the occipital region.

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Fig. 136. Lateral view of primordial cranium of human embryo of 80 mm. (3rd month). Gaupp, Hertwig. The membrane bones of the roof of the skull have been removed. Compare with Fig. 135. The maxilla, vomer, palate, and mandible are membrane bones.

In addition to the chondrocranium, other cartilaginous elements enter into the formation of the skull, all of which are derived from the visceral arches. Not all the arches, however, produce cartilage; for in the maxillary process of the first arch, which forms the upper boundary of the mouth, cartilage does not appear, and the bones which later develop in it are of the membranous type. The mandibular process of the first arch produces a rod of cartilage Meckel's cartilage. This gives rise, at its proximal end, to a part of the auditory ossicles, but the cartilage in the jaw proper soon wholly or almost wholly disappears. The cartilage of the second arch becomes connected with the skull in the region of the periotic capsule. The cartilages of the other three arches are only indirectly connected with the skull and will be considered later.

Figs. 135 and 136 show the condition of the chondrocranium in a human embryo of 80 mm. (third month) . Although at first glance it seems exceedingly complicated, a careful study and comparison of the various parts will aid the student in his comprehension of the cartilaginous foundation upon which the skull is built.

===Ossification of the Chondrocranium===

In the human foetus ossification begins in the occipital region during the third month. Four centers appear which correspond to the four parts of the adult occipital bone (Fig. 137). (i) An unpaired center situated ventral to the foramen magnum. From this center ossification proceeds in all directions to form the pars basilaris (basioccipital). (2 and 3) Two lateral centers, one on each side. From these, ossification proceeds to produce the partes laterales (exoccipital) which bear the condyles. (4) A center dorsal to the foramen magnum. This produces the pars squamosa (supraoccipital) as far as the superior nuchal line. Beyond this line the pars squamosa is of intramembranous origin. (See p. 160.) At birth the four parts are still separated by plates of cartilage. During the first or second year after birth the partes laterales unite with the pars squamosa, and about the seventh year the pars basilaris unites with the rest of the bone.

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'''Fig. 137. Occipital bone of human embryo of 21.5 cm.''' Kollmann's Atlas.

In the sphenoidal region ossification begins at a number of centers which, as in the occipital region, correspond generally to the parts of the adult sphenoid bone (Fig. 138). (i and 2) About the ninth week an ossification center appears on each side in the cartilage which corresponds to the ala magna (alisphenoid). (3 and 4) About the twelfth week a center appears on each side which corresponds to the ala parva (orbitosphenoid) . (5 and 6) A short time after this a center appears on each side of the medial line in the basal part of the cartilage, and the two centers subsequently fuse to produce the corpus (basisphenoid) . (7 and 8) Lateral to each basal center, another center appears which represents the beginning of the lingula. (9 and 10) Finally two centers appear in the basal part of the cartilage, in front of the other basal centers, and then fuse to form the presphenoid. As in the case of the occipital bone, not all of the adult sphenoid is of intracartilaginous origin; for the upper anterior angle of each ala magna is of intramembranous origin, as are also the medial and lateral laminae of the pterygoid process. The pterygoid hamulus, however, is formed by the ossification of a small piece of cartilage which develops on the tip of the medial lamina. The fusion of these various parts occurs at different times. The lateral pterygoid lamina unites with the alisphenoid before the sixth month of foetal life; about the sixth month the lingula fuses with the basisphenoid, and the presphenoid with the orbitosphenoid. The alisphenoid and medial pterygoid lamina fuse with the rest of the bone during the first year after birth. The union of the basisphenoid and basioccipital usually occurs when the growth of the individual ceases, though the two bones may remain separate throughout life.

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'''Fig. 138. Sphenoid bone of embryo of 3-4 months.''' Sappey. The parts that are still cartilaginous are represented in black.

In the region of the periotic capsule, several centers of ossification appear in the cartilage during the fifth month. During the sixth month these centers unite to form a single center which then gradually increases to form the pars petrosa and pars mastoidea of the adult temporal bone. The mastoid process is formed after birth by an evagination from the pars petrosa, and is lined by an evaginated portion of the mucosa of the middle ear. The other parts of the temporal bone are of intramembranous origin, except the styloid process which represents the proximal end of the second branchial arch.

In the ethmoidal region, conditions become more complicated on account of the peculiarities of the nasal cavities, and on account of the fact that the cartilage is never entirely replaced by bone, and that "membrane" bones also enter into more intimate relations with the "cartilage" bones. The ethmoidal cartilage at first consists of a medial mass, which extends from the presphenoid region to the end of the nasal process, and of a lateral mass on each side, which is situated lateral to the nasal pit (Fig. 136). Ossification in the lateral mass on each side produces the ethmoidal labyrinth (lateral mass of ethmoid). It is perhaps not quite correct to say that ossification produces the ethmoidal labyrinth, for at first there is only a mass of spongy bone with no indication of the honey-combed structure characteristic of the adult. The latter condition is produced by at certain amount of dissolution of the bone and the growth of the nasal mucosa into the cavities so formed. By the same process of dissolution and ingrowth of nasal mucosa the superior, middle and inferior concha (turbinated bones) are formed. The medial mass of cartilage begins to ossify after birth and then only in its upper (superior) edge. It forms the lamina perpendicular is and crista galli and extends into the nose as the nasal septum. The lower (inferior) edge remains as cartilage until the vomer, which is a membrane bone (p. 194), develops, after which it is partly dissolved. The lamina cribrosa (cribriform plate) is formed by bony trabeculae which extend across between the medial mass and the lateral masses and surround the bundles of fibers of the olfactory nerve.

==Membrane Bones of the Skull==

Under this head we shall consider only those bones which develop a from the visceral arches, those which involve the arches being considered later. It has been seen that by far the greater parts of the bones forming the base of th skull are of intracartilaginous origin. On the other hand, those forming the sides and roof of the skull are largely of intramembranous origin. In the case of the occipital bone, two centers of ossification appear in the membrane dorsal to the supraoccipital, and the bone so formed begins to unite with the supraoccipital during the third month of foetal life. At birth the union is usually complete, though for a time an open suture may persist on each side. The bone derived from the two centers forms that part of the occipital squama which is situated above the superior nuchal line; the part below the line is of intracartilaginous origin (p. 190). The adult occipital is thus a composite bone, partly of intramembranous, partly of intracartilaginous origin.

The temporal is also a composite bone, the petrous and mastoid parts and the styloid process being of intracartilaginous origin, while the temporal squama and the tympanic part are of intramembranous origin. During the eighth week of foetal life a center of ossification appears in the membrane in the temporal region, and the bone formed from this center subsequently unites with the petrous part and becomes the temporal squama. Another center appears in the membrane to the outer side of the periotic capsule and produces a ring of bone around the external auditory meatus, which fuses with the petrous part and forms the tympanic part of the adult bone. It gives attachment at its inner border to the tympanic membrane. While the union of the different parts begins during foetal life, it is usually completed after birth.

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'''Fig. 139. Diagram of skull of new-born child.''' Combined from McMurrich and Kollmann. White areas represent bones of intramembranous origin; dotted areas represent bones (not derived from branchial arches) of intracartilaginous origin; black areas represent derivatives of branchial arches.

The sphenoid bone is also composed of parts which have different origins. The body, small wings and large wings are of intracartilaginous origin, the pterygoid process of intramembranous origin. About the eighth week of development a center of ossification appears in the mesenchyme in the lateral wall of the posterior part of the nasal cavity and gives rise to the medial pterygoid lamina. On the tip of the latter a small piece of cartilage appears in which ossification later takes place to form the pterygoid hamulus (p. 159). The lateral pterygoid lamina is also of intramembranous origin and fuses with the medial lamina, the two laminae forming the pterygoid process which subsequently unites with the body of the sphenoid. (See Fig. 138.)

In the ethmoidal region, only the vomer is of intramembranous origin. An ossification center appears in the embryonic connective tissue on each side of the perpendicular plate (lamina perpendicularis) and these two centers produce two thin plates of bone which unite at their lower borders and invest the lower part of the perpendicular plate. The portion of the latter thus invested undergoes resorption.

The frontal and parietal bones are purely of intramembranous origin. About the eighth week two centers of ossification, one on each side, appear for the frontal. The bones produced by these centers unite in the medial line to form the single adult bone. In the event of an incomplete union an open suture remains the metopic suture. A single center of ossification appears for each parietal bone at about the same time as those for the frontal. The union of the bones which form the roof and the greater part of the sides of the skull does not occur till after birth. The spaces between them constitute the sutures and fontanelles so obvious in new-born children (Fig. 139).

A single center of ossification appears in the embryonic connective tissue for each zygomatic, lachrymal and nasal bone, all of which are of intramembranous origin.

==Bones Derived from the Branchial Arches==

The first branchial arch becomes divided into two portions. One of these, the maxillary process, is destined to give rise to the upper jaw and much of the upper lip and face region. The other, the mandibular process, is destined to give rise to the lower jaw, the lower lip and chin region, and two of the auditory ossicles. The angle between the two processes corresponds to the angle of the mouth, and the cavity enclosed by the processes is the forerunner of the mouth and nasal cavities. (See Fig. 96, also p. 119.) So far as the skeletal elements are concerned, cartilage develops only in the mandibular process where it forms a slender bar or rod known as MeckeVs cartilage. Only a small part of this becomes ossified, the greater portion of the mandible being of intramembranous origin. No cartilage develops in the maxillary process. This probably indicates a condensation of development in man and the higher animals, for among the lower animals cartilage precedes the bone. In man the maxilla and palate bone also are of intramembranous origin.

The palate bone develops from a single center of ossification which appears at the side of the nasal cavity in embryos of about 18 mm. This center represents the perpendicular part, the horizontal part appearing in embryos of about 24 mm. as an outgrowth from the perpendicular and not as a separate center of ossification. The orbital and sphenoidal processes also represent outgrowths from the primary center and appear much later.

Opinions regarding the development of the maxilla are at variance. One view is that it arises from five centers of ossification. One of these centers gives rise to that part of the alveolar border which bears the molar and premolar teeth; a second center forms the nasal process and that part of the alveolar border which bears the canine tooth; a third produces the part which bears the incisor teeth; and the two remaining centers give rise to the rest of the bone. All these parts effect a firm union at an early stage, with the exception of the part bearing the incisor teeth which remains more or less distinct as the incisive bone (premaxilla, intermaxilla) . Another view arising from recent work on human embryos is that there are primarily only two ossification centers; one of these gives rise to the incisive bone, the other to the rest of the maxilla (Mall). These centers appear at the end of the sixth week (embryos of 18 mm.).

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'''Fig. 140. Head of human embryo of 7 weeks.''' His. Ventral aspect of upper jaw region. Lower jaw and tongue have been removed.

A very important feature in the development of the maxilla is its agency in separating the nasal cavity from the mouth cavity. The palatine process of the bone grows medially and meets and fuses with its fellow of the opposite side in the medial line, the two processes together thus constituting about the anterior three-fourths of the bony part of the hard palate. It should be observed, however, that the palatine processes do not meet at their anterior borders, for the incisive bone is insinuated between them (see Figs. 140, 141).

The incisive bone is probably not derived from the maxillary process of the first visceral arch, but from the fronto-nasal process. The question thus arises as to whether it is derived from both the middle and lateral nasal processes or only from the middle. According to Kolliker's view, the lateral nasal process takes no part in the formation of the incisive bone. It is derived from the middle process, hence genetically it is a single bone on each side. According to Albrecht's view the incisive bone is genetically composed of two parts, one derived from the lateral, the other from the middle nasal process. While the matter is not one of great importance merely from the standpoint of development, it has an important bearing on the question of certain congenital malformations, e.g., hare lip, and will be discussed further under that head (p. 180).

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'''Fig. 141. Ventral aspect of hard palate of human embryo of 80 mm.''' Kollmann's Atlas.

In the mandibular process of the first visceral arch, the mandible develops as a bone which is partly of intramembranous and partly of intracartilaginous origin. In the first place a rod of cartilage, known as Meckel's cartilage, forms the core of the mandibular process and extends from the distal end of the process to the temporal region of the skull, where it passes between the tympanic bone and the periotic capsule and ends in the tympanic cavity of the ear (Fig. 136). During the sixth week of foetal life, intramembranous bone begins to develop in the mandibular process. In the region of the body of the mandible the bone encloses the cartilage, but in the region of the ramus and coronoid process the cartilage lies to the inner side of the bone. Development is further complicated by the appearance of cartilage in the region of the middle incisor teeth and on the coronoid and condyloid processes. These pieces of cartilage form independently of Meckel's cartilage and subsequently are replaced by the bone which constitutes the corresponding parts of the mandible. The part of Meckel's cartilage enclosed in the bone disappears; the part to the inner side of the ramus is transformed into the sphenomandibular ligament. (See Fig. 142.) In each half of the second branchial arch a rod of cartilage develops, which extends from the ventro-medial line to the region of the periotic capsule. The proximal end of this rod is then replaced by bone which fuses with the temporal bone and forms the styloid process. The distal (ventral) end is replaced by bone which forms the lesser horn of the hyoid bone. Between the styloid process and the lesser horn, the cartilage is transformed into the stylohyoid ligament (see Figs. 139 and 142).

In each half of the third branchial arch a piece of cartilage develops and subsequently is replaced by bone to form the greater horn of the hyoid bone. The two horns become connected at their ventral ends by the body of the hyoid bone which is also a derivative of the third arch. Later the lesser horn fuses with the greater horn to bring about the adult condition (Fig. 142).

In the ventral parts of the fourth and fifth arches pieces of cartilage develop and form the skeletal elements, of the larynx. A more detailed account of these will be found under the head of the larynx.

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'''Fig. 142. Lateral dissection of head of human foetus'''. Showing derivatives of branchial arches in natural position. Kollmann's Atlas.

The auditory ossicles are also derived largely from the branchial arches, the incus and malleus being derived from the proximal end of Meckel's cartilage (first arch) , the stapes having a double origin from the second arch and the embryonic connective tissue surrounding the periotic capsule. But since they form integral parts of the organ of hearing, a discussion of their formation is best included in the development of the ear.

The accompanying table indicates the types of development in the different bones of the head skeleton.

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==The Appendicular Skeleton==

The growth of the limb buds and their differentiation into arm, forearm and hand, thigh, leg and foot, along with the rotation which they undergo during development, have been discussed in the chapter on the external form of the body (p. 121). The metameric origin of the muscles of the extremities is discussed in the chapter on the muscular system (Chap. XI). It has been seen that the greater part of the axial skeleton is derived from the sclerotomes, is preformed in cartilage, and maintains its segmental character throughout life. It has also been seen that the head skeleton is in part preformed in cartilage, is in part of intramembranous origin, and shows but a trace of segmental character, and that only in the occipital region at a very early stage. The appendicular skeleton is derived wholly from the embryonic connective tissue which forms the cores of the developing extremities, and shows no trace of a segmental character. Here also, as in the axial skeleton, three stages may be recognized a blastemal, a cartilaginous (Fig. 143), and a final osseous,

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'''Fig. 143. Cartilages of left upper extremity of a human embryo of 17 mm.''' Hagen.

In the region of the shoulder girdle a plate of cartilage appears in the embryonic connective tissue which lies among the developing muscles dorso-lateral to the thorax. This plate of cartilage is the forerunner of the scapula, and in general resembles it in shape. During the eighth week of foetal life a single center of ossification appears and gives rise to the body and spine of the scapula. After birth certain accessory centers appear and produce the coracoid process, the supraglenoidal tuberosity, the acromion process, and the inferior angle and vertebral margin (Fig. 144). Later the supraglenoidal fuses with the coracoid and forms part of the wall of the glenoid cavity. About the seventeenth year the single center formed by the union of these two fuses with the rest of the scapula.

At the age of twenty to twenty-five years all the other accessory centers unite with the rest of the scapula to form the adult bone.

There are two views concerning the development of the clavicle: one that it is of intracartilaginous origin, the other that it is of intramembranous origin. Ossification begins during the sixth week, possibly from two centers. It is true that the cartilage that appears around the centers is of a looser character than the ordinary embryonic cartilage, but whether the centers appear in cartilage seems not to have been determined. At the age of fifteen to twenty years a sort of secondary center appears at the sternal end of clavicle and fuses with the body about the twenty-fifth year.

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'''Fig. 144. Scapula of new-born child.''' Showing primary center of ossification, and cartilage (lighter shading) in which secondary centers appear. Bonnet.

The humerus, radius and ulna are preformed in cartilage (Fig. 143) and develop as typical long bones. Ossification begins in each during the seventh week at a single center and proceeds in both directions to form the shaft. During the first four years after birth epiphyseal centers appear for the head, greater and smaller tubercles, trochlea and epicondyles. All these secondary centers unite with the shaft of the humerus when the growth of the individual ceases. In the case of the radius and ulna a secondary center appears at each end of each bone to form the epiphysis; and in the ulna another secondary center appears to form the olecranon. (For the growth of bones, see page 144) . The carpal bones are all preformed in cartilage (Fig. 143) but their development is somewhat complicated owing to the fact that pieces of cartilage appear which subsequently may disappear, or ossify and become incorporated in other bones. Primarily seven distinct pieces of cartilage develop and become arranged transversely in two rows; these represent seven of the carpal bones. The proximal row consists of three large pieces which are the forerunners of the navicular (radial, scaphoid), lunate (intermediate, semilunar) and triquetral (ulnar, pyramidal, cuneiform) . The distal row is composed of four elements which are the forerunners of the large multangular (trapezium), small multangular (trapezoid), capitate (os magnum), and hamatate or hooked (unciform). In addition to the cartilages mentioned, several others also appear in an inconstant way in different individuals. Two of these are important. One appears on the ulnar side of the proximal row and is the forerunner of the pisiform; the other is situated between the two rows and may either disappear entirely or fuse with the navicular. Ossification does not begin in the carpal cartilages until after birth; it begins in the hamatate and capitate during the third year, in the others at later periods, and is completed only when the growth of the individual ceases. The fact that the hamatate ossifies from two centers indicates that it is probably derived phylogenetically from two bones. Comparative anatomy teaches that the accessory cartilages in the human wrist are representatives of structures which are normally present in the lower forms.

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'''Fig. 145. Diagram of right hand of 5 year old girl.''' (Courtesy of Dr. Edward Learning). The ossification centers are indicated by the darker areas.

The metacarpals and phalanges are preformed in cartilages which correspond in shape to the adult bones. A center of ossification appears in each cartilage and produces the shaft of the bone. Only one epiphysis develops on each metacarpal and phalanx. In each metacarpal it develops at the distal end, except in the thumb where it appears at the proximal end. In each phalanx it develops at the proximal end (Fig. 145).

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'''Fig. 146. Cartilage of right side of pelvic girdle of a human embryo of 13.6 mm.''' (5 weeks). Petersen. The numerals indicate the vertebrae; the first sacral being opposite the ilium.

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'''Fig. 147. Cartilage of right side of pelvic girdle of a human embryo of 18.5 mm.''' (8 weeks). Petersen. The numerals indicate the vertebras; the first and second sacral being opposite the ilium. Compare with Fig. 146.

The skeletal elements of the lower extremities, including the pelvic girdle, are of intracartilaginous origin. Each hip bone (os coxae, innominate bone) is preformed in cartilage which, in a general way, resembles in shape the adult bone. The ventral part of the pubic cartilage does not at first join the ischial; but by the eighth week the junction is complete, leaving dorsal to it the obturator foramen. In the earliest stages the long axis of the cartilage is nearly at right angles to the ; vertebral column, and the ilium lies close to the fifth lumbar and first sacral | vertebrae; later (eighth week) the long axis lies nearly parallel with the vertebral l column and the whole cartilage has shifted so that the ilium is associated with I the first three sacral vertebrae (Figs. 146 and 147).

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'''Fig. 148 Right os coxae (innominate bone) of new-born child.''' Bonnet. Bone is indicated by darker areas/ cartilage by lighter areas.

Ossification begins at three centers which correspond to the ilium, ischium and pubis; the center for the ilium appears during the eighth week, the centers j for the ischium and pubis several weeks later (Fig. 148). The process of ossifi: cation is slow, and is far from complete at the time of birth, for at that time the entire crest of the ilium, the bottom of the acetabulum and all the region ventral to the obturator foramen are cartilaginous. During the eighth or ninth year the ventral parts of the pubis and ischium become partly ossified, but up to the time of puberty the pubis, ischium and ilium remain separated by plates of cartilage which radiate from a common center at the bottom of the acetabulum. Soon after this, the three bones unite to form the single os coxae, leaving only the crest of the ilium, the pubic tubercle and the sciatic tuber (tuberosity of the ; ischium) cartilaginous. In each of these regions an accessory ossification center appears and finally fuses with the corresponding bone about the twentyfourth year.

The femur, tibia and fibula are preformed in cartilage. In the femur a center of ossification appears about the end of the sixth week and gives rise to the shaft; similar centers appear in the tibia and fibula during the seventh and eighth week, respectively. In the femur a distal epiphyseal center appears shortly before birth, and during the first year after birth a proximal center appears for the head. These centers do not unite with the shaft until the individual ceases to grow. The great and lesser trochanters also have accessory ossification centers. In the tibia the center of ossification for the proximal epiphysis appears about the time of birth, the one for the distal during the second year. In the fibula the epiphyseal centers appear during the second and sixth years after birth. The cartilage of the patella appears during the third or fourth month of foetal life, and ossification begins two or three years after birth.

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'''Fig. 149. Diagram of cartilages of left leg and foot of human embryo of 17 mm'''. Hagen.

The bones of the tarsus, like those of the carpus, are preformed in pieces of cartilage which are arranged in two transverse rows. The proximal row consists of three pieces, one at the end of the tibia (tibial), one at the end of the fibula (fibular), and the third between the two (intermedial) . At an early stage the tibial and intermedial fuse to form a single piece of cartilage which corresponds to the talus (astragalus) bone. The fibular cartilage corresponds to the calcaneus (os calcis). The distal row is composed of four pieces of cartilage which correspond to the first cuneiform (internal), second cuneiform (middle), third cuneiform (external), and cuboid (Fig. 149). Between the two rows is a piece of cartilage which corresponds to the navicular (scaphoid). Ossification begins relatively late in the metatarsals. A center for the calcaneus appears during the sixth month of foetal life, and one for the talus shortly before birth. Centers appear in the cuboid and third cuneiform during the first year after birth, and in the first cuneiform, navicular and second cuneiform in order during the third and fourth years (Figs. 150 and 151). At the age of puberty ossification is nearly complete in all the metatarsals. In the talus two centers, corresponding to the tibial and intermedial, appear, but soon fuse into a single center. Occasionally the intermedial remains separate and forms the trigonum.

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'''Fig. 150. Ossification centers in foot of a child 9 months old.''' Hasselwander. An accessory center appears in the calcaneus at the insertion of the tendon of Achilles.

The metatarsals and phalanges develop in a manner corresponding to the metacarpals and phalanges (of fingers). Ossification begins in the metatarsals about the ninth week, in the first row of (proximal) phalanges about the thirteenth week, in the second row about the sixteenth week and in the third row (distal) about the beginning of the ninth week. Epiphyseal centers appear from the second to the eighth year after birth.

==Development of Joints==

The embryonic connective tissue from which the connective tissues, including cartilage and bone, are developed, at first forms a continuous mass. When cartilage appears it may form a continuous mass, as in the chondrocranium, or it may form a number of distinct and separate pieces, as in the vertebral column, the pieces being united by a certain amount of the undifferentiated embryonic connective tissue.

===Synarthrosis===

====Syndesmosis====

When ossification begins at one or more centers, either in cartilage or in embryonic connective tissue, the centers gradually enlarge and approach each other, and the bone so formed comes in contact with the bone formed in neighboring centers, (a) In a case where more than one center appears for any single adult bone, they may come in contact and fuse so completely that the line of fusion becomes indistinguishable, (b) In the case of adjacent bones the fusion may not be so complete; that is, the two bones may simply articulate, leaving a visible line of junction or suture. Such joints are immovable and are represented in the sutures of the skull.

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'''Fig. 151. Skeleton of right foot of a boy 3 years old, showing ossification centers.''' Toldt.

====Synchondrosis====

In some cases a small amount of embryonic connective tissue remains between adjacent bones, (a) In time, this embryonic connective tissue gives rise to cartilage which unites the bones quite firmly, thus producing a practically immovable joint, as in the case of the sacro-iliac joint, (b) Or the cells in the center of the cartilage disintegrate or become liquefied so that a small cavity is produced (articular cavity). This type of joint makes possible a slight degree of mobility and is exemplified by the symphysis of the pubic bones. Such a type is also represented by the joints of the vertebral column. In place of cavities, however, are the pulpy nuclei which are remnants of the notochord.

===Diarthrosis===

Where a great degree of mobility is necessary, the arrangement of the joint is different. The cells in the central part of the embryonic connective tissue between the ends of adjacent bones (or cartilages) (Fig. 152) liquefy so that a relatively large cavity, the joint cavity, is formed (Fig. 153). The liquefaction of the connective tissue cells may also extend for a short distance along the sides of the bones so that the joint cavity surrounds the ends of the bones (Figs. 154 and 155). The origin of the synovial fluid is not known with certainty, but it is probably in part the product of liquefaction of the connective tissue cells. The more peripheral part of the connective tissue which encloses the joint cavity is transformed into a dense fibrous tissue, the joint capsule. The cells lining the cavity become differentiated into oval or irregular cells, among which is a considerable amount of intercellular substance. By some it is held that these cells form a continuous single layer like endothelium, but the most recent researches tend to disprove this. The cells lining the cavity are the most highly differentiated, the cell bodies being large and apparently swollen, and there is gradually less differentiation as the distance from the surface increases, until finally they merge with the ordinary type of connective tissue cells of the joint capsule (Clarke). The more mobile joints of the body are all representatives of this type.

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'''Fig. 152. Section through axilla and arm of a human embryo of 26 mm.''' (2 months). Photograph. Note the mesenchymal tissue between the humerus and the radius the site of the elbow joint.

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'''Fig. 153. Longitudinal section of finger of human embryo of 26 mm.''' (2 months), showing beginning of joint cavity between adjacent ends of phalanges. (Photograph from preparation by Dr. W. C. Clarke.)

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'''Fig. 154. From longitudinal section of finger of child at birth, showing developing joint cavity between adjacent ends of phalanges.''' The darker portion at each end of the figure indicates the ossification center in the phalanx, the end of the latter (lighter area) being yet cartilaginous. The dark bands at each side of the joint indicate developing ligaments. Photograph.

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'''Fig. 155. From longitudinal section of finger of child at birth, showing joint cavity and synovial membrane between adjacent ends of the first metacarpal and proximal phalanx.''' Other description same as in Fig. 154. Photograph.

==Anomalies==

===The Axial Skeleton===

====The Vertebrae====

The number of cervical vertebrae in man is remarkably constant. Cases where the number is but six are extremely rare. The thoracic vertebrae may vary in number in different individuals from eleven to thirteen, twelve being the usual number. The lumbar vertebrae may vary from four to six, five being the usual number. The sacral vertebrae, fused in the adult to form the sacrum, are usually five in number, sometimes four, sometimes six. Occasionally a vertebra between the lumbar region and sacral region lumbo-sacral vertebra possesses both lumbar and sacral characters, one side being fused with the sacrum, the other side having a free transverse process. Variation occurs frequently in the coccygeal vertebrae; four and five are present with about equal frequency, more rarely there are only three.

The total number of true (presacral) vertebrae may be diminished by one or increased by one. In the former case the first sacral is the twenty-fourth vertebra, and, if the number of ribs remains normal, there are only four lumbar vertebrae. In case the total number is increased by one, the first sacral is the twenty-sixth vertebra, and there are twelve thoracic and six lumbar or thirteen thoracic and five lumbar.

From these facts it is seen that variation occurs most frequently in the more caudal portion of the vertebral column in the lumbar, sacral and coccygeal regions. According to a hypothesis advanced by Rosenberg, the sacrum in the earlier embryonic stages is composed of a more caudal set of vertebrae than those which belong to it in the adult, and during development lumbar vertebrae are converted into sacral and sacral vertebrae into coccygeal. In other words, the hip bone moves headward during development and finally becomes attached to vertebrae which are situated more cranially than those with which it was primarily associated. This change in the position of the pelvic attachment, and the corresponding reduction in the total number of vertebrae, during the development of the individual (i.e., during ontogenetic development) is believed to correspond to a similar change in position during the evolution of the race (i.e., during phylogenetic development).

According to Rosenberg, variation in the adult is due largely to a failure during ontogeny to carry the processes of reduction in the number of vertebrae as far as they are usually carried in the race, or to their being carried beyond this point.

The coccygeal vertebrae apparently represent remnants of the more extensively developed caudal vertebrae in lower forms. In human embryos of 8 to 16 mm., when the caudal appendage is at the height of its development, there are usually seven anlagen of coccygeal vertebrae. During later development this number becomes reduced by fusion of the more distally situated anlagen to the smaller number in the adult. This process of reduction varies in different individuals, so that five or four, rarely three, coccygeal vertebrae may be the result. In cases where children are born with distinct caudal appendages there is no good evidence that the number of coccygeal vertebrae is increased, although the coccyx may extend into the appendage.

====The Ribs====

Occasionally in the adult a rib is present on one side or on each side in connection with the seventh cervical vertebra (cervical rib), or in connection with the first lumbar vertebra (lumbar rib) . There seems to be no case on record where cervical and lumbar ribs are present in the same individual. The cervical rib may vary between a small piece of bone connected with the transverse process of the vertebra and a well developed structure long enough to reach the sternum. There are also great variations in the size of the lumbar rib. In case the number of ribs is normal, the last (twelfth) may be rudimentary.

The eighth costal cartilage not infrequently unites with the sternum. Occasionally the seventh costal cartilage fails to fuse with the sternum, owing to the shortening of the latter, but meets and fuses with its fellow of the opposite side in the midventral line.

The above mentioned anomalies can be referred back to aberrant development. Primarily costal processes appear in connection with the cervical, lumbar and sacral vertebrae. Normally these processes fuse with and finally form parts of the vertebrae (p. 153). In some cases, however, the seventh cervical or the first lumbar processes develop more fully and form more or less distinct ribs.

As an explanation of these variations in the number of ribs, it has been suggested that there is a tendency toward reduction in the total number of ribs, and that supernumerary ribs represent the result of a failure to carry the reduction as far as the normal number. In case the twelfth rib is rudimentary, the reduction has been carried beyond the normal limit. This hypothesis is a corollary to the hypothesis regarding the variations in the number of vertebrae. (See under "The Vertebrae.")

====The Sternum====

Certain anomalous conditions of the sternum can also be explained by reference to development. The condition known as cleft sternum, in which the sternum is partially or wholly divided into two longitudinal bars by a medial fissure, represents the result of a failure of the two bars to unite in the midventral line (p. 153, see also Fig. 130). This is sometimes associated with ectopia cordis (p. 255). The xyphoid process may also be bifurcated or perforated, according to the degree of fusion between the two primary bars

(P- I54)

Suprasternal bones may be present. They represent the ossified episternal cartilages which have failed to unite with the manubrium (p. 154). Morphologically the suprasternal bones possibly represent the omosternum, a bone situated cranially to the manubrium in some of the lower Mammals.

===The Head Skeleton===

The skull is sometimes decidedly asymmetrical. Probably no skull is perfectly symmetrical. The condition which most frequently accompanies the irregular forms of skulls is premature synosteosis or premature closure of certain sutures. The cranial bones increase in size principally at their margins, and when a suture is prematurely closed the growth of the skull in a direction at right angles to the line of suture is interfered with. Consequently compensatory growth must take place in other directions. Thus if the sagittal suture is prematurely closed and transverse growth prevented, increase occurs in the vertical and longitudinal directions. This results in the vault of the skull becoming heightened and elongated, like an inverted skiff, a condition known as scaphocephaly. After premature closure of the coronal suture, growth takes place principally upward and gives rise to acrocephaly. In case only one-half the coronal or lambdoidal suture is closed, the growth is oblique and results in plagiocephaly.

A suture the metopic suture sometimes exists in the medial line between the two halves of the frontal bone, a condition known as metopism. This is due to an imperfect union of the two plates of bone produced by the two centers of ossification in the frontal region (p. 162).

Certain malformations in the face region and in the roof of the mouth are brought about by defective fusion or complete absence of fusion between certain structures during the earlier embryonic stages. The maxillary process of the first branchial arch sometimes fails to unite with the middle nasal process (Kolliker's view, p. 164; see also Fig. 98). The result is a fissure in the upper lip, a condition known as hare lip, which may or may not be accompanied by a cleft in the alveolar process of the maxilla, extending as far as the incisive (palatine) foramen. The same result may be produced by a defective fusion between the middle nasal process and the lateral nasal process (Albrecht's view, p. 164; see also Fig. 98). Hare lip may be either unilateral (single) or bilateral (double), accordingly as defective fusion occurs on one or both sides, but never medial.

Occasionally the palatine process of the maxillary process fails to meet not only its fellow of the opposite side, but also the vomer (see Fig. 141) . The result is a cleft in the hard palate, a condition known as cleft palate. This malformation may be unilateral or bilateral, but not medial. Sometimes the cleft extends into the soft palate where it occupies, however, a medial position.

Cleft palate may accompany hare lip, or either may exist without the other, depending upon the degree of fusion between the processes mentioned above. In bilateral hare lip, with or without cleft palate, the incisive (intermaxillary) bone is sometimes pushed forward by the vomer and projects beyond the surface of the face, a condition known as "wolf's snout."

The causes underlying the origin of harelip and cleft palate are obscure.

===The Appendicular Skeleton===

====The Humerus====

On the medial side of the humerus, just proximal to the medial condyle, there is not infrequently a small hook-like process directed distally the supracondyloid process. This process represents a portion of bone which in some of the lower mammals (cat, for example) joins the internal condyle and completes the supracondyloid foramen, through which the median nerve and brachial artery pass.

====The Carpal Bones====

Occasionally an os centrale is present in addition to the usual carpal bones. It is situated on the dorsal side of the wrist between the navicular, capitate and small multangulum. In the embryo an additional piece of cartilage is of constant occurrence in this location, but usually disappears during later development; in cases where it persists, ossification takes place to form the os centrale. In some of the apes the os centrale is of constant occurrence in the adult.

====The Femur====

The gluteal tuberosity (ridge) sometimes projects like a comb, forming the so-called third trochanter, a structure homologous with the third trochanter in the horse and some other mammals.

====The Tarsal Bones====

Cases have been recorded in which the total number of tarsal bones was reduced, owing to congenital synosteosis (fusion) of the calcaneus (os calcis) and scaphoid (navicular), of the talus (astragalus) and calcaneus, or of the talus and scaphoid. Occasionally an additional bone the trigonum is present at the back of the talus. In the embryo, the talus ossifies from two centers which normally fuse at an early stage into a single center. The trigonum probably represents a bone produced by one of the centers which has remained separate.

====Polydactyly====

This anomaly consists of an increase in the number of fingers or toes, or both. Any degree of variation may exist from a supernumerary finger or toe to a double complement of fingers or toes. The causes underlying the origin of such anomalies are not clear. Some assign the supernumerary digits to the category of pathological growths or neoplasms, linking them with partial duplicate formations. Others explain the extra digits on the ground of atavism or reversion to an ancestral type. The latter explanation assumes an ancestral type with more than five digits. But neither zoology nor paleontology has found any vertebrate form, above the Fishes, which normally possesses more than five digits on each extremity. Consequently one must refer to the Fishes for some ancestral type to explain the existence of more than five digits. Going back so far in phylogenetic history, no certainty whatever can be attached to the origin of supernumerary digits, for it is not even known from what fins the extremities of the higher forms are derived. Still another view regarding the origin of supernumerary digits is that they are due to certain external influences among which the most important is the mechanical impression of amniotic folds or bands. This, however, could not be the sole cause of polydactylism, since such malformations are common in amphibian embryos where no amnion is present.

:'''Next:''' [[Book_-_Text-Book_of_Embryology_10|Vascular]]

==References for Further Study==

ADOLPHI, H. : Ueber die Variationen des Brustkorbes und der Wirbelsaule des Menschen. Morph. Jahrbuch, Bd. XXIII, 1905.

BADE, P. : Die Entwickelung des menschlichen Skeletts bis zur Geburt. Arch. f. mik. Anat., Bd. LV, 1900.

AREY, LESLIE B.: The Origin, Growth and Fate of Osteoclasts and their Relation to Bone Resorption. American Jour, of Anat., Vol. XXVI, No. 3, 1920.

BARDEEN, C. R.: Numerical Vertebral Variations in the Human Adult and Embryo. Anat. Anz., Bd. XXV, 1904.

BARDEEN, C. R.: Studies of the Development of the Human Skeleton. American Jour, of Anat., Vol. IV, 1905.

BARDEEN, C. R.: The Development of the Thoracic Vertebrae in Man. American Jour, of Anat., Vol. IV, 1905.

BARTELS, M.: Ueber Menschenschwanze. Arch. f. Anthropol., Bd. XII.

BELL, E. T.: II. On the Histogenesis of the Adipose Tissue of the Ox. American Jour. of. Anat., Vol. IX, 1909.

BOLL, F.: Die Entwickelung des fibrillaren Bindegewebes. Arch. /. mik. Anat., Bd. VIII, 1872.

BOLK, L. : Beziehungen zwischen Skelett, Muskulatur und Nerven der Extremitaten, etc. Morph. Jahrbuch, Bd. XXI, 1894.

BONNET, R.rLehrbuch der Entwickelungsgeschichte. Berlin, 1907.

BRAUS, H.: Die Entwickelung der Form der Extremitaten und des Extremitatenskeletts. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1904.

BROWN, ALFRED J.: The Development of the Vertebral Column in the Domestic Cat. Anat. Record, Vol. X, No. 3, 1916.

CAREY, EBEN J.: Studies in the Dynamics of Histogenesis. American Jour, of Anat., Vol. XXIX, No. i, 1921.

FAWCETT E.: On the Early Stages in the Ossification of the Pterygoid Plates of the Sphenoid Bone of Man. Anat. Anz., Bd. XXVI, 1905.

FAWCETT, E.: Ossification of the Lower Jaw in Man. Jour. Amer. Med. Assoc., Bd. XLV, 1905.

FAWCETT, E.: On the Development, Ossification and Growth of the Palate Bone. Jour, of Anat. and Physiol., Bd. XL, 1906.

FERGUSON, JEREMIAH S.: The Behavior and Relations of Living Connective Tissue Cells in the Fins of Fish Embryos with Special Reference, to the Histogenesis of the Collaginous or White Fibers. American Jour, of Anat., Vol. XIII, No. 2, 1912.

FLEMMING, W.: Die Histogenese der Stiitzsubstanzen der Bindesubstanzgruppe. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1901.

FLEMMING, W.: Morphologic der Zelle. Ergebnisse der Anat. u. Entwick., Bd. VII, 1897.

GAUPP, E.: Alte Probleme und neuere Arbeiten iiber den Wirbeltierschadel. Ergebnisse der Anat. u. Entwick., Bd. X, 1901.

GAUPP, E.: Die Entwickelung des Kopfskeletts. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1905.

GEGENBAUR, C.: Die Metamerie des Kopfes und die Wirbeltheorie des Kopfskeletts. Morph. Jahrbuch, Bd. XIII, 1887.

GR^FENBERG, E.: Die Entwickelung der Knochen, Muskeln und Nerven der Hand und der fur die Bewegungen der Hand bestimmten Muskeln des Unterarms. Anat. Hefte, Heft XC, 1905.

HAGEN, W. : Die Bildung des Knorpelskeletts beim menschlichen Embryonen. Arch. f. Anat. u. PhysioL, Anal. Abth., 1900.

HANSEN, C.: Ueber die Genese einiger Bindegewebsgrundsubstanzen. Anat. Anz., Ed. XVI, 1899.

HANSON, FRANK BLAIR: The Ontogeny and Phylogeny of the Sternum. American Jour, of Anat., Vol. XXVI, No. i, 1919.

HASSELWANDER, A.: Untersuchungen iiber die Ossification des menschlichen Fussskeletts. Zeitschr. f. Morphol. u. AnthropoL, Bd. V, 1903.

HERTWIG, O.:Lehrbuch der Entwickelungsgeschichte des Menschen u. der Wirbeltiere. Jena, 1906.

HUNTINGTON, G. S.: Modern Problems of Evolution, Variation, and Inheritance in the Anatomical Part of the Medical Curriculum. Anat. Record, Vol. XIV, No. 6, 1918.

JAKOBY, M.: Beitrag zur Kenntniss des menschlichen Primordialcraniums. Arch. f. mik. Anat., Ed. XLIV, 1894.

JORDAN, H. E.: A Contribution to the Problems Concerning the Origin, Genetic Relationship and Function of the Giant-cells of Hemopoietic and Osteolytic Foci. American Jour, of Anat., Vol. XXIV, No. 2, 1918.

KEIBEL, F. : Ueber den Schwanz des menschlichen Embryo. Arch.f. Anat. u. PhysioL, Anat. Abth., 1891.

KEIBEL, F.: Zur Entwickelungsgeschichte der Chorda bei Saugern. Arch.f. Anat. u. PhysioL, Anat. Abth., 1889.

{{Ref-KeibelMall1910}} [[Book - Manual of Human Embryology 11|Chap. XI.]]

KJELLBERG, K.: Beitrage zur Entwickelungsgeschichte des Kiefergelenks. Morph. Jahrbuch, Bd. XXXII, 1904.

KOCH, JOHN C.: The Laws of Bone Architecture. American Jour, of Anat., Vol. XXI, No. 2, 1917.

KOLLMANN, J.: Entwickelung der Chorda dorsalis bei dem Menschen. Anat. Anz., Bd. V, 1890.

KOLLMANN, J.: Lehrbuch der Entwickelungsgeschichte des Menschen. Jena, 1898.

KOLLMANN, J.: Handatlas der Entwickelungsgeschichte des Menschen. Jena, 1907.

{{Ref-Mall1902ct}}

{{Ref-Mall1906bone}}

{{Ref-McMurrich1914}}

{{Ref-Paterson1900}}

PETERSEN, H.: Untersuchungen zur Entwickelung des menschlichen Beckens. Arch, f. Anat. u. PhysioL, Anat. Abth., 1893.

RABL, C.: Theorie des Mesoderms. Morph. Jahrbuch, Bd. XV, 1889.

ROSENBERG, E.: Ueber die Entwickelung der Wirbelsaule und das Centrale carpi des Menschen. Morph. Jahrbuch, Bd. I, 1876.

SCHAUINSLAND, H.: Die Entwickelung der Wirbelsaule nebst Rippen und Brustbein. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. Ill, Teil II, 1905.

SPULER, A.: Beitrage zur Histologie und Histogenese der Binde- und Stutzsubstanz. Anat. Hefte, Heft XXI, 1896.

THILENIUS, G.: Untersuchungen iiber die morphologische Bedeutung accessorischer Elemente am menschlichen Carpus (und Tarsus). Morph. Arbeiten, Bd. V, 1896.

{{Ref-Thomson1899}}

TORNIER, G.: Das Entstehen der Gelenkformen. Arch. f. Entw.-Mechanik, Bd. I, 1895.

WALDEYER, W.: Kittsubstanz und Grundsubstanz, Epithel und.Endothel. Arch. f. mik. Anat., Bd. LVII, 1900.

WEISS, A.: Die Entwickelung der Wirbelsaule der weissen Ratte, besonders der vordersten Halswirbel. Zeitschr. f. wissensch. Zool., Bd. LXIX, 1901.

ZIMMERMANN, K.: Ueber Kopfhohlenrudimente beim Menschen. Arch./, mik. Anat., Bd. LIII, 1899.

{{Bailey_1921_Footer}}

Paper - Development and vascularization of the testis (1906)

2024-01-25T00:12:56Z

Z8600021:

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{| class="wikitable mw-collapsible mw-collapsed"
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| [[file:Mark_Hill.jpg|90px|left]] This historic 1906 paper by Hill describes development off the testis.
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See also by this author: {{Ref-Flint1906}}
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'''Modern Notes:''' {{Testis}} | {{pig}} | {{artery}}
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{{Pig links}}
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{{Male links}}
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{{Genital Links}}
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{{Historic Disclaimer}}
=On the Gross Development and Vascularization of the Testis=

By

Eben C. Hill.

From the Anatomical Laboratory of the Johns Hopkins University.

With 14 Text Figures.

==Introduction==
While studying the development of the blood supply to the Wolffian bodies, my attention was called to the interesting manner in which the {{testis}} becomes vaseularized. Accordingly, following a suggestion from Professor Mall, I injected a series of embryo pigs and later the testes of adult {{pig}}s, hoping that a thorough knowledge of the blood supply of this gland in the {{pig}} would facilitate the study ofithe vascularization of the human {{testis}}. In this I was mistaken, for the information gained from corrosions, injections, and cleared preparations of the testis of the pig was of comparatively little value in unrayelling the interesting though complex blood supply of the sex gland in man. Hence, in this paper I shall conﬁne myself to the gross development and blood supply of the pig testis, and will later publish the results of studies of the human gland.

The blood supply to the human male sex gland, to use a rather unique term for anatomical literature, is rational. It is much as one might expect, knowing the lobular arrangement. The vascularity of the pig testis, on the other hand, is quite unusual and it is difficult to imagine what causes could have produced such an unique arrangement.

==Literature==
The literature on the vascularization of the testis is surprisingly meagre, considering the enormous bibliography which has accumulated on spermatogenesis and the descent of the testis. Kölliker, Mihalkovics, Bardeleben, Pﬂiiger, Waldeyer, and many others have added much to our knowledge of these two subjects, but as yet comparatively little has been accomplished toward unravelling the blood supply. Kölliker traced the spermatic artery as it branched to supply the cord, epididymis and testis. He states that the blood vessels follow the trabeculae of the sex gland after penetrating the albuginea near the epididymis. He also describes a capillary network around the tubules. Astley Cooper has investigated a capillary plexus covering the internal surface of the tunica albuginea which he has termed the tunica vasculosa. But beyond this there is little to be found in the literature of the subject.

The vascular units which Professor [[Embryology History - Franklin Mall|Mall]] and his students have shown to be present in several organs and which they assume are to be found in all organs, have not as yet been demonstrated in the testis, and, indeed, aside from what has been cited above, nothing is known of the arterial or venous supply of the male sex gland. Dr. [[Embryology History - Franklin Mall|Mall]] has frequently demonstrated the presence of certain units of the blood system which may or may not be peculiar to the organ in which they are found and which correspond to the histological or structural unit of the organ. These units are composed of small branching blood vessels which pass into capillaries and the blood from which is collected into small veins. This theory of vascular units may be brieﬂy summed up in the statement “similar blood supply to similar histological units.” These vascular units have been proved to be present in the {{liver}}, {{spleen}}, and {{adrenal}},“ but in the testis of the pig I can make out no deﬁnite units. In man, however, the lobular arrangement is less complex, and results have been so encouraging that probably these units will be shortly discovered.

1 Mall, F. P.: A Study of the Structural Unit of the Liver. Am. Jour. Anat., Vol. V, No. 3.

2 Mall, F. P.: The Structure of the Spleen. Johns Hop. Hosp. Rep.

3 Flint, J. M.: The Blood Vessels, Angiogenesis, Organogenesis, Reticulum and Histology of the Adrenal. Johns Hop. Hosp. Rept., Vol. IX.

==Methods and Material==
The necessity of clearly understanding the development of the circulatory system in the earliest embryonic stages in order to properly interpret the course of the blood stream in the adult organs has been frequently emphasized. Accordingly, in attempting this research frequent use has been made of embryonic material. Embryo pigs, many of which were alive when delivered at the laboratory, were injected and cleared, and, after tracing the development of the circulation in these stages, the investigations were completed with adult material. For adult human testes I am indebted to Professor MacCallum of the pathological laboratory. To Professor Brodel I also wish to express my appreciation for several valuable specimens of human embryonic testes as well as for his helpful suggestions in making the illustrations. For the courtesies of their laboratory I wish to thank Professors Wiedersheim and [[Embryology History - Franz Keibel|Keibel]] of Freiburg.

All injections of embryonic material were made with Indiaink. In the youngest stages, measuring from eighteen mm. to seventy-five mm., a hypodermic syringe with a fine needle forced the injection fluid into one of the umbilical arteries, and by watching the hind legs and head excellent results devoid of extravasation could be obtained. This mode of injection is particularly desirable in these early stages for it is not necessary to rupture the surrounding membranes and thus the embryo is protected against injury in handling. In larger embryos injections were made directly into the aorta by puncturing the left ventricle. Considerable pressure was necessary to overcome in the earlier stages the resistance resulting from the small lumen of the spermatic artery, and in larger embryos because of its remarkable tortuosity. On account of this pressure the Wolﬂian bodies were frequently doubly injected, the injection mass passing through the sinusoids and capillaries described by [[Embryology History - Charles Minot|Minot]] into the veins. In nearly all such specimens the testes showed only an arterial and capillary injection. In this connection it may not be amiss to emphasize the advantages of India ink in all cases where a ﬂuid is desired which will flow wherever the blood stream goes, and yet is resistant to the ordinary laboratory acids and to concentrated solutions of potassium or sodium hydroxide.

After the injection of each embryo, the right {{testis}} together with the {{Wolffian body}}, kidney, and aorta were removed and placed in ninety-five per cent alcohol for clearing, while the left sex gland with its appendages was prepared for sectioning. Of the various clearing procedures, the modified Schultze method‘ was found to give the most satisfactory results. This method is as follows:

After the injections have been completed all unnecessary tissues surrounding the parts under investigation are removed and the specimens are placed in ninety—five per cent alcohol. The removal of adventitial tissue is most important, though entire embryos may be successfully cleared if openings are made into the abdomen, thorax and cranium. In embryos ranging above one hundred and fifty mm. in size, it is still better to make sagittal sections of the hardened specimens and to clear in halves. The alcohol should be frequently changed and large quantities should be used. In order to obtain transparent specimens the tissues must be completely shrivelled before removal from the alcohol, and the length of time necessary to accomplish this result depends, of course, upon the size of the objects. For very small specimens at least three days should be allowed, while for large objects the time should not be less than a week. Experiments with absolute alcohol in place of ninety—five per cent alcohol gave no better results, and its use is an unnecessary expense. The coagulation of the proteid occurs almost as quickly in one percentage as in the other.

‘Hill, E. C.: On the Schultze Clearing Method as Used in the Anatomical Laboratory of the Johns Hopkins University. Johns Hop. Hosp. Bull., Vol.

After the specimens have been suﬂiciently shriveled they should be placed in one per cent potassium hydroxide. When a higher percentage is resorted to, so rapid is the action that the safety of the specimen is endangered, and it was the use of the strong solutions recommended by Schultze which caused the loss of much valuable material. In this weaker solution the tissues become transparent in from four to fortyeight hours, depending upon the size of the specimens. After sufficient clearing in this medium they should be transferred to twenty per cent glycerine, in which clearing continues and a certain amount of hardening occurs, rendering the tissues firm enough to permit of dissection. Should the specimens be as tra.nsparent as is desired, they may be removed from time to time to higher percentages of glycerine till at last they are permanently stored in pure glycerine. A certain amount of shrinkage is noted in some organs after an immersion in this ﬂuid for a year or more, but when the specimens are studied immediately after being cleared the measurements are practically the same as in the fresh tissue. The shrinkage which some observers have noticed is probably due to transferring the specimens too rapidly to higher percentages of glycerine. After some experimenting we have found that embryos hardened in formalin can be cleared also, though in this case 10 per cent potassium hydroxide is essential and the specimens must remain in this solution for several weeks or months.

Blood pigment in some instances will not be entirely removed by this process alone and in organs, such as the kidney, transparency can sometimes only be obtained by a secondary treatment. After passing through the one per cent potassium hydroxide as outlined above and being placed in twenty per cent glycerine, the specimens containing the objectionable pigment are treated with equal parts of fifty per cent ammonium hydroxide and one per cent potassium hydroxide. In this solution there is comparatively little danger to the specimen on account of the hardening produced by the twenty per cent glycerine. Indeed, in cases where it is deemed advisable for any reason to stop the clearing action, or it is found to be more convenient to continue the process at some future time, the objects may be removed to this twenty per cent glycerine and retained in this medium until a more fitting time when much higher percentages of the caustic solution may be resorted to without danger to the specimens. The specimens may be studied in glycerine or by a method devised by Bardeen may be mounted upon glass slides and placed in any desired position in jars of glycerine. The objects are removed from pure glycerine, wiped and quickly washed. They are then placed in a little _thick gelatin solution and are laid upon a warm glass slide. As soon as the gelatin is hardened the specimens are returned to the pure glycerine without any danger of becoming loosened from the slide. The purity of the glycerine should be assured, as the presence of foreign substances such as water may tend to soften the gelatin.

The clearing reagents advocated by Van Wijhe“ and Lundval1° did not give the same degree of transparency as was gained by following the above method, though in clearing the capsule of the adult testis beautiful specimens were obtained by using absolute alcohol and xylol as outlined by Van Wijhe. In following the distribution of the blood vessels in the capsule, quite satisfactory results were obtained by the very practical and simple method devised by Flint in his work on the adrenal.‘ “After carefully dissecting away all of the paricapsular connective tissue from the injected and hardened gland, it is cut in half, longitudinally, with a sharp razor and the parenchyma is scraped out with a scalpel. The remaining fibrous capsule is then treated exactly like a section and, after dehydration, is cleared and mounted in a cell.”

Although the modified Schultze method is particularly applicable to embryonic tissues, yet sections of the adult testis 3-4 mm. thick, the arteries and veins of which had been injected with India ink were speedily rendered transparent by a clearing treatment similar to that for the less resistant embryonic tissue.

In preparing injections for corrosion specimens of larger embryonic and adult testes, great difficulty was experienced until it was discovered that seven per cent celloidin would ﬂow quite readily through a medium.sized hypodermic needle. Thus in injecting the adult sex gland it was only necessary to find the point at which the spermatic artery reached the gland in order to avoid the difficulty met. with in forcing the injection mass through the many coils of artery which lie in the cord of the pig near its attachment to the {{epididymis}}. The corrosion was accomplished with hydrochloric acid and pepsin, after which the specimens were washed and placed permanently in glycerine. Because of the thick and very resistant albuginea a rapid corrosion was more easily obtained when the fresh gland was placed for an hour in concentrated hydrochloric acid, after which it was treated in the usual way with a ten per cent aquous solution of this acid for twenty-four hours, followed by the ordinary peptic digestion in the thermostat.

5 Van Wijhe, J. W.: A New Method for Demonstrating Cartilaginous Mikroskeletons. Kononklijke Akademie van Wetenschappen Te Amsterdam, 1902.

6 Lundval1, H.: Ueber Demonstration Embryonaler Knorpelskelette. Anat. Anz., pp. 219-223, Band XXV.

==Gross Development of the Testis==

Keibel in his Normentafel for the pig gives the anlages and traces histologically the development of the organs, but gives no measurements of these organs.

===Table Showing in Millimeters the Length of the Bony as Compared to that of the Kidney, Wolffian Body, and Sex Gland of Pig Embryos===

The measurements were made from vertex to breech, and include all of the embryos in each uterus. In case of asymmetric development of these glands in any embryo averages were made of the lengths of both organs.

{{Hill1906 table1}}

‘éiéiilii Kidw ‘l;%‘.§‘§“?" T8’i?;iy".*

[20 1.2 7.3 1.5 21 1.2 7.3 1.5 20 1.1 7.4 1.4 Uterus 1 . . . . . . . . . . . . . . .. 23 L2 7.2 1.5 22 1.3 7.1 1.4 121 1.0 7.3 1.5 20 1.2 7.2 1.5 28 2.5 9.0 1.7 28 2.6 8.0 1.6 Uterus 2 . . . . . . . . . . . . . . . .. 29 2'5 85 1'7 27 2.4 9.2 1.7 28 3.0 7.0 1.7 [29 2.7 8.7 1.4

31 3.9 9.2 2

33 4.0 9.1 2

Uterus 3 . . . . . . . . . . . . . .. 33 3.8 9.0 2 35 3.7 9.1 1.9

33 4.1 8.9 2 40 5.8 10.0 3.2 [41 5.9 10.0 3.2 40 5.9 11.0 3.1 r 42 5.9 11.0 3.1 Uterus 4 . . . . . . . . . . . . . . . .. 41 5-8 10-0 3-1 43 6.0 11.2 3.2 1 41 5.8 10.5 3.2

42 5.9 11.3 3.2
[39 5.6 11.5 3.1 41 5.9 10.0 3.0 Eben 0. Hill 445

l§‘3§.§‘$l§T Kidnw ‘V3333? T8sv‘§§y".’ f 49 7.3 11.0 3.5 49 7.8 10.5 3.2 Uterus 5 . . . . . . . . . . . . . . . 49 (,-_g 12_() 3_2 ‘ 48 8.0 10.0 3.5 ‘ 50 7.8 10.5 3.5 68 11.7 11.8 4.0 67 11.5 12.0 4.0 68 11.5 11.4 4.0 Uterus 6 . . . . . . . . . .‘ . . . . .< 69 11.4 11.5 3.7 67 11.2 11.2 3.8 68 11.5 11.7 4.0 l 67 11.6 11.4 3.8 85.0 14.5 10.2 4.6 Uterus 7 . . . . . . . . . . . . ..g 84.6. 14.7 10.0 4.4 L 84.4 14.3 10.5 4.6 , 94.3 15.7 9.2 4.8 94.5 15.9 9.0 5.0 94.3 15.6 9.0 5.1 Uterus 8 . . . . . . . . . . . . . .. 94.0 15.5 as 5.0 94.4 15.7 8.7 5.0 94.3 15.6 8.9 4.7 120.0 18.0 7.0 5.0 121.0 19.0 7.2 5.3 Uterus :1 . . . . . . . . . . . . . .. 120_() 19_() 7_5 5,0 120.5 18.5 7.0 5.5 120.8 18.2 7.0 5.2 Epididymis Testis 15.5 23.5 Uterus 10 . . . . . . . . . . . . . . 150 223 7'0’ 5‘8 15.8 23.0 7.0 5.6 15.0 24.0 7.3 5.5 f210.0 31.0 8.2 6.0 Uterus 11 . . . . . . . . . . . .i211.o 30.0 8.0 6.3 210.5 35.0 6.5

A study of the foregoing table shows little variation in the body lengths of the embryos in each uterus. In the cases of abnormal development of the kidney. it is interesting to note the corresponding size of the Wolfﬁan body. That a. balancing of function exists between these two glands is suggested by the fact that an embryo having an unusually large kidney development has correspondingly small Wolfﬁan bodies.

The measurements were made regardless of whether the sex gland was male or female, although in embryos beyond thirty-three mm. in length this sex distinction is observable.

In the adult pig testis the measurements vary considerably. The average might be placed at sixty-five mm. long, forty—two mm. deep and thirty-seven mm. wide with an average weight of sixty-eight grammes. These results are of interest when compared with those obtained by Krause ' for the human adult sex gland. His averages were thirty—seven mm. long, twenty-eight mm. deep and twenty-four mm. wide, with the weight falling fifteen and twenty-four and a half grammes.

==Development of the Blood Supply==
Concerning the embryonic development of the testis much has been written and it seems useless to enter into a discussion of the histogenesis and descent of the gland. Among the more recent studies of these subjects the article by Allen 5 on the ovary and testis of mammals will be found to contain a comprehensive survey of the literature and in this monograph the author outlines minutely the growth of the testis of the pig. He, however, makes no mention of the blood supply.

The first macroscopic indication of the vascularization of the testis is found when the embryo pig is thirty-three mm. in length. At this time the sex gland is situated relatively lower on the mesial surface of the Wolﬂian body, which may to some extent account for the low level at which the spermatic artery arises from the aorta. Concerning the origin of this artery there has been some discussion as to whether at times it may arise from one of the lower Wolfﬁan arteries. Of the seventy—five or more specimens ranging in length from twenty—ﬁve mm. to two hundred and twenty mm., only one was found in which the artery arose otherwise than from the aorta. In this exception the spermatic artery came from the most caudal Wolfﬁan artery close to its origin from the aorta.

In the thirty—three mm stage seen in Fig. 1 no convolution is apparent in the spermatic artery which courses ventral to the Wolfﬁan arteries. In this figure, as well as in the two following ones, it was found advisable to lay back the Wolffian body from its normal position in order to more clearly demonstrate the vascular supply to these glands. The renal artery which penetrates the kidney when the embryo is twentyeight mm. in length is quite prominent and a few glomeruli are seen in the cleared specimen. As in the human embryo, rotation of the kidney occurs before the entrance of the blood supply, as has been shown by Pohlman.° Hy study of sections of pig embryos places the rotation of the kidneys in this genus between twelve and fifteen mm." In the human embryo Pohlnian has shown that the vascularization occurs between twenty-five and thirty 1nm., while in the pig I find this vascularization of the kidney at twenty-eight mm. The adrenal, which is depicted in the illustration merely as a land mark, is densely injected but no attempt has been made to show its blood supply and in this and the following series it appears as if uninjected.

’Krause, W.: Zum Spiralsaum der Samenfaden. Biol. Cent., 1881.

‘Allen, B. M.: Embryonic Development of Ovary and Testis of Mammals. Am. Jour. Anat., Vol. III, No. 2.

'''FIG. 1.''' Cleared specimen of the testis, kidney, and Wolffian body of an embryo pig 33 mm. in length, showing the ﬂrst appearance of vascular supply to the testis. X 6. W. B., right Wolﬁian body, 8.6 mm. in length; Ad., adrenal; A., aorta; T., testis measuring 2 mm. in length; S. A., spermatic artery; K., kidney, 3.8 mm. in length; W. D., Wolﬁian and Miillerian ducts; U. A., umbilical artery.

'''FIG. 2.''' Cleared specimen of the right testis, kidney, and Wolﬂlan body of an embryo pig 48 mm. in length, showing the commencement of convolutions in the spermatic artery and the increased blood supply. X 6. K., right kidney, 6.5 mm. in length; Ad., adrenal; W. B., Wolﬂian body, 10 mm. in length; A., dorsal aorta; R. A., renal artery; T., testis, 3.5 mm. in length; S. A., spermatic artery; W. D., Wolﬂian and Mullerian ducts; U. A., umbilical artery.

°Pohlman, A. G.: Concerning the Embryology of Kidney Anomalies. Am. Medicine, Vol. VII, No. 25.

“Hill, E. C.: On the First Appearance of the Renal Artery and the Relative Development of the Kidneys and Wolﬂian Bodies in Pig Embryos. Johns Hop. Hosp. bull, Vol. XVI.

The Wolffian body at this time receives from ten to twelve arteries which richly supply the gland. In many cases a pressure sufficient to insure a perfect injection of the sex gland resulted in a double injection of the Wolﬁian bodies and kidneys. In the Wolffian bodies the sinusoids described by Minot are beautifully demonstrated in sections of ﬁve to twenty ,u. in thickness.

Allen“ has noted a great activity in the formation of the primitive sex cells of the seminiferous tubules and of the cords of Pﬂiiger and rete cords about this time, and it is possible that this increased activity is due to the presence of the blood stream. Allen has also shown a sex differentiation in the embryo of twenty-ﬁve mm. which he bases upon histological observations. Through a study of the vascularization, this sex distinction is clearly marked at 33 mm., for as Clark “ has shown “upon the peculiarities of each circulation the differential signs of sex are based, a visible dorsal vessel always indicating a male; an alabasterlike non—vascular white cortex a female embryo.” This distinction, however, is true more particularly of the pig and is of doubtful value in differentiating the human sex glands.

In the embryo of forty-eight mm. (Fig. 2) the spermatic artery is found to have encircled a greater portion of the capsule of the sex gland and a certain amount of convolution is evident in the artery just before it reaches the testis. These convolutions are more marked as descent of the gland occurs, and this may be due in part to an attempt to shorten the artery. Thoma, however, in his studies of the development of the vascular system gives no such method of shortening. Nor, indeed, could this explanation account for the subsequent convolutions which occur after the testis has begun its descent from below the lower pole of the kidney. In this latter case there is a most decided lengthening accompanied by more marked convolutions. A similar condition is not found in the human embryo, nor to such marked extent in the mouse of this stage.

Microscopic sections demonstrate the capsular artery branching with a certain deﬁnite regularity on the surface of the gland, and sending minute arteries into the substance of the testis. A thick section shows these vessels entering perpendicularly and giving off branches which form capillary anastomoses around the medullary cords.

11 {{Ref-Clark1899b}}

When the embryo has attained a length of eighty-seven mm. (Fig. 3) several of the anterior Wolﬁian arteries have disappeared and there is a decided atrophy of the organ itself. The capsular artery, a name which may be applied to that portion. of the spermatic artery which supplies the albug-inea and glandular substance proper, is seen to give off many small branches, some of which are growing over the surface of the organ While others are penetrating deeply into the substance of the gland. In several specimens of this and later stages the capsular artery is found to divide into two main branches immediately after reaching the gland.

FIG. 3. Cleared specimen of the right testis, Wolffian body and kidney of an embryo pig 87 mm. long, showing descent of testis and atrophy of the anterior Wolﬁian arteries. X 6. A., dorsal aorta; K., right kidney, 14.7 mm. in length; S. A., spermatic artery; W. B., Wolﬁian body, 9.5 mm. in length; W. D., Woltnan and Miillerian ducts; I. A., iliac artery; U. A., umbilical artery.

The attachment of the sex gland to the Wolffian body is quite firm at this time.

Fig. 4 (128 mm.) shows a marked increase in the diameter of the spermatic artery, and also greater tortuosity of this vessel. The sex gland is seen to have assumed a different position in relation to the remains of the Wolfﬁan body. This semi-rotation is, perhaps, caused by the convexity of the lower pole of the kidney as the testis in descending assumes a more dorsal position. Frequent anastomoses are noticed upon the capsule, and a small twig at the anterior end of the gland anastomoses with the branch from the spermatic artery which supplies the future globus major. Since the blood supply to the epididymis is not shown in any of the drawings, this branch has not been indicated.

FIG. 4. Abdominal cavity of an embryo pig 128 mm. in length, cleared specimen of a right testis taken from an embryo or the same size and substituted in order to show the relative positions of the organs. X 6. This ﬁgure also shows the great tortuosity of the spermatic artery and by a comparison with Fig. 3, illustrates the occurrence of semi-rotation; K., right kidney, 18.2 mm. in length; S. A., spermatic artery; A., dorsal aorta; T., testis, 5.3 mm. in length; U., ureter; R., rectum; W. M., Wolfﬁan and Miillerian ducts; U. A., umbilical artery; B., bladder.

The entrance of the testis into the internal ring occurs between the sizes of one hundred and ninety and two hundred and twenty mm. The left gland usually enters the internal ring first, and in Fig. 5 (210 mm.) only the globus major of the epididymis is apparent. The capsular artery has sent out branches which nearly encircle the sex gland, and these encircling arteries have almost completed their growth around the testis. A certain limited portion lying close to the epididymis is never encroached upon by these branching arteries. From the spermatic artery before it reaches the testis several branches arise, from ﬁve to seven in number, which supply the cord and globus major and minor. Frequent anastomoses are seen on the albiginea, and small branches which encircle the anterior portion of the gland form anastomoses with arteries supplying the globus major: thus allowing blood to penetrate the testis should the posterior portion of the capsular artery become occluded. The Miillerian ducts are atrophied and appear as ridges upon the Wolﬂian (lucts which have increased in diameter of lumen and in thickness of wall.

FIG. 5. A transparent specimen of the right testis of an embryo pig 210 mm. in length. The relation of this gland to the other organs was obtained from a fresh tissue specimen of an embryo of the same size. X 6. In this ﬂgure the left testis is seen to have nearly passed the internal ring, while the right sex gland has just entered. K., right kidney; A., dorsal aorta; E., epididymis; U., ureter; R., rectum; M. D., W. D., Miillerian and Woltﬁan ducts; U. A., umbilical artery; B., bladder; T., testis, 6 mm. in length.

FIG. 6. The macroscopic appearance of an arterially injected adult pig testis, showing peculiar tortuous arrangement of the branches of the capsular artery in the tunica albuginea. >< %.

FIG. 7. A macroscopic drawing of the left injected testis of a human foetus Of Seven months. X 6%.. The dotted lines show the position of the cord and epididymis.

The relations of the superﬁcial blood supply in the testes of the adult pig and mouse and of the human foetus of seven months together with the comparative positions of the spermatic cords is shown in ﬁgures 6, 7 and 8. In the illustration showing the testis of the human embryo, the arteries are found to encircle the gland, being distributed to the under surface of the albuginea. Frequent anastomoses are formed similar in many ways to the adult superﬁcial supply in the mouse, but differing materially from the arterial distribution in the capsule of the pig testis. The relative position of the spermatic cord to the epididymis is quite noticeable and may be due to the differences in the manner of suspension of the gland with reference to the horizontal plane of the body. The comparative size of the globus major and minor is also markedly different. In the pig the globus minor is at times as large and not infrequently larger than the globus major. Few convolutions are apparent in the human embryonic gland, while in the testis of the embryo mouse as well as in the adult a certain amount of tortuosity is met with, not, however, anywhere near as marked as in the pig.

==Arterial and Venous Supply of the Adult Testis of the Pig==

The capsular artery gives off on the internal surface of the tunica albuginea at rather regular intervals tortuous rib—like branches which nearly encircle the gland. These branches

Fig. 8. The capsular distribution of the spermatic penetrate the substance of the gland follow artery in the testis of the adult mouse. X 3%.

ing the septa. and entering perpendicularly This illustration, Except in a very few instances no branches are
together with till they reach the mediastinum.

Figs 6 and 7, Show the relative positions of the cords given off from these perpendicular arteries and the albugineal blood supply.

until after the abrupt retro-flexion occurs near the center of the gland. After this sudden backward bending, many branches are given off which, coursing toward the surface of the testis, send off smaller twigs which in turn divide into capillaries around the seminiferous tubules and supply the stroma of the gland. The veins collect from these capillaries and merging into larger vessels follow the septa directly toward the albuginea where passing under the arteries on the internal surface of the tunica albuginea, they encircle the gland and passing toward the epididymis form the pampiniform plexus. These veins are about twice the size of the branches from the capsular artery and show an intricate anastomosis. Upon cross section of a doubly injected gland some seven or eight perpendicular descending arteries will appear and perhaps eight to twelve collecting veins.

The extreme vascularity of the gland is shown in Fig. 10, which is an arterial and capillary injection made with India ink and cleared by the modiﬁed Schultze method. The anastomoses around the tubules are so profuse that they give the section an appearance of ancient mail armor.

FIG. 9. A semi-diagrammatic representation of the circulation in the left testis of the adult pig. X 1%. E., globus minor of the epididymis. The arrows indicate the course of the blood stream. The arteries and capillaries are red; the veins, blue.

A microscopic section of the injected testis, stained and cleared by the Van Wijhe method shows beautifully under low power the manner in which the capillaries encircle the tubules. In Fig. 11 are seen the capillaries, some larger arteries and a portion of one of the large ascending perpendicular branches given oﬁ shortly after the looping of the descending perpendicular branch near the center of the gland. The tubules of the pig testis show this capillary arrangement somewhat better than do those of the human adult male sex gland, for as was shown by Krause the tubules of the human testis measure two—tenths of a mm. in diameter, while I ﬁnd that the tubules of the sex gland of the pig are between two-tenths and three-tenths mm. in diameter.

FIG. 10. A thick cleared cross section of the testis of an adult pig. X 1%. This shows the arteries and rich capillary network. (7. A., tortuous branch of the capsular artery which can be seen penetrating to the mediastinum of the gland and there forming the typical loop before giving off any branches. A.., spermatic artery in its course along the epididymis. The section was taken about midway between the globus major and minor, and as most of the epididymis was dissected away an atypically shaped piece of tissue remains.

FIG. 11. A microscopic section of an injected testis of an adult pig cut 50/1, showing the capillary supply around the tubules. x about 40.

FIG. 12. Corrosion specimen of the testis of an adult pig, showing the typical arterial loops. X 2.

The various types of arterial loops comprising the descending perpendicular artery and its ascending branches are shown in Fig. 12. These loops were taken from corrosion specimens of the adult testis of the pig. In the ﬁgure they are arranged in order of frequency, the last having a recurrent branch before the abrupt looping, being very rare. No similar arrangement was found from studies of corrosions of the human gland.

What the causes are which produce this peculiar arrangement it is difﬁcult to say. In the first ﬁve ﬁgures representing early embryonic stages the arteries were found to penetrate the gland perpendicularly but to give off branches as they descended.

This is depicted in Fig. 13.

No typical looping occurs till after the gland is in the scrotum and the subsequent rapid development has begun. This leads one to surmise that the sudden growth, which changes the embryonic organ from one measuring, 6 mm. X 3 mm. X 2.8 mm. unto the adult gland measuring 65 mm. X42 mm. X 37 mm., is accountable for this peculiarity of blood supply. This seems to be especially plausible when the relative positions of the mediastina of the human and pig testes are compared. Probably the development is so rapid that the arteries which enter perpendicularly
in order to penetrate to the center are of necessity twisted back upon themselves in supplying the rapidly growing tubules whose development must be toward the circumference. The mediastinum is in .the center of the gland and hence the tubules in developing radiate from this as a center.

FIG. 13.

Fig. 13a shows the left testis of an embryo pig 48 mm. in length. Then entrance of the perpendicular branches of the capsular artery is shown. X 9.

Fig. 13b illustrates the depth of penetration of these same arteries in the testis of an embryo pig of 87 mm. X 9.

Fig. 13c shows the entrance and distribution of these same arteries in the left testis of an embryo pig of 210 mm. X 9.

==The Blood Supply to the Albuginea==

The vascular supply to the albuginea is shown in Fig. 14. Above the large capsular arterial branches and veins which supply the glandular tissue of the testis and which lie on the inner side of the tunica albuginea, is found a delicate plexus of small arteries, capillaries and veins grouped in irregular polyhedral forms, mostly of four or ﬁve sides, having an area of from nine to sixteen square millimeters. The arteries enclosing these polyhedrons spring from the encircling capsular branches and lie external to them. These small vessels are usually ac companied by venae comites which carry back the blood to the encircling veins. Each lobule is filled with a network of capillaries. In corrosion specimens this superﬁcial albugineal blood supply appears as a ﬁne mesh over the larger encircling arteries and Veins. A few of the veins collecting from these superﬁcial vascular lobules empty directly into the pampiniform plexus, but as a rule the course is as described.

FIG. 14. A cleaned specimen of the tunica albuginea of the testis of an adult pig, showing the arrangement of the vessels supplying this tunic. X 9. This specimen was studied in glycerine with a magniﬁcation of 80 diameters (Leitz) for the capillaries of the individual lobules, and with a magniﬁcation of 8 diameters for the arrangement of the lobules. Drawn with camera. lucida. A., one of the tortuous capsular arteries given off from the main capsular artery. These vessels lie below the small arteries supplying the albuginea. B, an encircling capsular vein which ultimately empties into the pampiniforni plexus. These veins also lie beneath the arteries and veins supplying the albuginea and also pass under the large capsular arteries. 0, a small artery arising from a capsular artery. D, a small vein emptying into a capsular vein. The arrows indicate the course of the blood stream.

==Summary==

# The measurements of the embryonic {{testis}}, {{Wolffian body}} and {{kidney}} from the time that the embryo is 20 mm in length till the sex gland enters the internal ring are given.
# A comparison of the size and weight of the human {{testis}} with that of the adult testis of the {{pig}} is made. The comparative sizes of the semniferous tubules of the adult pig testis and human testis is noted.
# The testis of the pig receives its first blood supply when the embryo is 33 mm in length, the kidney having received its blood supply when the embryo has attained a length of 28 mm.
# Out of seventy-five specimens only one exception was found to the usual source of the spermatic artery, and in this case the artery instead of coming directly from the aorta arose as a branch from the most caudal Wolﬂian artery.
# Marked convolutions in the spermatic artery are first evident when the embryo is 48 mm. in length.
# A change in the position of the testis relative to the remains of the Wolfﬁan body is noted between 110 and 130 mm. This change is almost a semi-rotation; the testis assuming a more lateral position and having the future epididymis between it and the aorta.
# The entrance of the testes into the internal rings occurs when the embryo has attained a size of 190-220 mm. Generally the left testis enters ﬁrst.
# The differences between the superficial blood supply in the human embryonic testis and the testes of the adult pig and mouse are indicated, and the relative positions of the spermatic cords to the epididymes are shown.
# The vascularization of the testis of the adult pig is diagram1natically represented, and a theory to explain the peculiarities of the arrangement of the vessels is advanced. This hypothesis is based upon a suggestion from Dr. Mall that the sudden growth of the testis brings about a backward looping of the arteries in order to supply the rapidly developing semi-inferous tubules.
# The vascularization of the tunica albuginea is illustrated by a drawing made with the aid of a camera lucida.

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[[Category:Historic Embryology]][[Category:1900's]][[Category:Testis]][[Category:Artery]][[Category:Pig]]
[[Category:Draft]]

Paper - Development and vascularization of the testis (1906)

2024-01-25T00:12:00Z

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| [[file:Mark_Hill.jpg|90px|left]] This historic 1906 paper by Hill describes development off the testis.
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'''Modern Notes:''' {{Testis}} | {{pig}} | {{artery}}
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{{Historic Disclaimer}}
=On the Gross Development and Vascularization of the Testis=

By

Eben C. Hill.

From the Anatomical Laboratory of the Johns Hopkins University.

With 14 Text Figures.

==Introduction==
While studying the development of the blood supply to the Wolffian bodies, my attention was called to the interesting manner in which the {{testis}} becomes vaseularized. Accordingly, following a suggestion from Professor Mall, I injected a series of embryo pigs and later the testes of adult {{pig}}s, hoping that a thorough knowledge of the blood supply of this gland in the {{pig}} would facilitate the study ofithe vascularization of the human {{testis}}. In this I was mistaken, for the information gained from corrosions, injections, and cleared preparations of the testis of the pig was of comparatively little value in unrayelling the interesting though complex blood supply of the sex gland in man. Hence, in this paper I shall conﬁne myself to the gross development and blood supply of the pig testis, and will later publish the results of studies of the human gland.

The blood supply to the human male sex gland, to use a rather unique term for anatomical literature, is rational. It is much as one might expect, knowing the lobular arrangement. The vascularity of the pig testis, on the other hand, is quite unusual and it is difficult to imagine what causes could have produced such an unique arrangement.

==Literature==
The literature on the vascularization of the testis is surprisingly meagre, considering the enormous bibliography which has accumulated on spermatogenesis and the descent of the testis. Kölliker, Mihalkovics, Bardeleben, Pﬂiiger, Waldeyer, and many others have added much to our knowledge of these two subjects, but as yet comparatively little has been accomplished toward unravelling the blood supply. Kölliker traced the spermatic artery as it branched to supply the cord, epididymis and testis. He states that the blood vessels follow the trabeculae of the sex gland after penetrating the albuginea near the epididymis. He also describes a capillary network around the tubules. Astley Cooper has investigated a capillary plexus covering the internal surface of the tunica albuginea which he has termed the tunica vasculosa. But beyond this there is little to be found in the literature of the subject.

The vascular units which Professor [[Embryology History - Franklin Mall|Mall]] and his students have shown to be present in several organs and which they assume are to be found in all organs, have not as yet been demonstrated in the testis, and, indeed, aside from what has been cited above, nothing is known of the arterial or venous supply of the male sex gland. Dr. [[Embryology History - Franklin Mall|Mall]] has frequently demonstrated the presence of certain units of the blood system which may or may not be peculiar to the organ in which they are found and which correspond to the histological or structural unit of the organ. These units are composed of small branching blood vessels which pass into capillaries and the blood from which is collected into small veins. This theory of vascular units may be brieﬂy summed up in the statement “similar blood supply to similar histological units.” These vascular units have been proved to be present in the {{liver}}, {{spleen}}, and {{adrenal}},“ but in the testis of the pig I can make out no deﬁnite units. In man, however, the lobular arrangement is less complex, and results have been so encouraging that probably these units will be shortly discovered.

1 Mall, F. P.: A Study of the Structural Unit of the Liver. Am. Jour. Anat., Vol. V, No. 3.

2 Mall, F. P.: The Structure of the Spleen. Johns Hop. Hosp. Rep.

3 Flint, J. M.: The Blood Vessels, Angiogenesis, Organogenesis, Reticulum and Histology of the Adrenal. Johns Hop. Hosp. Rept., Vol. IX.

==Methods and Material==
The necessity of clearly understanding the development of the circulatory system in the earliest embryonic stages in order to properly interpret the course of the blood stream in the adult organs has been frequently emphasized. Accordingly, in attempting this research frequent use has been made of embryonic material. Embryo pigs, many of which were alive when delivered at the laboratory, were injected and cleared, and, after tracing the development of the circulation in these stages, the investigations were completed with adult material. For adult human testes I am indebted to Professor MacCallum of the pathological laboratory. To Professor Brodel I also wish to express my appreciation for several valuable specimens of human embryonic testes as well as for his helpful suggestions in making the illustrations. For the courtesies of their laboratory I wish to thank Professors Wiedersheim and [[Embryology History - Franz Keibel|Keibel]] of Freiburg.

All injections of embryonic material were made with Indiaink. In the youngest stages, measuring from eighteen mm. to seventy-five mm., a hypodermic syringe with a fine needle forced the injection fluid into one of the umbilical arteries, and by watching the hind legs and head excellent results devoid of extravasation could be obtained. This mode of injection is particularly desirable in these early stages for it is not necessary to rupture the surrounding membranes and thus the embryo is protected against injury in handling. In larger embryos injections were made directly into the aorta by puncturing the left ventricle. Considerable pressure was necessary to overcome in the earlier stages the resistance resulting from the small lumen of the spermatic artery, and in larger embryos because of its remarkable tortuosity. On account of this pressure the Wolﬂian bodies were frequently doubly injected, the injection mass passing through the sinusoids and capillaries described by [[Embryology History - Charles Minot|Minot]] into the veins. In nearly all such specimens the testes showed only an arterial and capillary injection. In this connection it may not be amiss to emphasize the advantages of India ink in all cases where a ﬂuid is desired which will flow wherever the blood stream goes, and yet is resistant to the ordinary laboratory acids and to concentrated solutions of potassium or sodium hydroxide.

After the injection of each embryo, the right {{testis}} together with the {{Wolffian body}}, kidney, and aorta were removed and placed in ninety-five per cent alcohol for clearing, while the left sex gland with its appendages was prepared for sectioning. Of the various clearing procedures, the modified Schultze method‘ was found to give the most satisfactory results. This method is as follows:

After the injections have been completed all unnecessary tissues surrounding the parts under investigation are removed and the specimens are placed in ninety—five per cent alcohol. The removal of adventitial tissue is most important, though entire embryos may be successfully cleared if openings are made into the abdomen, thorax and cranium. In embryos ranging above one hundred and fifty mm. in size, it is still better to make sagittal sections of the hardened specimens and to clear in halves. The alcohol should be frequently changed and large quantities should be used. In order to obtain transparent specimens the tissues must be completely shrivelled before removal from the alcohol, and the length of time necessary to accomplish this result depends, of course, upon the size of the objects. For very small specimens at least three days should be allowed, while for large objects the time should not be less than a week. Experiments with absolute alcohol in place of ninety—five per cent alcohol gave no better results, and its use is an unnecessary expense. The coagulation of the proteid occurs almost as quickly in one percentage as in the other.

‘Hill, E. C.: On the Schultze Clearing Method as Used in the Anatomical Laboratory of the Johns Hopkins University. Johns Hop. Hosp. Bull., Vol.

After the specimens have been suﬂiciently shriveled they should be placed in one per cent potassium hydroxide. When a higher percentage is resorted to, so rapid is the action that the safety of the specimen is endangered, and it was the use of the strong solutions recommended by Schultze which caused the loss of much valuable material. In this weaker solution the tissues become transparent in from four to fortyeight hours, depending upon the size of the specimens. After sufficient clearing in this medium they should be transferred to twenty per cent glycerine, in which clearing continues and a certain amount of hardening occurs, rendering the tissues firm enough to permit of dissection. Should the specimens be as tra.nsparent as is desired, they may be removed from time to time to higher percentages of glycerine till at last they are permanently stored in pure glycerine. A certain amount of shrinkage is noted in some organs after an immersion in this ﬂuid for a year or more, but when the specimens are studied immediately after being cleared the measurements are practically the same as in the fresh tissue. The shrinkage which some observers have noticed is probably due to transferring the specimens too rapidly to higher percentages of glycerine. After some experimenting we have found that embryos hardened in formalin can be cleared also, though in this case 10 per cent potassium hydroxide is essential and the specimens must remain in this solution for several weeks or months.

Blood pigment in some instances will not be entirely removed by this process alone and in organs, such as the kidney, transparency can sometimes only be obtained by a secondary treatment. After passing through the one per cent potassium hydroxide as outlined above and being placed in twenty per cent glycerine, the specimens containing the objectionable pigment are treated with equal parts of fifty per cent ammonium hydroxide and one per cent potassium hydroxide. In this solution there is comparatively little danger to the specimen on account of the hardening produced by the twenty per cent glycerine. Indeed, in cases where it is deemed advisable for any reason to stop the clearing action, or it is found to be more convenient to continue the process at some future time, the objects may be removed to this twenty per cent glycerine and retained in this medium until a more fitting time when much higher percentages of the caustic solution may be resorted to without danger to the specimens. The specimens may be studied in glycerine or by a method devised by Bardeen may be mounted upon glass slides and placed in any desired position in jars of glycerine. The objects are removed from pure glycerine, wiped and quickly washed. They are then placed in a little _thick gelatin solution and are laid upon a warm glass slide. As soon as the gelatin is hardened the specimens are returned to the pure glycerine without any danger of becoming loosened from the slide. The purity of the glycerine should be assured, as the presence of foreign substances such as water may tend to soften the gelatin.

The clearing reagents advocated by Van Wijhe“ and Lundval1° did not give the same degree of transparency as was gained by following the above method, though in clearing the capsule of the adult testis beautiful specimens were obtained by using absolute alcohol and xylol as outlined by Van Wijhe. In following the distribution of the blood vessels in the capsule, quite satisfactory results were obtained by the very practical and simple method devised by Flint in his work on the adrenal.‘ “After carefully dissecting away all of the paricapsular connective tissue from the injected and hardened gland, it is cut in half, longitudinally, with a sharp razor and the parenchyma is scraped out with a scalpel. The remaining fibrous capsule is then treated exactly like a section and, after dehydration, is cleared and mounted in a cell.”

Although the modified Schultze method is particularly applicable to embryonic tissues, yet sections of the adult testis 3-4 mm. thick, the arteries and veins of which had been injected with India ink were speedily rendered transparent by a clearing treatment similar to that for the less resistant embryonic tissue.

In preparing injections for corrosion specimens of larger embryonic and adult testes, great difficulty was experienced until it was discovered that seven per cent celloidin would ﬂow quite readily through a medium.sized hypodermic needle. Thus in injecting the adult sex gland it was only necessary to find the point at which the spermatic artery reached the gland in order to avoid the difficulty met. with in forcing the injection mass through the many coils of artery which lie in the cord of the pig near its attachment to the {{epididymis}}. The corrosion was accomplished with hydrochloric acid and pepsin, after which the specimens were washed and placed permanently in glycerine. Because of the thick and very resistant albuginea a rapid corrosion was more easily obtained when the fresh gland was placed for an hour in concentrated hydrochloric acid, after which it was treated in the usual way with a ten per cent aquous solution of this acid for twenty-four hours, followed by the ordinary peptic digestion in the thermostat.

5 Van Wijhe, J. W.: A New Method for Demonstrating Cartilaginous Mikroskeletons. Kononklijke Akademie van Wetenschappen Te Amsterdam, 1902.

6 Lundval1, H.: Ueber Demonstration Embryonaler Knorpelskelette. Anat. Anz., pp. 219-223, Band XXV.

==Gross Development of the Testis==

Keibel in his Normentafel for the pig gives the anlages and traces histologically the development of the organs, but gives no measurements of these organs.

===Table Showing in Millimeters the Length of the Bony as Compared to that of the Kidney, Wolffian Body, and Sex Gland of Pig Embryos===

The measurements were made from vertex to breech, and include all of the embryos in each uterus. In case of asymmetric development of these glands in any embryo averages were made of the lengths of both organs.

{{Hill1906 table1}}

‘éiéiilii Kidw ‘l;%‘.§‘§“?" T8’i?;iy".*

[20 1.2 7.3 1.5 21 1.2 7.3 1.5 20 1.1 7.4 1.4 Uterus 1 . . . . . . . . . . . . . . .. 23 L2 7.2 1.5 22 1.3 7.1 1.4 121 1.0 7.3 1.5 20 1.2 7.2 1.5 28 2.5 9.0 1.7 28 2.6 8.0 1.6 Uterus 2 . . . . . . . . . . . . . . . .. 29 2'5 85 1'7 27 2.4 9.2 1.7 28 3.0 7.0 1.7 [29 2.7 8.7 1.4

31 3.9 9.2 2

33 4.0 9.1 2

Uterus 3 . . . . . . . . . . . . . .. 33 3.8 9.0 2 35 3.7 9.1 1.9

33 4.1 8.9 2 40 5.8 10.0 3.2 [41 5.9 10.0 3.2 40 5.9 11.0 3.1 r 42 5.9 11.0 3.1 Uterus 4 . . . . . . . . . . . . . . . .. 41 5-8 10-0 3-1 43 6.0 11.2 3.2 1 41 5.8 10.5 3.2

42 5.9 11.3 3.2
[39 5.6 11.5 3.1 41 5.9 10.0 3.0 Eben 0. Hill 445

l§‘3§.§‘$l§T Kidnw ‘V3333? T8sv‘§§y".’ f 49 7.3 11.0 3.5 49 7.8 10.5 3.2 Uterus 5 . . . . . . . . . . . . . . . 49 (,-_g 12_() 3_2 ‘ 48 8.0 10.0 3.5 ‘ 50 7.8 10.5 3.5 68 11.7 11.8 4.0 67 11.5 12.0 4.0 68 11.5 11.4 4.0 Uterus 6 . . . . . . . . . .‘ . . . . .< 69 11.4 11.5 3.7 67 11.2 11.2 3.8 68 11.5 11.7 4.0 l 67 11.6 11.4 3.8 85.0 14.5 10.2 4.6 Uterus 7 . . . . . . . . . . . . ..g 84.6. 14.7 10.0 4.4 L 84.4 14.3 10.5 4.6 , 94.3 15.7 9.2 4.8 94.5 15.9 9.0 5.0 94.3 15.6 9.0 5.1 Uterus 8 . . . . . . . . . . . . . .. 94.0 15.5 as 5.0 94.4 15.7 8.7 5.0 94.3 15.6 8.9 4.7 120.0 18.0 7.0 5.0 121.0 19.0 7.2 5.3 Uterus :1 . . . . . . . . . . . . . .. 120_() 19_() 7_5 5,0 120.5 18.5 7.0 5.5 120.8 18.2 7.0 5.2 Epididymis Testis 15.5 23.5 Uterus 10 . . . . . . . . . . . . . . 150 223 7'0’ 5‘8 15.8 23.0 7.0 5.6 15.0 24.0 7.3 5.5 f210.0 31.0 8.2 6.0 Uterus 11 . . . . . . . . . . . .i211.o 30.0 8.0 6.3 210.5 35.0 6.5

A study of the foregoing table shows little variation in the body lengths of the embryos in each uterus. In the cases of abnormal development of the kidney. it is interesting to note the corresponding size of the Wolfﬁan body. That a. balancing of function exists between these two glands is suggested by the fact that an embryo having an unusually large kidney development has correspondingly small Wolfﬁan bodies.

The measurements were made regardless of whether the sex gland was male or female, although in embryos beyond thirty-three mm. in length this sex distinction is observable.

In the adult pig testis the measurements vary considerably. The average might be placed at sixty-five mm. long, forty—two mm. deep and thirty-seven mm. wide with an average weight of sixty-eight grammes. These results are of interest when compared with those obtained by Krause ' for the human adult sex gland. His averages were thirty—seven mm. long, twenty-eight mm. deep and twenty-four mm. wide, with the weight falling fifteen and twenty-four and a half grammes.

==Development of the Blood Supply==
Concerning the embryonic development of the testis much has been written and it seems useless to enter into a discussion of the histogenesis and descent of the gland. Among the more recent studies of these subjects the article by Allen 5 on the ovary and testis of mammals will be found to contain a comprehensive survey of the literature and in this monograph the author outlines minutely the growth of the testis of the pig. He, however, makes no mention of the blood supply.

The first macroscopic indication of the vascularization of the testis is found when the embryo pig is thirty-three mm. in length. At this time the sex gland is situated relatively lower on the mesial surface of the Wolﬂian body, which may to some extent account for the low level at which the spermatic artery arises from the aorta. Concerning the origin of this artery there has been some discussion as to whether at times it may arise from one of the lower Wolfﬁan arteries. Of the seventy—five or more specimens ranging in length from twenty—ﬁve mm. to two hundred and twenty mm., only one was found in which the artery arose otherwise than from the aorta. In this exception the spermatic artery came from the most caudal Wolfﬁan artery close to its origin from the aorta.

In the thirty—three mm stage seen in Fig. 1 no convolution is apparent in the spermatic artery which courses ventral to the Wolfﬁan arteries. In this figure, as well as in the two following ones, it was found advisable to lay back the Wolffian body from its normal position in order to more clearly demonstrate the vascular supply to these glands. The renal artery which penetrates the kidney when the embryo is twentyeight mm. in length is quite prominent and a few glomeruli are seen in the cleared specimen. As in the human embryo, rotation of the kidney occurs before the entrance of the blood supply, as has been shown by Pohlman.° Hy study of sections of pig embryos places the rotation of the kidneys in this genus between twelve and fifteen mm." In the human embryo Pohlnian has shown that the vascularization occurs between twenty-five and thirty 1nm., while in the pig I find this vascularization of the kidney at twenty-eight mm. The adrenal, which is depicted in the illustration merely as a land mark, is densely injected but no attempt has been made to show its blood supply and in this and the following series it appears as if uninjected.

’Krause, W.: Zum Spiralsaum der Samenfaden. Biol. Cent., 1881.

‘Allen, B. M.: Embryonic Development of Ovary and Testis of Mammals. Am. Jour. Anat., Vol. III, No. 2.

'''FIG. 1.''' Cleared specimen of the testis, kidney, and Wolffian body of an embryo pig 33 mm. in length, showing the ﬂrst appearance of vascular supply to the testis. X 6. W. B., right Wolﬁian body, 8.6 mm. in length; Ad., adrenal; A., aorta; T., testis measuring 2 mm. in length; S. A., spermatic artery; K., kidney, 3.8 mm. in length; W. D., Wolﬁian and Miillerian ducts; U. A., umbilical artery.

'''FIG. 2.''' Cleared specimen of the right testis, kidney, and Wolﬂlan body of an embryo pig 48 mm. in length, showing the commencement of convolutions in the spermatic artery and the increased blood supply. X 6. K., right kidney, 6.5 mm. in length; Ad., adrenal; W. B., Wolﬂian body, 10 mm. in length; A., dorsal aorta; R. A., renal artery; T., testis, 3.5 mm. in length; S. A., spermatic artery; W. D., Wolﬂian and Mullerian ducts; U. A., umbilical artery.

°Pohlman, A. G.: Concerning the Embryology of Kidney Anomalies. Am. Medicine, Vol. VII, No. 25.

“Hill, E. C.: On the First Appearance of the Renal Artery and the Relative Development of the Kidneys and Wolﬂian Bodies in Pig Embryos. Johns Hop. Hosp. bull, Vol. XVI.

The Wolffian body at this time receives from ten to twelve arteries which richly supply the gland. In many cases a pressure sufficient to insure a perfect injection of the sex gland resulted in a double injection of the Wolﬁian bodies and kidneys. In the Wolffian bodies the sinusoids described by Minot are beautifully demonstrated in sections of ﬁve to twenty ,u. in thickness.

Allen“ has noted a great activity in the formation of the primitive sex cells of the seminiferous tubules and of the cords of Pﬂiiger and rete cords about this time, and it is possible that this increased activity is due to the presence of the blood stream. Allen has also shown a sex differentiation in the embryo of twenty-ﬁve mm. which he bases upon histological observations. Through a study of the vascularization, this sex distinction is clearly marked at 33 mm., for as Clark “ has shown “upon the peculiarities of each circulation the differential signs of sex are based, a visible dorsal vessel always indicating a male; an alabasterlike non—vascular white cortex a female embryo.” This distinction, however, is true more particularly of the pig and is of doubtful value in differentiating the human sex glands.

In the embryo of forty-eight mm. (Fig. 2) the spermatic artery is found to have encircled a greater portion of the capsule of the sex gland and a certain amount of convolution is evident in the artery just before it reaches the testis. These convolutions are more marked as descent of the gland occurs, and this may be due in part to an attempt to shorten the artery. Thoma, however, in his studies of the development of the vascular system gives no such method of shortening. Nor, indeed, could this explanation account for the subsequent convolutions which occur after the testis has begun its descent from below the lower pole of the kidney. In this latter case there is a most decided lengthening accompanied by more marked convolutions. A similar condition is not found in the human embryo, nor to such marked extent in the mouse of this stage.

Microscopic sections demonstrate the capsular artery branching with a certain deﬁnite regularity on the surface of the gland, and sending minute arteries into the substance of the testis. A thick section shows these vessels entering perpendicularly and giving off branches which form capillary anastomoses around the medullary cords.

11 {{Ref-Clark1899b}}

When the embryo has attained a length of eighty-seven mm. (Fig. 3) several of the anterior Wolﬁian arteries have disappeared and there is a decided atrophy of the organ itself. The capsular artery, a name which may be applied to that portion. of the spermatic artery which supplies the albug-inea and glandular substance proper, is seen to give off many small branches, some of which are growing over the surface of the organ While others are penetrating deeply into the substance of the gland. In several specimens of this and later stages the capsular artery is found to divide into two main branches immediately after reaching the gland.

FIG. 3. Cleared specimen of the right testis, Wolffian body and kidney of an embryo pig 87 mm. long, showing descent of testis and atrophy of the anterior Wolﬁian arteries. X 6. A., dorsal aorta; K., right kidney, 14.7 mm. in length; S. A., spermatic artery; W. B., Wolﬁian body, 9.5 mm. in length; W. D., Woltnan and Miillerian ducts; I. A., iliac artery; U. A., umbilical artery.

The attachment of the sex gland to the Wolffian body is quite firm at this time.

Fig. 4 (128 mm.) shows a marked increase in the diameter of the spermatic artery, and also greater tortuosity of this vessel. The sex gland is seen to have assumed a different position in relation to the remains of the Wolfﬁan body. This semi-rotation is, perhaps, caused by the convexity of the lower pole of the kidney as the testis in descending assumes a more dorsal position. Frequent anastomoses are noticed upon the capsule, and a small twig at the anterior end of the gland anastomoses with the branch from the spermatic artery which supplies the future globus major. Since the blood supply to the epididymis is not shown in any of the drawings, this branch has not been indicated.

FIG. 4. Abdominal cavity of an embryo pig 128 mm. in length, cleared specimen of a right testis taken from an embryo or the same size and substituted in order to show the relative positions of the organs. X 6. This ﬁgure also shows the great tortuosity of the spermatic artery and by a comparison with Fig. 3, illustrates the occurrence of semi-rotation; K., right kidney, 18.2 mm. in length; S. A., spermatic artery; A., dorsal aorta; T., testis, 5.3 mm. in length; U., ureter; R., rectum; W. M., Wolfﬁan and Miillerian ducts; U. A., umbilical artery; B., bladder.

The entrance of the testis into the internal ring occurs between the sizes of one hundred and ninety and two hundred and twenty mm. The left gland usually enters the internal ring first, and in Fig. 5 (210 mm.) only the globus major of the epididymis is apparent. The capsular artery has sent out branches which nearly encircle the sex gland, and these encircling arteries have almost completed their growth around the testis. A certain limited portion lying close to the epididymis is never encroached upon by these branching arteries. From the spermatic artery before it reaches the testis several branches arise, from ﬁve to seven in number, which supply the cord and globus major and minor. Frequent anastomoses are seen on the albiginea, and small branches which encircle the anterior portion of the gland form anastomoses with arteries supplying the globus major: thus allowing blood to penetrate the testis should the posterior portion of the capsular artery become occluded. The Miillerian ducts are atrophied and appear as ridges upon the Wolﬂian (lucts which have increased in diameter of lumen and in thickness of wall.

FIG. 5. A transparent specimen of the right testis of an embryo pig 210 mm. in length. The relation of this gland to the other organs was obtained from a fresh tissue specimen of an embryo of the same size. X 6. In this ﬂgure the left testis is seen to have nearly passed the internal ring, while the right sex gland has just entered. K., right kidney; A., dorsal aorta; E., epididymis; U., ureter; R., rectum; M. D., W. D., Miillerian and Woltﬁan ducts; U. A., umbilical artery; B., bladder; T., testis, 6 mm. in length.

FIG. 6. The macroscopic appearance of an arterially injected adult pig testis, showing peculiar tortuous arrangement of the branches of the capsular artery in the tunica albuginea. >< %.

FIG. 7. A macroscopic drawing of the left injected testis of a human foetus Of Seven months. X 6%.. The dotted lines show the position of the cord and epididymis.

The relations of the superﬁcial blood supply in the testes of the adult pig and mouse and of the human foetus of seven months together with the comparative positions of the spermatic cords is shown in ﬁgures 6, 7 and 8. In the illustration showing the testis of the human embryo, the arteries are found to encircle the gland, being distributed to the under surface of the albuginea. Frequent anastomoses are formed similar in many ways to the adult superﬁcial supply in the mouse, but differing materially from the arterial distribution in the capsule of the pig testis. The relative position of the spermatic cord to the epididymis is quite noticeable and may be due to the differences in the manner of suspension of the gland with reference to the horizontal plane of the body. The comparative size of the globus major and minor is also markedly different. In the pig the globus minor is at times as large and not infrequently larger than the globus major. Few convolutions are apparent in the human embryonic gland, while in the testis of the embryo mouse as well as in the adult a certain amount of tortuosity is met with, not, however, anywhere near as marked as in the pig.

==Arterial and Venous Supply of the Adult Testis of the Pig==

The capsular artery gives off on the internal surface of the tunica albuginea at rather regular intervals tortuous rib—like branches which nearly encircle the gland. These branches

Fig. 8. The capsular distribution of the spermatic penetrate the substance of the gland follow artery in the testis of the adult mouse. X 3%.

ing the septa. and entering perpendicularly This illustration, Except in a very few instances no branches are
together with till they reach the mediastinum.

Figs 6 and 7, Show the relative positions of the cords given off from these perpendicular arteries and the albugineal blood supply.

until after the abrupt retro-flexion occurs near the center of the gland. After this sudden backward bending, many branches are given off which, coursing toward the surface of the testis, send off smaller twigs which in turn divide into capillaries around the seminiferous tubules and supply the stroma of the gland. The veins collect from these capillaries and merging into larger vessels follow the septa directly toward the albuginea where passing under the arteries on the internal surface of the tunica albuginea, they encircle the gland and passing toward the epididymis form the pampiniform plexus. These veins are about twice the size of the branches from the capsular artery and show an intricate anastomosis. Upon cross section of a doubly injected gland some seven or eight perpendicular descending arteries will appear and perhaps eight to twelve collecting veins.

The extreme vascularity of the gland is shown in Fig. 10, which is an arterial and capillary injection made with India ink and cleared by the modiﬁed Schultze method. The anastomoses around the tubules are so profuse that they give the section an appearance of ancient mail armor.

FIG. 9. A semi-diagrammatic representation of the circulation in the left testis of the adult pig. X 1%. E., globus minor of the epididymis. The arrows indicate the course of the blood stream. The arteries and capillaries are red; the veins, blue.

A microscopic section of the injected testis, stained and cleared by the Van Wijhe method shows beautifully under low power the manner in which the capillaries encircle the tubules. In Fig. 11 are seen the capillaries, some larger arteries and a portion of one of the large ascending perpendicular branches given oﬁ shortly after the looping of the descending perpendicular branch near the center of the gland. The tubules of the pig testis show this capillary arrangement somewhat better than do those of the human adult male sex gland, for as was shown by Krause the tubules of the human testis measure two—tenths of a mm. in diameter, while I ﬁnd that the tubules of the sex gland of the pig are between two-tenths and three-tenths mm. in diameter.

FIG. 10. A thick cleared cross section of the testis of an adult pig. X 1%. This shows the arteries and rich capillary network. (7. A., tortuous branch of the capsular artery which can be seen penetrating to the mediastinum of the gland and there forming the typical loop before giving off any branches. A.., spermatic artery in its course along the epididymis. The section was taken about midway between the globus major and minor, and as most of the epididymis was dissected away an atypically shaped piece of tissue remains.

FIG. 11. A microscopic section of an injected testis of an adult pig cut 50/1, showing the capillary supply around the tubules. x about 40.

FIG. 12. Corrosion specimen of the testis of an adult pig, showing the typical arterial loops. X 2.

The various types of arterial loops comprising the descending perpendicular artery and its ascending branches are shown in Fig. 12. These loops were taken from corrosion specimens of the adult testis of the pig. In the ﬁgure they are arranged in order of frequency, the last having a recurrent branch before the abrupt looping, being very rare. No similar arrangement was found from studies of corrosions of the human gland.

What the causes are which produce this peculiar arrangement it is difﬁcult to say. In the first ﬁve ﬁgures representing early embryonic stages the arteries were found to penetrate the gland perpendicularly but to give off branches as they descended.

This is depicted in Fig. 13.

No typical looping occurs till after the gland is in the scrotum and the subsequent rapid development has begun. This leads one to surmise that the sudden growth, which changes the embryonic organ from one measuring, 6 mm. X 3 mm. X 2.8 mm. unto the adult gland measuring 65 mm. X42 mm. X 37 mm., is accountable for this peculiarity of blood supply. This seems to be especially plausible when the relative positions of the mediastina of the human and pig testes are compared. Probably the development is so rapid that the arteries which enter perpendicularly
in order to penetrate to the center are of necessity twisted back upon themselves in supplying the rapidly growing tubules whose development must be toward the circumference. The mediastinum is in .the center of the gland and hence the tubules in developing radiate from this as a center.

FIG. 13.

Fig. 13a shows the left testis of an embryo pig 48 mm. in length. Then entrance of the perpendicular branches of the capsular artery is shown. X 9.

Fig. 13b illustrates the depth of penetration of these same arteries in the testis of an embryo pig of 87 mm. X 9.

Fig. 13c shows the entrance and distribution of these same arteries in the left testis of an embryo pig of 210 mm. X 9.

==The Blood Supply to the Albuginea==

The vascular supply to the albuginea is shown in Fig. 14. Above the large capsular arterial branches and veins which supply the glandular tissue of the testis and which lie on the inner side of the tunica albuginea, is found a delicate plexus of small arteries, capillaries and veins grouped in irregular polyhedral forms, mostly of four or ﬁve sides, having an area of from nine to sixteen square millimeters. The arteries enclosing these polyhedrons spring from the encircling capsular branches and lie external to them. These small vessels are usually ac companied by venae comites which carry back the blood to the encircling veins. Each lobule is filled with a network of capillaries. In corrosion specimens this superﬁcial albugineal blood supply appears as a ﬁne mesh over the larger encircling arteries and Veins. A few of the veins collecting from these superﬁcial vascular lobules empty directly into the pampiniform plexus, but as a rule the course is as described.

FIG. 14. A cleaned specimen of the tunica albuginea of the testis of an adult pig, showing the arrangement of the vessels supplying this tunic. X 9. This specimen was studied in glycerine with a magniﬁcation of 80 diameters (Leitz) for the capillaries of the individual lobules, and with a magniﬁcation of 8 diameters for the arrangement of the lobules. Drawn with camera. lucida. A., one of the tortuous capsular arteries given off from the main capsular artery. These vessels lie below the small arteries supplying the albuginea. B, an encircling capsular vein which ultimately empties into the pampiniforni plexus. These veins also lie beneath the arteries and veins supplying the albuginea and also pass under the large capsular arteries. 0, a small artery arising from a capsular artery. D, a small vein emptying into a capsular vein. The arrows indicate the course of the blood stream.

==Summary==

# The measurements of the embryonic {{testis}}, {{Wolffian body}} and {{kidney}} from the time that the embryo is 20 mm in length till the sex gland enters the internal ring are given.
# A comparison of the size and weight of the human {{testis}} with that of the adult testis of the {{pig}} is made. The comparative sizes of the semniferous tubules of the adult pig testis and human testis is noted.
# The testis of the pig receives its first blood supply when the embryo is 33 mm in length, the kidney having received its blood supply when the embryo has attained a length of 28 mm.
# Out of seventy-five specimens only one exception was found to the usual source of the spermatic artery, and in this case the artery instead of coming directly from the aorta arose as a branch from the most caudal Wolﬂian artery.
# Marked convolutions in the spermatic artery are first evident when the embryo is 48 mm. in length.
# A change in the position of the testis relative to the remains of the Wolfﬁan body is noted between 110 and 130 mm. This change is almost a semi-rotation; the testis assuming a more lateral position and having the future epididymis between it and the aorta.
# The entrance of the testes into the internal rings occurs when the embryo has attained a size of 190-220 mm. Generally the left testis enters ﬁrst.
# The differences between the superficial blood supply in the human embryonic testis and the testes of the adult pig and mouse are indicated, and the relative positions of the spermatic cords to the epididymes are shown.
# The vascularization of the testis of the adult pig is diagram1natically represented, and a theory to explain the peculiarities of the arrangement of the vessels is advanced. This hypothesis is based upon a suggestion from Dr. Mall that the sudden growth of the testis brings about a backward looping of the arteries in order to supply the rapidly developing semi-inferous tubules.
# The vascularization of the tunica albuginea is illustrated by a drawing made with the aid of a camera lucida.

{{Footer}}
[[Category:Historic Embryology]][[Category:1900's]][[Category:Testis]][[Category:Artery]][[Category:Pig]]
[[Category:Draft]]

Paper - The development of the cloaca in human embryos

2024-01-25T00:04:24Z

Z8600021: /* Bibliography */

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{{Ref-Pohlman1911}}
{| class="wikitable mw-collapsible mw-collapsed"
! Online Editor  
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| [[file:Mark_Hill.jpg|90px|left]] A number of [[Carnegie Embryos]] and models generated from these embryos are described in this historic study of human {{cloaca}} development. Note that Polman numbers the embryos examined in sequence 1-30, but also gives Mall's Carnegie embryo numbers in the tabulation.

See also by this author - {{Ref-Pohlman1904}}

Carnegie Embryo {{CE186}}

'''{{Cloaca}}''' - (cloacal cavity) The term describing the common cavity into which the intestinal, genital, and urinary tracts open in vertebrates. Located at the caudal end of the embryo it is located on the surface by the cloacal membrane. In many species this common cavity is later divided into a ventral urogenital region (urogenital sinus) and a dorsal gastrointestinal (rectal) region.

'''{{Cloacal membrane}}''' - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by {{ectoderm}} and {{endoderm}} without a middle (intervening) layer of {{mesoderm}}. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract. The upper end of the gastrointestinal tract has a similar embryonic membrane, the [[B#buccopharyngeal_membrane|buccopharyngeal membrane]].
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'''Modern Notes:''' {{cloaca}} | {{gastrointestinal tract}} | {{genital}} | {{renal}}
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{{#pmid:30294789}}
:"Subdivision of cloaca into urogenital and anorectal passages has remained controversial because of disagreements about the identity and role of the septum developing between both passages. This study aimed to clarify the development of the cloaca using a quantitative 3D morphological approach in human embryos of 4-10 post-fertilisation weeks. ...Our main finding was a pronounced difference in growth between rapidly expanding central and ventral parts, and slowly or non-growing cranial and dorsal parts. The entrance of the Wolffian duct into the cloaca proved a stable landmark that remained linked to the position of vertebra S3. Suppressed growth in the cranial cloaca resulted in an apparent craniodorsal migration of the entrance of the Wolffian duct, while suppressed growth in the dorsal cloaca changed the entrance of the hindgut from cranial to dorsal on the cloaca. Transformation of this 'end-to-end' into an 'end-to-side' junction produced temporary 'lateral (Rathke's) folds'. The persistent difference in dorsoventral growth straightened the embryonic caudal body axis and concomitantly extended the frontally oriented 'urorectal (Tourneux's) septum' caudally between the ventral urogenital and dorsal anorectal parts of the cloaca. The dorsoventral growth difference also divided the cloacal membrane into a well-developed ventral urethral plate and a thin dorsal cloacal membrane proper, which ruptured at 6.5 weeks. The expansion of the pericloacal mesenchyme followed the dorsoventral growth difference and produced the genital tubercle. Dysregulation of dorsal cloacal development is probably an important cause of anorectal malformations: too little regressive development may result in anorectal agenesis, and too much regression in stenosis or atresia of the remaining part of the dorsal cloaca."

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{{Genital Links}}
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{{Renal Links}}
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{{Historic Disclaimer}}
=The Development of the Cloaca in Human Embryos=
[[File:Augustus Pohlman.jpg|thumb|150px|alt=Augustus G. Pohlman|link=Embryology History - Augustus Pohlman|Augustus G. Pohlman]]
[[Embryology History - Augustus Pohlman|Augustus G. Pohlman]]

Indiana University

From the Anatomical Laboratory, Johns Hopkins University

==Introduction==

The active work in the embryology of the urogenital system began about 1880 and continued for a period of some fifteen years when Keibel's monograph was published. The writer's investigation of the cloacal region was started in 1903, and was undertaken in part as a control of Keibel's work, and in part with a view toward solving some of the points on which differences in opinion existed. The publication of this report has been delayed in the hope that certain facts in comparative embryology might be established and help to clarify some of the obscure relations found in the human embryo. Inasmuch as the extensive investigations of Fleischmann and his students have come to naught in this respect, the major differences in opinion will be considered, and the doubtful points answered in so far as it is possible. The short literature review covers the essential facts and effort has been made to reduce the description of the material to a concise tabulation. The writer expresses his indebtedness to Prof. Keibel at whose suggestion the development of the later stages in the embryology was undertaken, and to Prof. F. P. Mall for the use of his collection of embryos and for the many courtesies shown him in the Anatomical Laboratory of Johns Hopkins University.

Born's article ('93) reviews the earlier development of the cloacal region in a very complete manner, and the substance is as follows: The entoderm of the enteron comes into direct relation with the surface ectoderm in the pharyngeal and cloacal membranes during the formation of the head and tail folds. Both of these membranes lose their primitive position and become folded into the substance of the embryo through increase in the surrounding mesoderm. The allantois, which is developed dorsally in the mammalian embryo (human and guinea pig excepted), shifts to a ventral position on the gut, and is gradually displaced from its intimate relation to the yolk sac through increase in the amount of mesodermal tissue. The primitive streak is carried to the ventral surface of the body during the formation of the tail fold, and forms the whole or part of the cloacal membrane. Kolliker f'83), Strahl ('83, '84), and Bonnet ('88) believe that the caudal end of the primitive streak is made up of applied layers of ectoand entoderm, and that it enters as such into the formation of the cloacal membrane. Keibel ('88) argues that this primitive relation of the ecto- and entoderm is lost through interposition of mesoderm; the latter disappearing later with restoration of the original two layered condition.

The model of the 4.2 mm. human embryo presented by Keibel ('88) shows the hind gut and widely lumened allantois opening cephalward into the caudal entodermal sac or cloaca. Ventrally, this cloaca is limited as far as the dermal navel by the epithelial cloacal membrane. Caudalward, the limit of the cloacal membrane comes about by a mesodermic separation of the epithelial layers. The gut segment distal to the lower limit of the cloacal membrane may be termed the tail gut and terminates in an undifferentiated cell mass formed by itself, the chorda and neural tube. Born emphasizes the length of the cloacal membrane as follows: "I call particular attention to the original extent of the cloacal membrane. It reaches cephalward to the point where the allantois leaves the body at right angles; i.e., as far as the caudal border of the dermal navel."

The cloacal membrane does not extend as far as the allantois in the model of an 8.0 mm. human embryo presented by Keibel ('91) . Mesodermic tissue has apparently wandered in from above and separated the layers of epithelium. The cloacal membrane is therefore shorter than in the 4.2 mm. stage. The tail gut shows degeneration. The precloacal mesodermic tissue has increased in amount but instead of displacing the cloacal membrane caudal-ward, has folded it into the lower surface of the genital tubercle as was first described by Tourneux ('89), and verified by Retterer ('90) and Reichel ('93). No intermediate stage in the development has been described up to this time ('93). With the increase in size of the genital tubercle, the entodermal cloaca becomes more deeply placed as was demonstrated by Reichel ('93). Born states that the epithelial plate contained within the genital tubercle is ectodermic and that it is continuous with the superficial ectoderm. The epithelial plate occupies the caudal surface of the eminence and is bordered laterally by folds of mesoderm (repli ano-genitaux of Retterer) , while the cloacal membrane itself terminates at the postanal fold (replis postanal)., "The depression arises (as in the mouth region) through increase in the height of the limiting borders. The depression is always closed in by epithelium, and the base of the depression is never separated from the entodermal cloaca by mesodermic tissue." (Born.)

The cloaca is gradually divided into a ventral (bladder-urogenital sinus) segment, and a dorsal (gut) segment. As to the manner of this division, Retterer and Born agree with the Tiedemann-Rathke idea of the gradual separation into two segments through approximation of two lateral folds of mesoderm, while Tourneux believes it to be accomplished by a septal (frontal) downgrowth. Lieberkiihn ('82) and Keibel ('89) dispute the theory of Rathkc ('32) championed bj' von Mihlacovics ('85), that the bladder arises from the allantois, and state that it is made up for the most part from the ventral cloacal segment - agreed to by Retterer and Reichel. Born takes a neutral position and believes that at least the trigone of the human bladder may be developed in a manner like that found in the guinea pig (Keibel). Born and Minot do not think that the anlage of the upper part of the bladder is of particular importance. "We are probably not mistaken when we grant that not only the bladder (as far as the apex) but the male urethra as far as the caput gallinaginis, the entire female urethra, and in the male, also the pars prostatica and the entire pars membranacea are developed from the ventral cloacal segment."

The most important of the recent works is that of Ke bel ('96) who sums up the development of the cloacal region in the following words : "The human embryo possesses a large entodermal cloaca in the early stages of its development which however is never opened to the outside through a cloacal anus ('Cloakenafter' of Prenant), but remains closed through the cloacal membrane (the 'anal membrane' of the earlier writers) as long as it exists as such. An ectodermal cloaca is to be found only in traces if at all. The entodermal cloaca is separated into a ventral and a dorsal segment by a frontal septum. A large part or all of the bladder, the urethra and the urogenital sinus as far as the cloacal membrane are derived from the ventral segment; while the dorsal segment becomes continuous with the ectodermal segment of the rectal canal. The primitive perineum is formed when the frontal septum fuses with the cloacal membrane and the rudimentary ectodermal cloaca is then divided by the permanent perineum. The ectodermal anal pit (protodaeum) is situated behind the permanent perineum, while the ectodermal portion of the urogenital sinus is ventral to it."

[[File:Pohlman1911 fig1.jpg|thumb|'''Fig. 1.''']]

Another investigator, who has been particularly fortunate in the amount of embryological material at his disposal, expresses a somewhat different view. Nagel ('02) practically reiterates his statements of 1894. "The inspection of the tail end of human embryos of 11-13 mm. length reveals an oval pit extending from the coccygeal prominence to the tip of the genital eminence. This pit (cloaca) receives the openings of the gut dorsally, and the Canalis urogenitalis ventrally; the two separated by a partition of some 0.3 mm. thickness. The Wolffian and Mullerian ducts open higher up in the Canalis urogenitalis and will not be considered in the description of this depression. The Canalis urogenitalis and the gut open into this pit (cloaca) which would reach (comparing with adult relations) from the dorsal border of the anus to the ventral border of the urethral opening {i.e. Frenulum clitoridis). Later he states: "In what manner the division of the cloaca is accomplished is not perfectly understood either in man or in mammals. I found the relations in the youngest human embryo that I had opportunity to examine like those pictured in fig, 1, naturally with exception of the form of the bladder. I commit myself therefore, as far as the human embryo is concerned, to the view of Rathke which has recently been substantiated by Retterer and von Mihalcovics in the animals."

The work of von Mihalcovics ('85) referred to, says in part; "This septum between the urogenital canal and the gut arises in part through increase in length of the afore-mentioned perineal Told (septum) to which, distalward, two lateral folds join to the perineal folds. The cloaca takes no part in the formation of the urogenital canal." The opinion of Retterer ('94), mentioned by Nagel, is summarized as follows: "In the guinea pig, as in other mammals studied up to the present time (man, pig, sheep and rabbit), a fold of mesoderm appears at the cephalic extremity of each lateral cloacal wall, and extends little by little toward the caudal end of the cloaca. These lateral folds encroach upon the lumen of the cloaca and divide it into two canals, the one dorsal or rectal, and the other ventral or vesico-urogenital."

That these opinions, while they are in the main contrary to the views of Keibel although they appeared at an earlier date, are accepted at the present time can be illustrated by an extract from Zuckerakndls Handbuch der Urologie ('03): "In the second fetal month, the proximal segment of the allantois widens to form the bladder, while the distal and narrow portion (urachus) obliterates to form the Lig. vesico-umbilicale," "The division of the cloaca is accomplished by three folds, a median and two lateral. The former occupies the angle between the allantois and hind gut, while the latter are developed in the lateral walls of the cloaca."

The investigations of Tourneux ('94) agree with those of Keibel in that he also states the cloaca to be a closed sac. His objections to the method of cloacal division as described by Retterer are as follows: "The form of the inferior border of the recto-urogenital septum is that of a vaulted arch and not that of an elliptical arch with the vertex upward - " a fact easity demonstrated in frontal sections. In addition to this, the transverse sections show that the lateral folds are found only toward the summit of the arch and converge rapidly. Further, the septum shows no signs of an epithelial raphe at the supposed line of fusion to indicate the transition that one encounters, as Keibel states, "at the line of union of the palatine ridges."

Nagel ('96) answers Keibel's article by stating ''If Keibel did not find the facts as presented by myself in all of his embryos of 11.0 mm. and upwards, then the embryos are at fault." "Furthermore in order that an embryo may be declared of scientific value, I demand that the urogenital canal be open into the cloacal pit in all embryos over 8.0 mm., and that the cloacal membrane have disappeared as far as the tip of the genital eminence. Inasmuch as th& allantois contained within the umbilical cord is practically obliterated at this stage, where could the secretion from the mesonephros be stored up if the cloacal membrane were intact?"

The questions that appeal to the writer as doubtful ones may be expressed as follows:

# Does the cloaca proper ever open to the outside?
# Does the cloacal membrane arise directly by displacement of applied layers of ecto- and entoderm in the primitive streak or is it formed in situ through disappearance of the intervening mesoderm?
# In what manner is the cloacal division effected?
# What is the anlage for the bladder?
# Can the urinary function of the mesonephros assumed by Nagel be demonstrated?

==Material==

The study of the cloacal region was done in part by working out the relations in serial sections, and in part through reconstruction. Thirty embryos in all were examined; reconstruction employed in thirteen, of which six stages will be presented. The material, with the exception of these six , is given entirely in the tabulation. The serial number, used throughout this paper, refers to the age of the embryo based on the development of the urogenital tract and with no particular reference to its length. It is interesting to note that with the exception of nos. 4, 11, 13, and 21, the development of the tract has proved to be an excellent check on the determination of the age by the greatest length method. The Mall number refers to the catalogue number of the collection of human embryos at Johns Hopkins University and the section thickness (indicated in microns) ; the section direction (+ for transverse, = for sagittal, and || for coronal; and the condition (f for fair and g for good) are recorded in this manner in the Mall catalogue. The modelling of the embryo is indicated by the magnification of the same, and where the model is presented in this paper it is designated by a capital letter. The brief normentafel shows the major points of difference in the development of the cloacal region. The embryo 30 is the Piper II embryo of the collection, and will be presented later in connection with the origin of the bulbovestibular glands. This embryo and also no. 20 have been reported in connection with the condition of complete double ureter (Johns Hopkins Bull., vol. 16, Feb. '04).

===Tabulation===
:'''Online editor''' - Carnegie stages have been added to the original tabulation and the text information is now edited in a sortable table.

{|
{| class="wikitable sortable"
|-
! Embryo
! Mall
! Stage
! CRL
! Plane
! Thickness (microns)
! Quality
! Notes
|-
| 1 || {{CE12}} || [[Carnegie stage 11|11]] || 2.1 mm|| transverse|| 10|| good|| Modelled by Mall ('97). Allantois of small lumen and in relation with the caudal border of the yolk sac. No evidences of a cloacal membrane.
|-
| 2 || {{CE391}} || [[Carnegie stage 10|10]] || 2.0 mm || transverse || 10|| Good|| Appearance of hind gut. An interval of several sections between allantois and yolk sac. No cloacal membrane.
|-
| 3 || {{CE164}} || [[Carnegie stage 11|11]] || 3.5 mm || transverse || 20|| Good || [[:File:Pohlman1911 plate1A.jpg|Model A]]. x 100. Cloaca well developed and limited for caudal half of the ventral border by epithelial cloacal membrane. Allantois comes off at right angles and at lower border of dermal navel. Lateral furrow along later line of division.
|-
| 4 || {{CE209}} || [[Carnegie stage 12|12]] || 3.0 mm || transverse || 50|| Fair|| Relations about the same as the fore-going stage. Sections too thick for detailed study. [[Carnegie stage 12]]
|-
| 5 || {{CE186}} || [[Carnegie stage 13|13]] || 3.5 mm|| transverse|| 20|| Good|| [[:File:Pohlman1911 plate1B.jpg|'''Model B''']]. x 100. Allantois wide lumened and no distinct line of demarkation from the ventral cloacal segment. Wolflian ducts have arrived but not as yet opened. Tail gut maximum of development. Probably the first signs of cloacal division.
|-
| 6 || {{CE87}} || || 4.0 mm|| transverse|| 20|| Fair|| About the same as the foregoing. [[Carnegie stage 13|13]]
|-
| 7 || {{CE148}} || [[Carnegie stage 13|13]] || 4.3 mm || transverse || 10|| Good || x 100 Wolffian ducts open into cloaca. Allantois of small lumen. Ventral cloacal segment widening. Evidences of division quite apparent.
|-
| 8 || {{CE76}} || [[Carnegie stage 13|13]] || 4.5 mm || transverse || 20|| Good|| x 100. Widened ventral cloacal segment goes over indistinctly into allantois. Tail gut still quite large. Renal buds well developed. With exception of large allantois and wider tail gut, quite similar to Model C.
|-
| 9 || {{CE80}} || [[Carnegie stage 14|14]] || 5.0 mm|| transverse || 10|| Good|| [[:File:Pohlman1911 plate2C.jpg|Model C]]. x 100. About the same as the foregoing stage. Tail gut undergoing degenerative changes.
|-
| 10 || 371|| [[Carnegie stage 15|15]] || 6.6 mm|| sagittal || 10|| Good|| Tail gut rudimentary. Development of cloaca and renal buds about the same as in no. 12.
|-
| 11 || 116|| [[Carnegie stage 13|13]] || 5.0 mm || sagittal || 20|| Good|| x 100. Intracloacal epithelial plug well marked. Stage about the same as that found in no. 12.
|-
| 12 || {{CE2}} || [[Carnegie stage 15|15]] || 7.0 mm|| transverse|| 15|| Good|| [[:File:Pohlman1911 plate2D.jpg|Model D]] x 100. Marked development of renal buds. Kidney and ureter segments evident. Ventral cloacal segment much widened. Allantois of narrow lumen. Intracloacal epithelial plug marked. Tail gut maximum in length and slightly widened at caudal end.
|-
| 13 || {{CE241}} || [[Carnegie stage 15|15]] || 6.0mm|| transverse|| 10|| Goo(l|| Tailgutmore rudimentary than in no. 12. Cloacal membrane wide and shows intracloacal epithelial plug. Otherwise about the same as in no. 12.
|-
| 14 || {{CE383}} || [[Carnegie stage 16|16]] || 7.0 mm|| transverse || 10|| Good|| State similar to no. 12. Cloacal membrane intact.
|-
| 15 || {{CE397}} || [[Carnegie stage 16|16]] || 8.0 nma.|| transverse|| 10|| Good|| Similar to foregoing.
|-
| 16 || {{CE113}} || [[Carnegie stage 15|15]] || 8.0 mm|| sagittal|| 10 || Fair|| x 100. Stage of cloacal division between than found in no. 12 and that found in no. 19. Cloacal membrane intact. Division of ureteral pelvis. Ureter segment elongated.
|-
| 17 || {{CE114}} || || 10.0 mm|| sagittal|| 10|| Fair|| x 100. Stage of cloacal division about the same as the foregoing. Cloacal membrane intact. Kidney a little higher up. Upper and lower pelvis evident.
|-
| 18 || {{CE109}} || [[Carnegie stage 18|18]] || 11.0 mm|| transverse|| 20|| Good|| Sections directly through lower part of cloacal region somewhat damaged. Otherwise about the same as no. 19.
|-
| 19 || {{CE221}} || [[Carnegie stage 16|16]] || 12.0 mm|| sagittal || 20|| Good|| [[:File:Pohlman1911 plate3E.jpg|Model E]] x 100. All traces of tail gut lost. Cloacal membrane somewhat depressed from surface. Cloacal segment of Wolffian duct shortened and opening of ureter and duct common into ventral cloacal segment. Beginning formation of genital eminence and lengthening of the ventral cloacal wall. Cloacal membrane intact.
|-
| 20 || {{CE175}} || || 13.0 mm|| transverse|| 20|| Good|| x 100. Cloaca about divided. Complete double ureter. Orifices of lateral, and medial ureter and Wolffian duct at same level into cloaca.
|-
| 21 || {{CE353}} || [[Carnegie stage 17|17]] || 11.0 mm|| transverse || 10|| Good|| Cloaca completely divided. Anal and urogenital membranes intact. Ureteral orifice independent and on level with Wolffian opening.
|-
| 22 || {{CE317}} || [[Carnegie stage 18|18]] || 15.0 mm|| coronal || 20|| Good|| About the same stage as in no. 21.
|-
| 23 || {{CE350}} || [[Carnegie stage 19|19]] || 15.0 mm|| coronal || 10|| Good|| About the same as the foregoing, and no. 24.
|-
| 24 || {{CE43}} || [[Carnegie stage 19|19]] || 16.0mm|| sagittal || 50|| Good|| [[:File:Pohlman1911 plate3F.jpg|Model F]] . x 50. Anal and urogenital membranes separated. Genital eminence more marked. Ectodermic inclusion in furrow on caudal surface. Ureteral orifice on same level but some distance lateral to Wolffian orifice.
|-
| 25 || {{CE256}} || [[Carnegie stage 20|20]] || 16.0 mm|| sagittal || 50|| Good|| Urogenital sinus open to outside through rupture of urogenital membrane. Kidney nearly up to normal position and rotated.
|-
| 26 || {{CE296}} || [[Carnegie stage 18|18]] || 7.0mm|| coronal|| 20|| Good|| Slightly older than above. Appearance of secondary genital folds at the sides of the phallus.
|-
| 27 || {{CE128}} || [[Carnegie stage 21|21]] || 20.0 mm|| coronal|| 50|| Good|| About same as above.
|-
| 28 || {{CE240}} || [[Carnegie stage 20|20]] || 20.0 mm|| coronal|| 20|| Good||
|-
| 29 || {{CE22}} || [[Carnegie stage 21|21]] || 20.0 mm|| transverse|| 50|| Good|| One Mullerian duct has reached the urogenital sinus.
|-
| 30 || Embryo KP|| || 22.0 mm|| transverse|| 15|| Good|| X 66. Both Mullerian ducts at sinus.
|}

The last six embryos of this series have been introduced merely to carry out the idea of a brief arrangement according to the development of the tract in so far as it was possible and to indicate the position of Model of no. 30 referred to in reference to the measurements on the inter-ureteral and inter- Wolffian widths mentioned in the discussion of the anlage for the trigonum. Embryo no. 30 has additional interest in that it like no. 20 has a complete duplication of the ureter on one side.

The description of the models has been made in as brief a manner as feasible, and a discussion of the various points in question will be brought up after they have been described. All of these models represent epithelial casts, and all of them with the exception of Model F. are X 100.

{|
| [[:File:Pohlman1911 plate1A.jpg|'''Model A''']]. {No. 3; Mall no. 164; 3.5 mm.) This model shows the cloaca to be a sort of conical sac receiving the wider lumened hind gut dorsally, and the narrow lumened allantois ventrally. The latter joining the cloaca at about a right angle. The cloaca is much wider dorsally and is somewhat wedged-shaped in section. Ventrally, it is limited for about one-half of its extent by the epithelial cloacal membrane which is indicated by a surface contact. The right wall of the cloaca is concaved from before backwards while the left side (shown) is correspondingly convex, and presents a well marked furrow extending from the saddle between the allantois and hind gut to about the mid area of the cloacal membrane. This furrow is interesting because while it indicates the probable line of the later division, it was found in but two embryos of the series examined. The part of the cloaca caudal to the cloacal membrane - the tail gut - is quite short and cone-shaped. The model with the exception of the furrow conforms to Keibel's model of the His embryo EB (3 mm.)
| [[File:Pohlman1911 plate1A.jpg|thumb|200px|Model A]]
|}
{|
| [[:File:Pohlman1911 plate1B.jpg|'''Model B''']] {No. 5; Mall no. {{CE186}}; 3.5 mm.) This model, although made from an embryo of the same length as the above, shows a distinctly older stage in the development of the tract. The allantois has a much wider lumen and the angle between it and the hind gut is much more acute. The Wolffian ducts have reached the cloaca, and attach but do not open into it ventrally near the upper limit of the cloacal membrane. The tail gut is much larger both in length and in thickness, and terminates in an undifferentiated cell mass formed by itself, the chorda and the neural tube (shown as a knob-like ending). The cloaca is wider dorsally than ventrally. A stage similar to the one described was found in two other embryos (nos. 7 and 8), in both of which the allantois was wide at its apparent opening into the cloaca. The possibility of some minor degree of development abnormality suggested itself but on careful study, it was decided that the first evidences of cloacal division were at hand.

[[:File:Pohlman1911 plate1B.jpg|'''Model B''']], other than a better developed tail gut, a slightly higher position of the Wolffian ducts and a shorter cloacal membrane agrees with Keibel's model of the 4.2 mm. embryo. Keibel's model shows this same evidence of division; a frontal septum between the allantois and hind gut slipping down to a level approaching the upper limit of the cloacal membrane. The writer has found no embryo where the cloacal membrane approaches the level of the dermal navel, and will consider this point later.
| [[File:Pohlman1911 plate1B.jpg|thumb|200px|Model B]]
|}
{|
| [[:File:Pohlman1911 plate2C.jpg|'''Model C''']]. {No. 9; Mall no. 80; 5.0 mm..) This model shows marked degeneration of the tail gut. The allantois is narrow lumened, while the widely lumened ventral cloacal segment lies ventral to the hind gut and dorsal segment, and is separated from them by peritoneum. The Wolffian ducts open in the same situation as in the foregoing model, and present dorsal diverticulae, the renal buds. The ventral portion of the cloaca, especially the area above the cloacal membrane, is markedly widened and flattened. The lateral furrow of Model A was not present. This model conforms to the Keibel model of a 6.5 mm. embryo (a considerably older stage if we go by the greatest length rule). The cloaca has lost its more or less even width and attains its greatest lateral diameter at the level of the Wolffian orifices. There is no evidence of displacement of the Wolffian ducts from their primitive position in relation with the upper limit of the cloacal membrane.
| [[File:Pohlman1911 plate2C.jpg|thumb|200px|Model C]]
|}
{|
| [[:File:Pohlman1911 plate2D.jpg|'''Model D''']] {No. 12; Mall no. 2; 7.0 mm.) This model fills in a gap in the Keibel series which may be considered quite an important one. The hind gut and all that pertains to the dorsal segment of the cloaca has retained an even caliber, while the ventral segment has widened progressively. The division of the cloaca may be traced to the level of the Wolffian orifices. The Wolffian ducts are much better developed and the renal anlage has resolved itself into distinct ureter and kidney segments. The segment of Wolffian duct between the orifice of the ureter and the cloaca is relatively shorter. The renal anlagen have assumed the position of dorsal convergence (mentioned by Keibel) but this is only a relative matter (see later). The tail gut has undergone further degeneration and has lost its lumen in part.
| [[File:Pohlman1911 plate2D.jpg|thumb|200px|Model D]]
|}
{|
| [[:File:Pohlman1911 plate3E.jpg|'''Model E''']]. {No. 19; Mall no. 221; 12.0 mm.) This stage shows the cloaca about half divided along the furrow line indicated in Model A. The cloacal membrane has thickened but mostly through addition of ectodermal cells, and has been displaced through development of the ' precloacal mesoderm' from its primitive position parallel to the dorsal line of the cloaca to one more nearly at right angles to it. In so far as it was possible to ascertain, this downward displacement of the cloacal membrane in no way affects its caudal limit. The dorsal segment has retained the original proportions while the ventral segment has widened - most marked again at the level of the Wolffian orifices. The further development of the kidney and ureter will be noted and the gradual approach of the ureteral orifice to the cloaca proper is evident. The ureter shows signs of shifting from its primitive dorsal position on the Wolffian duct to a more lateral one. The peritoneum has descended to the level of the ducts while the cloacal division is relatively far advanced. The model agrees with Keibel's model of an 11.5 mm. embryo.
| [[File:Pohlman1911 plate3E.jpg|thumb|200px|Model E]]
|}
{|
| [[:File:Pohlman1911 plate3F.jpg|'''Model F''']]. {No. 24; Mall no. 43; 16.0 mm. X 50.) Unfortunately this embryo was cut too thick for minute reconstruction. The stage however fills in another gap in the Keibel series. Here the cloaca and the cloacal membrane are completely divided - the ventral segment limited by the urogenital plate and the dorsal segment by the anal plate. The ureter is displaced from its dorso-lateral position on the Wolffian duct to a supero-lateral one and opens distinctly into the ventral cloacal segment. The marked increase in precloacal tissue has resulted not only in the large genital eminence, but the urogenital plate has been dislocated deeper into the base of the phallus and a marked heaping up of ectodermal cells has occurred in the furrow on the caudal surface of the eminence. The two resultant segments of the cloacal membrane, the urogenital and anal plates are apparently no longer than they were in much younger stages; a point that will be brought out in greater detail later.
| [[File:Pohlman1911 plate3F.jpg|thumb|200px|Model F]]
|}

==The Cloacal Membrane==

While authorities seem to agree that the cloacal membrane arises from the primitive streak, or at least that portion which has been displaced ventrally in the formation of the tailfold, they disagree on the point whether this part of the primitive streak consists in applied layers of ecto- and entoderm, or whether it is composed of all three germ layers. Stated in an simple manner, is the cloacal membrane formed dorsally as an epithelial membrane or is it formed ventrally through disappearance of intervening mesodermal tissue? One of the earliest stages in the formation of the tail fold is found in the Spee reconstruction ('96) of [[:Category:Glaevecke Embryo|embryo Gle]] (2.0 mm.). A schematic sagittal section is presented in his fig. 1, and emphasis is laid on the point that the primitive streak is composed of all three germ layers. No. 1 of the present tabulation was reconstructed by Mall ('97), and while a slightly older stage in the development, shows the cloacal sac limited ventrally by all three germ layers. No. 2 presents a similar condition. The first embryo of this series to show a cloacal membrane is no. 3 (3.5 mm.) which is quite a little farther advanced in the development than no. 2; unfortunately the transition stages are wanting. It is the writer's opinion therefore that the view held by Keibel is the correct one, and that while the cloacal membrane is derived from the primitive streak area, it is formed in situ as an epithelial membrane on the ventral cloacal surface, naturally after the formation of the tail fold.

The sagittal width of the cloacal membrane varies somewhat with the stage in the development. Born's statement that it extends as far cephalward as the dermal navel is based on Keibel's model of a 4.2 mm. embryo ('88). A somewhat similar condition is noted in two of the embryos of this series. The writer does not believe this to be the normal relation, but rather one which through persistence may have a decided bearing on bladder exstrophy and epispadias. The epithelial plate, if it extends to the dermal navel, and persists in this relation, separates the precloacal tissue into two lateral halves, and accounts quite satisfactorily for the deficience in the abdominal wall and for the gutter on the upper surface of the phallus. In practically all of the embrj'os exam- ined, the cloacal membrane did not extend higher than the level of the Wolffian orifices. The membrane is normally shortest in length at the time of its formation but attains its greatest length in Model C. (0.29 mm.); in Model D (0.27 mm.); in Model E (0.34 mm.). This increase is not marked when we consider that these stages represent 5, 7 and 12 mm. embryos respectively.

The width of the cloacal membrane is a rather indefinite quantity to measure ; it widens progressively however with the widening of the ventral cloacal segment, and in the proportion of 5 in B to 8 in C to 12 in D or in other words in proportion to the greatest length measurement of the embryo.

The position of the cloacal membrane is about parallel to the long axis of the embryo in Models A, B and C. With the development of the precloacal tissue, the cloacal membrane is displaced so that its upper end is pushed caudalward â€” beginning in D; more marked in E ; and culminating in F where the upper end of the membrane has been displaced through practically 90° with the caudal end as the fixed point of the radius. The displacement is probably due to the active lengthening of the ventral cloacal wall and to the development of the genital eminence. The membrane is divided into two parts in Model F â€” a ventral or urogenital membrane and a dorsal or anal membrane; both of which have been displaced from the surface in the manner suggested by Born. The anal membrane persists beyond the stages described in this paper, and is dealt with in sufficient detail in Keibels' article. The urogenital membrane ruptures with its formation and is of particular interest in its relation to the position of the bulbovestibular glands ; a point to be brought in a paper which is to appear shortly. It may be noted that in Model D the cloacal membrane is much thicker in its midarea, and not infrequently one finds a heaping up of cells in this region and a corresponding eminence on the inner surface of the cloacal (intracloacal epithelial plug) . The significance of this is not understood but it may be due to the more active proliferation of the ectodermal cells which contribute to the formation of the cloacal membrane.

==The Ectodermal Cloaca==

An ectodermal cloaca has been stated by Keibel to be present only in traces, if at all. None of the embryos examined showed a surface depression, and we may therefore critically examine Nagel's fig. 1 and his contention concerning the cloacal membrane. It will be seen that in fig. 1, while the embryo shows a cloacal division comparable to our Model E; the phallus is developed to the extent of that found in Model F ; while the cloacal membrane is ruptured. None of the embryos of this stage, or younger than this stage, showed rupture of the cloacal membrane, and we may therefore agree with Keibel that the cloacal membrane remains intact normally as long as it persists as such. Nagel believes that the rupture of the membrane is essential or where would the secretion of the mesonephros be passed? We may answer this question. The ventral cloacal segment and the allantois do not show the degree of widening necessary to accommodate the urinary excretion, and we call to mind Hill's work on the pig embryo ('04) and our own ('04) on the human embrj'o, in both of which it is conclusively shown that the mesonephros is actively degenerate long before the kidney is developmentally fitted to take up a urinary function. Cases of atresia urethrae commonly occur without bladder distension ; monstrosities may go to term without kidneys and with no undue persistence of the mesonephros; and experimentally, it has been shown that there is no evidence of urinary excretion into the amniotic fluid even in term children. We do not believe it necessary to assume that the mesonephros functionates as an organ of excretion in the placental mammals, and do not consider Nagel's contention for a functional rupture of the cloacal membrane as a serious one.

==The Tail Gut==

The tail gut is that portion of the enteron that lies caudal to the lower limit of the cloacal membrane and before the formation of the cloacal membrane has no definite line of demarkation from the cloaca proper. The tail gut is represented by a conical sac in Model A and attains its largest proportions in Model B or at about the time that the Wolffian ducts reach the cloaca. Its relation to the neural tube and to the chorda is most marked at this stage in the development but the histogenesis of this region (shown in ]\Iodel B as a terminal knob) together with its possible connection with the ano-coccygeal body is not definitely known. The degenerative changes have already set in in Model C and are more apparent in Model D. The shrinkage in size does not affect the tail gut evenly throughout its length, but is less marked at the caudal extremity where a cord of cells may be found even after all traces of the primitive connection with the cloaca have disappeared. In general, the tail gut arises with the tail and accompanies the tail in its development and resorbtion. It appears at a 3.5 mm. stage and has almost completely disappeared in an 8.0 mm. embryo. The comparative embryology of this rudimentary and transient segment of the gut deserves careful study.

==The Cloaca==

Morphologically, we may hardly consider that portion of the gut caudal to the orifices of the allantois and hind gut as cloaca until the arrival of the Wolffian ducts contribute a connection with. the urogenital system, and practically we may not consider the sac as such until the formation of the cloacal membrane indicates how much is cloaca and how much is tail gut. The condition in the development which antedates these structures might be termed the precloacal stage.

Born states that the allantois arises ventrally in the human embryo and in close relation to the yolk sac, and that the allantois is displaced caudalward through growth in the intervening mesoderm. We may agree with the first part of this statement from the relations demonstrated in the Spee embryo and in Mall's reconstruction of no. 1. The last point, the downward displacement of the allantois, may be seriously questioned. In the formation of the hind gut, either the allantois is displaced caudalward, or the yolk sac is pushed upward on the gut. A comparison of embryos 1 and 3 favors the latter view. The development of the hind gut does not seem to take place at the expense of the cloaca, but the allantois appears to occupy a relatively fixed position at the lower border of the dermal navel. This argument is strengthened by the active increase in length of the hind gut, and by such conditions of strictly pathological nature such as bladder exstrophy. The line of demarkation however between what is allantois and what is ventral cloacal segment is largely a matter of topography, but is after all of some importance in a definite determination of the anlage for the urinary bladder.

==The Division Of The Cloaca==

The division of the cloaca manifests itself in a separation into ventral and a dorsal segment. According to Tourneux, the division is accomplished through the downgrowth of a single mesodermic fold (the saddle between the allantois and hindgut), while Retterer maintains that two lateral mesodermic folds encroach upon the lumen of the cloaca and pinch it off, as it were, into the two resulting segments. Minot ('97) and Keibel hold the manner of division to be of little moment, and even Fleischmann ('07) appears to have given up hope of solving the question from the standpoint of comparative embryology. Tourneux's idea is, according to the writer, a much better description of the process than that of Retterer.

Taking the Wolffian ducts as a fixed point, it is easily seen that a coronal septum grows down dorsal to the Wolffian orifices until finally the entoderm covering the septum comes into relation with the entoderm of the cloacal membrane. With the disappearance of the epithelium in this fused area, the mesoderm of the setpum touches the ectoderm of the surface and the cloacal membrane is split into its two resulting segments. While this division of the cloaca results in two segments that are about of equal size as far as their antero-posterior measurements are concerned, and inasmuch as the cloacal membrane does not materially increase in length, it may be assumed that the cloacal membrane is split into about equal parts in its transformation into the urogenital and anal membranes. This would mean that the increase in the apparent length of the urogenital membrane is due to proliferation of the ectodermal cells or to inclusion of the surface ectoderm as Born states it. The difference in opinion on this point will be brought out in a later article.

The development of the ventral cloacal segment interests us because it has to do with the formation of the bladder. Detailed measurements of this region have been suppressed because of the variable size of the cloaca proper, but the union of the allantois to the cloaca seems to be fairly definite in Models C, D and E. In all of these embryos the Wolffian ducts open a little above the center of a line drawn from the caudal extremity of the cloacal membrane to the apparent line of union of allantois with cloaca. We have therefore no material reason for not believing, inasmuch as this is the primitive relation of the Wolffian orifices and there is no evidence of downward displacement of the allantois, that the gradually constricting area above the Wolffian orifices is ventral cloacal segment (see Model B).

The active widening of the ventral cloacal segment, particularly at the level of the Wolffian orifices, is evident to every observer of the cross sections in this region, and in the dorsal convergence of the ureters â€” a fact first noted by Lieberkuhn and Keibel. It is evident also, as suggested by them, that the distal segment of the Wolffian ducts may become incorporated into the anlage for the bladder. This alone does not however account for the lateral rotation of the ureter to gain the position noted in Model F, nor does it explain the later upper displacement of the ureter to its normal position in the bladder.

It is seen in our models that the renal buds appear on the dorsal aspect of the Wolffian ducts at some distance from the cloaca, and the intervening segment of duct may be termed the ' cloacal segment' merely for convenience in the description. It is well known that this gradual shifting of the ureter is not due alone to the resorption of the cloacal segment of the Wolffian duct, for when two ureters arise from the same duct, the one with the orifice nearest the cloaca assumes the more lateral position. In this region we have to deal with the relations as they appear from their topography for it is not possible as yet to differentiate mesodermal epithelium from that of entodermal origin.

The widening of the ventral cloacal segment is made evident from the following measurements. A comparison of the inter-Wolfiian width and the width of the dorsal segment gives a proportion of 20 : 9 in B; 28 : 8 in C ; 36 : 9 in D ; and 46 : 9 in E. This means that the ventral cloacal segment increases markedly in width while the dorsal segment remains about the same. Observed in transverse sections, this active widening gives the impression of two lateral mesodermic folds encroaching upon the cloacal lumen (Retterer's idea.) The widening of the ventral cloacal segment is most marked at the level of the Wolffian orifices and progresses equally both upward and downward giving the idea coronal section of the cloaca in Model E a diamond shape.

In conclusion we may sum up the points that have been investigated in this paper in a review of the development of the cloaca and of the structures in relation with it. The article has been written largely as a check on the earlier stages in the development in order that the writer might have first hand information regarding this important segment of the enteron.

==Summary==

The cloaca is a closed entodermal sac and is never normally opened to the outside (amniotic cavity) through rupture of the cloacal membrane. It represents that portion of the enteron which lies caudal to the opening of the allantois and may not be separated from the tail gut until the formation of the cloacal membrane, when the inferior border of the membrane forms an arbitrary limit between the cloaca and the tail gut. The cloacal membrane arises from the primitive streak area. The primitive streak at the time of its ventral displacement in the formation of the tail fold, is composed of three germ layers, and the cloacal membrane is formed in situ through disappearance of the intervening mesoderm. Normally, the cloacal membrane occupies the caudal half of the ventral cloacal border, but in some cases, the membrane may extend as far cephalward as the dermal navel.. This latter condition has an important bearing on the embryology of bladder exstrophy and epispadias. The increase in width and thickness of the cloacal membrane is concomitant with the corresponding changes in the ventral segment of the cloaca, and is due to ectodermic proliferation. The membrane is displaced in the process of cloacal division through development of the precloacal mesodermic tissue to form the genital eminence, and at the same time, the original membrane comes to lie deeper in the substance of the embryo. The division of the cloaca begins before the arrival of the Wolffian ducts, and is effected by the downgrowth of a coronal septum. The division, when completed, results in a ventral, (or bladder-urogenital sinus,) segment and a dorsal, (or rectal,) segment which are about of equal size as far as their antero-posterior measurements are concerned. The same holds true of the resultants of the division of the cloacal membrane - the urogenital and anal membranes ; both of which are about of the same length and both of which are displaced from the surface through upgrowth of the surrounding mesoderm. The ventral cloacal segment enlarges progressively in length and in width during the division of the cloaca, and as the widening is most marked at the orifices of the Wolffian ducts, the cloacal segment of the ducts may contribute to this active enlargement, or in other words, some of the epithelium of the bladder may be of mesodermic origin. The displacement of the ureter on the Wolffian duct, and the later upward displacement of its orifice from that of the duct, is due in part to the disappearance of the cloacal segment of the duct. The orifices of both ureter and Wolffian duct are however shifted medianward after the completion of the cloacal division, so that the trigonum may be spoken of as distinctly of entodermic origin. The greater part of the bladder and urachus are developed from the ventral segment including the mesodermic contributions from the Wolffian ducts. The allantois probably contributes no part in the formation of the bladder and retains its original relation to the lower border of the dermal navel. The urogenital membrane ruptures normally when the division of the cloaca is completed, or in other words, with its formation, and before the arrival of the Mullerian ducts at the urogenital sinus. The contribution of the entoderm and ectoderm in the formation of the urethra, together with the developmental relations of the bulbovestibular glands, will be considered in a later paper.

Born has stated that the trigonum may be of mesodermic origin. We have measured Model F and compared it wdth Model 30 and find the following: that the inter-ureteral distance (between the orifices) is greater in F (0.55 mm.) than in no. 30 (0.34) ; while the Wolffian ducts in the former are almost twice as far apart as in the latter. This implies that the ureter is not displaced lateral-ward from the duct but that both are displaced medianward, and that if there is any part of the bladder to which the mesoderm has definitely not contributed it is the trigonum.

We are of the opinion that the ventral segment of the cloaca probably forms the anlage for the bladder including the urachus, as was stated in Born's article, and that the cloacal segment of the Wolffian ducts (mesodermic) contributes some part. How much is impossible to determine. When the cloacal membrane extends as far upward as the dermal navel and persists as an epithelial membrane, we have the origin of the cases of complete bladder exstrophy which take in the whole ventral wall of the bladder and urachus. The present champion of the allantoigen origin of the bladder is not supported by our investigations. Rather we agree with Disse ('02) who states that Nagel misunderstood the relations found in the earlier stages through examination of embryos too far advanced in the development.

==Bibliography==

Bonnet, K. 1888 Ucber die Entwickelung der Allantois und die Bildung des Afters bei den Wiederkiiuem. Anat. Anz.

Born, G. 1893 Die Entwickelung der Ableitungswege, etc. Ergebnisse der Anat. und Entwickelungsgesch.

DissE, J. 1902 Harnorgane. In von Bardeleben's Handbuch der Anatomie.

Hill, E. C. 1904 On the first appearance of the renal artery, etc. Johns Hopkins Bull., vol 16, February.

Fleischmann, 1907 Die Stilcharactere am Urodaeum und Phallus. Morph-Jahrbuch, vol. 36.

Keibel, F. 1888 Die Entwickelungsvorgange am hinteren Ende des Meersch" weinchenembryo. Arch. f. Anat. und Entw.

1891 Zur Entwickelungsgeschichte der Harnblase. Anat. Anz.

1896 Zur Entwickelungsgeschichte desmensch. Urogenitalapparates. Arch. f. Anat. und Phys. Anat. Abt.

Kolliker, A. Von 1898 Entwickelungsgeschichte des Menschen.

Lieberkuhn, N. 1882 Qucrschnittc von der Anlage der AUantois und der Harnblase, etc. Marburger Sitzungsberichte.

{{Ref-Mall1893humanembryo}}

{{Ref-Mall1904}}

{{Ref-Mall1897}}

Mihaicovics, G. von 1885 Untersuchungen uber die Entw. des Harn- und Geschlechtsapparates der Amnioten. Internat. Monatschrift. f. Anat. u. Hist.

Minot C. S. 1894 Human Embryology.

Nagel, W. 1894 Ueber die Entw. der inneren u. ausseren Genitalien beim mensch lichen Weibe. Arch. f. Gynilkologie.

1896 Zur Entwickelungsgeschichte des Urogenitalsystems beim Menschen. Arch. f. Anat. u. Phys. Anat. Abt.

{{Ref-Pohlman1904}}

Ratuke, 1832 Abhandlungen zur Bildungs- u. Entwickelungsgeschichte des Menschen u. der Thiere. Leipzig.

Reichel, P 1893 Die Entwickelung der Harnblase und Harnrohre. Verhand. d. mod. -phys. Gcsell. zu Wiirzburg.

Retterer, E. 1890 Sur I'origin et de revolution de la region ano-genitale des mammifreres. Jr. de I'anat. et de la phys.

1893-4 Mode de cloisonnement du cloaque chez le cobaye. Bibliog. Anat.

Spee, Graf 1896 Neue Beobachtungen uber sehr friihe Entwickelungsstufen des menschlichen Eies. Arch. f. Anat. u. Phys. Anat. Abt.

Strahl 1886 Zur Bildung der Cloake des Kaninchens. Arch. f. Anat. u. Phys. Anat. Abt.

Tourneux, F. 1893-4 Sur le mode de cloisonnement du cloaque, etc. Bibliog. Anat.

Zuckenkandl 1903 Handbuch der Urologie. Wien, Austria.

==Plates==
===Key to Lettering===

A., Allantois K., Kidney

A.M., Position of anal membrane P.T., Precloacal mesodermic tissue

C, Cloaca R.B., Renal bud

CM., Cloacal membrane T.G., Tail cut

C.S., Cloacal segment of Wolffian duct U., Ureter

G.E., Genital eminence U.G., Urogenital sinus

H.G., Hind gut U.M., Position of urogenital membrane

* Probable position of point where allantois joins cloaca.

All drawings represent 100 diameters enlargement except of Model F which is 50 diameters.

===Plate 1===
[[File:Pohlman1911 plate1.jpg|800px]]

===Plate 2===
[[File:Pohlman1911 plate2.jpg|800px]]

===Plate 3===
[[File:Pohlman1911 plate3.jpg|800px]]

{{Footer}}
[[Category:1910's]][[Category:Renal]][[Category:Gastrointestinal Tract]]
[[Category:Draft]]

Paper - The development of the cloaca in human embryos

2024-01-24T23:31:22Z

Z8600021: /* Bibliography */

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{{Ref-Pohlman1911}}
{| class="wikitable mw-collapsible mw-collapsed"
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| [[file:Mark_Hill.jpg|90px|left]] A number of [[Carnegie Embryos]] and models generated from these embryos are described in this historic study of human {{cloaca}} development. Note that Polman numbers the embryos examined in sequence 1-30, but also gives Mall's Carnegie embryo numbers in the tabulation.

See also by this author - {{Ref-Pohlman1904}}

Carnegie Embryo {{CE186}}

'''{{Cloaca}}''' - (cloacal cavity) The term describing the common cavity into which the intestinal, genital, and urinary tracts open in vertebrates. Located at the caudal end of the embryo it is located on the surface by the cloacal membrane. In many species this common cavity is later divided into a ventral urogenital region (urogenital sinus) and a dorsal gastrointestinal (rectal) region.

'''{{Cloacal membrane}}''' - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by {{ectoderm}} and {{endoderm}} without a middle (intervening) layer of {{mesoderm}}. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract. The upper end of the gastrointestinal tract has a similar embryonic membrane, the [[B#buccopharyngeal_membrane|buccopharyngeal membrane]].
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'''Modern Notes:''' {{cloaca}} | {{gastrointestinal tract}} | {{genital}} | {{renal}}
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{{#pmid:30294789}}
:"Subdivision of cloaca into urogenital and anorectal passages has remained controversial because of disagreements about the identity and role of the septum developing between both passages. This study aimed to clarify the development of the cloaca using a quantitative 3D morphological approach in human embryos of 4-10 post-fertilisation weeks. ...Our main finding was a pronounced difference in growth between rapidly expanding central and ventral parts, and slowly or non-growing cranial and dorsal parts. The entrance of the Wolffian duct into the cloaca proved a stable landmark that remained linked to the position of vertebra S3. Suppressed growth in the cranial cloaca resulted in an apparent craniodorsal migration of the entrance of the Wolffian duct, while suppressed growth in the dorsal cloaca changed the entrance of the hindgut from cranial to dorsal on the cloaca. Transformation of this 'end-to-end' into an 'end-to-side' junction produced temporary 'lateral (Rathke's) folds'. The persistent difference in dorsoventral growth straightened the embryonic caudal body axis and concomitantly extended the frontally oriented 'urorectal (Tourneux's) septum' caudally between the ventral urogenital and dorsal anorectal parts of the cloaca. The dorsoventral growth difference also divided the cloacal membrane into a well-developed ventral urethral plate and a thin dorsal cloacal membrane proper, which ruptured at 6.5 weeks. The expansion of the pericloacal mesenchyme followed the dorsoventral growth difference and produced the genital tubercle. Dysregulation of dorsal cloacal development is probably an important cause of anorectal malformations: too little regressive development may result in anorectal agenesis, and too much regression in stenosis or atresia of the remaining part of the dorsal cloaca."

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{{Genital Links}}
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{{Renal Links}}
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{{Historic Disclaimer}}
=The Development of the Cloaca in Human Embryos=
[[File:Augustus Pohlman.jpg|thumb|150px|alt=Augustus G. Pohlman|link=Embryology History - Augustus Pohlman|Augustus G. Pohlman]]
[[Embryology History - Augustus Pohlman|Augustus G. Pohlman]]

Indiana University

From the Anatomical Laboratory, Johns Hopkins University

==Introduction==

The active work in the embryology of the urogenital system began about 1880 and continued for a period of some fifteen years when Keibel's monograph was published. The writer's investigation of the cloacal region was started in 1903, and was undertaken in part as a control of Keibel's work, and in part with a view toward solving some of the points on which differences in opinion existed. The publication of this report has been delayed in the hope that certain facts in comparative embryology might be established and help to clarify some of the obscure relations found in the human embryo. Inasmuch as the extensive investigations of Fleischmann and his students have come to naught in this respect, the major differences in opinion will be considered, and the doubtful points answered in so far as it is possible. The short literature review covers the essential facts and effort has been made to reduce the description of the material to a concise tabulation. The writer expresses his indebtedness to Prof. Keibel at whose suggestion the development of the later stages in the embryology was undertaken, and to Prof. F. P. Mall for the use of his collection of embryos and for the many courtesies shown him in the Anatomical Laboratory of Johns Hopkins University.

Born's article ('93) reviews the earlier development of the cloacal region in a very complete manner, and the substance is as follows: The entoderm of the enteron comes into direct relation with the surface ectoderm in the pharyngeal and cloacal membranes during the formation of the head and tail folds. Both of these membranes lose their primitive position and become folded into the substance of the embryo through increase in the surrounding mesoderm. The allantois, which is developed dorsally in the mammalian embryo (human and guinea pig excepted), shifts to a ventral position on the gut, and is gradually displaced from its intimate relation to the yolk sac through increase in the amount of mesodermal tissue. The primitive streak is carried to the ventral surface of the body during the formation of the tail fold, and forms the whole or part of the cloacal membrane. Kolliker f'83), Strahl ('83, '84), and Bonnet ('88) believe that the caudal end of the primitive streak is made up of applied layers of ectoand entoderm, and that it enters as such into the formation of the cloacal membrane. Keibel ('88) argues that this primitive relation of the ecto- and entoderm is lost through interposition of mesoderm; the latter disappearing later with restoration of the original two layered condition.

The model of the 4.2 mm. human embryo presented by Keibel ('88) shows the hind gut and widely lumened allantois opening cephalward into the caudal entodermal sac or cloaca. Ventrally, this cloaca is limited as far as the dermal navel by the epithelial cloacal membrane. Caudalward, the limit of the cloacal membrane comes about by a mesodermic separation of the epithelial layers. The gut segment distal to the lower limit of the cloacal membrane may be termed the tail gut and terminates in an undifferentiated cell mass formed by itself, the chorda and neural tube. Born emphasizes the length of the cloacal membrane as follows: "I call particular attention to the original extent of the cloacal membrane. It reaches cephalward to the point where the allantois leaves the body at right angles; i.e., as far as the caudal border of the dermal navel."

The cloacal membrane does not extend as far as the allantois in the model of an 8.0 mm. human embryo presented by Keibel ('91) . Mesodermic tissue has apparently wandered in from above and separated the layers of epithelium. The cloacal membrane is therefore shorter than in the 4.2 mm. stage. The tail gut shows degeneration. The precloacal mesodermic tissue has increased in amount but instead of displacing the cloacal membrane caudal-ward, has folded it into the lower surface of the genital tubercle as was first described by Tourneux ('89), and verified by Retterer ('90) and Reichel ('93). No intermediate stage in the development has been described up to this time ('93). With the increase in size of the genital tubercle, the entodermal cloaca becomes more deeply placed as was demonstrated by Reichel ('93). Born states that the epithelial plate contained within the genital tubercle is ectodermic and that it is continuous with the superficial ectoderm. The epithelial plate occupies the caudal surface of the eminence and is bordered laterally by folds of mesoderm (repli ano-genitaux of Retterer) , while the cloacal membrane itself terminates at the postanal fold (replis postanal)., "The depression arises (as in the mouth region) through increase in the height of the limiting borders. The depression is always closed in by epithelium, and the base of the depression is never separated from the entodermal cloaca by mesodermic tissue." (Born.)

The cloaca is gradually divided into a ventral (bladder-urogenital sinus) segment, and a dorsal (gut) segment. As to the manner of this division, Retterer and Born agree with the Tiedemann-Rathke idea of the gradual separation into two segments through approximation of two lateral folds of mesoderm, while Tourneux believes it to be accomplished by a septal (frontal) downgrowth. Lieberkiihn ('82) and Keibel ('89) dispute the theory of Rathkc ('32) championed bj' von Mihlacovics ('85), that the bladder arises from the allantois, and state that it is made up for the most part from the ventral cloacal segment - agreed to by Retterer and Reichel. Born takes a neutral position and believes that at least the trigone of the human bladder may be developed in a manner like that found in the guinea pig (Keibel). Born and Minot do not think that the anlage of the upper part of the bladder is of particular importance. "We are probably not mistaken when we grant that not only the bladder (as far as the apex) but the male urethra as far as the caput gallinaginis, the entire female urethra, and in the male, also the pars prostatica and the entire pars membranacea are developed from the ventral cloacal segment."

The most important of the recent works is that of Ke bel ('96) who sums up the development of the cloacal region in the following words : "The human embryo possesses a large entodermal cloaca in the early stages of its development which however is never opened to the outside through a cloacal anus ('Cloakenafter' of Prenant), but remains closed through the cloacal membrane (the 'anal membrane' of the earlier writers) as long as it exists as such. An ectodermal cloaca is to be found only in traces if at all. The entodermal cloaca is separated into a ventral and a dorsal segment by a frontal septum. A large part or all of the bladder, the urethra and the urogenital sinus as far as the cloacal membrane are derived from the ventral segment; while the dorsal segment becomes continuous with the ectodermal segment of the rectal canal. The primitive perineum is formed when the frontal septum fuses with the cloacal membrane and the rudimentary ectodermal cloaca is then divided by the permanent perineum. The ectodermal anal pit (protodaeum) is situated behind the permanent perineum, while the ectodermal portion of the urogenital sinus is ventral to it."

[[File:Pohlman1911 fig1.jpg|thumb|'''Fig. 1.''']]

Another investigator, who has been particularly fortunate in the amount of embryological material at his disposal, expresses a somewhat different view. Nagel ('02) practically reiterates his statements of 1894. "The inspection of the tail end of human embryos of 11-13 mm. length reveals an oval pit extending from the coccygeal prominence to the tip of the genital eminence. This pit (cloaca) receives the openings of the gut dorsally, and the Canalis urogenitalis ventrally; the two separated by a partition of some 0.3 mm. thickness. The Wolffian and Mullerian ducts open higher up in the Canalis urogenitalis and will not be considered in the description of this depression. The Canalis urogenitalis and the gut open into this pit (cloaca) which would reach (comparing with adult relations) from the dorsal border of the anus to the ventral border of the urethral opening {i.e. Frenulum clitoridis). Later he states: "In what manner the division of the cloaca is accomplished is not perfectly understood either in man or in mammals. I found the relations in the youngest human embryo that I had opportunity to examine like those pictured in fig, 1, naturally with exception of the form of the bladder. I commit myself therefore, as far as the human embryo is concerned, to the view of Rathke which has recently been substantiated by Retterer and von Mihalcovics in the animals."

The work of von Mihalcovics ('85) referred to, says in part; "This septum between the urogenital canal and the gut arises in part through increase in length of the afore-mentioned perineal Told (septum) to which, distalward, two lateral folds join to the perineal folds. The cloaca takes no part in the formation of the urogenital canal." The opinion of Retterer ('94), mentioned by Nagel, is summarized as follows: "In the guinea pig, as in other mammals studied up to the present time (man, pig, sheep and rabbit), a fold of mesoderm appears at the cephalic extremity of each lateral cloacal wall, and extends little by little toward the caudal end of the cloaca. These lateral folds encroach upon the lumen of the cloaca and divide it into two canals, the one dorsal or rectal, and the other ventral or vesico-urogenital."

That these opinions, while they are in the main contrary to the views of Keibel although they appeared at an earlier date, are accepted at the present time can be illustrated by an extract from Zuckerakndls Handbuch der Urologie ('03): "In the second fetal month, the proximal segment of the allantois widens to form the bladder, while the distal and narrow portion (urachus) obliterates to form the Lig. vesico-umbilicale," "The division of the cloaca is accomplished by three folds, a median and two lateral. The former occupies the angle between the allantois and hind gut, while the latter are developed in the lateral walls of the cloaca."

The investigations of Tourneux ('94) agree with those of Keibel in that he also states the cloaca to be a closed sac. His objections to the method of cloacal division as described by Retterer are as follows: "The form of the inferior border of the recto-urogenital septum is that of a vaulted arch and not that of an elliptical arch with the vertex upward - " a fact easity demonstrated in frontal sections. In addition to this, the transverse sections show that the lateral folds are found only toward the summit of the arch and converge rapidly. Further, the septum shows no signs of an epithelial raphe at the supposed line of fusion to indicate the transition that one encounters, as Keibel states, "at the line of union of the palatine ridges."

Nagel ('96) answers Keibel's article by stating ''If Keibel did not find the facts as presented by myself in all of his embryos of 11.0 mm. and upwards, then the embryos are at fault." "Furthermore in order that an embryo may be declared of scientific value, I demand that the urogenital canal be open into the cloacal pit in all embryos over 8.0 mm., and that the cloacal membrane have disappeared as far as the tip of the genital eminence. Inasmuch as th& allantois contained within the umbilical cord is practically obliterated at this stage, where could the secretion from the mesonephros be stored up if the cloacal membrane were intact?"

The questions that appeal to the writer as doubtful ones may be expressed as follows:

# Does the cloaca proper ever open to the outside?
# Does the cloacal membrane arise directly by displacement of applied layers of ecto- and entoderm in the primitive streak or is it formed in situ through disappearance of the intervening mesoderm?
# In what manner is the cloacal division effected?
# What is the anlage for the bladder?
# Can the urinary function of the mesonephros assumed by Nagel be demonstrated?

==Material==

The study of the cloacal region was done in part by working out the relations in serial sections, and in part through reconstruction. Thirty embryos in all were examined; reconstruction employed in thirteen, of which six stages will be presented. The material, with the exception of these six , is given entirely in the tabulation. The serial number, used throughout this paper, refers to the age of the embryo based on the development of the urogenital tract and with no particular reference to its length. It is interesting to note that with the exception of nos. 4, 11, 13, and 21, the development of the tract has proved to be an excellent check on the determination of the age by the greatest length method. The Mall number refers to the catalogue number of the collection of human embryos at Johns Hopkins University and the section thickness (indicated in microns) ; the section direction (+ for transverse, = for sagittal, and || for coronal; and the condition (f for fair and g for good) are recorded in this manner in the Mall catalogue. The modelling of the embryo is indicated by the magnification of the same, and where the model is presented in this paper it is designated by a capital letter. The brief normentafel shows the major points of difference in the development of the cloacal region. The embryo 30 is the Piper II embryo of the collection, and will be presented later in connection with the origin of the bulbovestibular glands. This embryo and also no. 20 have been reported in connection with the condition of complete double ureter (Johns Hopkins Bull., vol. 16, Feb. '04).

===Tabulation===
:'''Online editor''' - Carnegie stages have been added to the original tabulation and the text information is now edited in a sortable table.

{|
{| class="wikitable sortable"
|-
! Embryo
! Mall
! Stage
! CRL
! Plane
! Thickness (microns)
! Quality
! Notes
|-
| 1 || {{CE12}} || [[Carnegie stage 11|11]] || 2.1 mm|| transverse|| 10|| good|| Modelled by Mall ('97). Allantois of small lumen and in relation with the caudal border of the yolk sac. No evidences of a cloacal membrane.
|-
| 2 || {{CE391}} || [[Carnegie stage 10|10]] || 2.0 mm || transverse || 10|| Good|| Appearance of hind gut. An interval of several sections between allantois and yolk sac. No cloacal membrane.
|-
| 3 || {{CE164}} || [[Carnegie stage 11|11]] || 3.5 mm || transverse || 20|| Good || [[:File:Pohlman1911 plate1A.jpg|Model A]]. x 100. Cloaca well developed and limited for caudal half of the ventral border by epithelial cloacal membrane. Allantois comes off at right angles and at lower border of dermal navel. Lateral furrow along later line of division.
|-
| 4 || {{CE209}} || [[Carnegie stage 12|12]] || 3.0 mm || transverse || 50|| Fair|| Relations about the same as the fore-going stage. Sections too thick for detailed study. [[Carnegie stage 12]]
|-
| 5 || {{CE186}} || [[Carnegie stage 13|13]] || 3.5 mm|| transverse|| 20|| Good|| [[:File:Pohlman1911 plate1B.jpg|'''Model B''']]. x 100. Allantois wide lumened and no distinct line of demarkation from the ventral cloacal segment. Wolflian ducts have arrived but not as yet opened. Tail gut maximum of development. Probably the first signs of cloacal division.
|-
| 6 || {{CE87}} || || 4.0 mm|| transverse|| 20|| Fair|| About the same as the foregoing. [[Carnegie stage 13|13]]
|-
| 7 || {{CE148}} || [[Carnegie stage 13|13]] || 4.3 mm || transverse || 10|| Good || x 100 Wolffian ducts open into cloaca. Allantois of small lumen. Ventral cloacal segment widening. Evidences of division quite apparent.
|-
| 8 || {{CE76}} || [[Carnegie stage 13|13]] || 4.5 mm || transverse || 20|| Good|| x 100. Widened ventral cloacal segment goes over indistinctly into allantois. Tail gut still quite large. Renal buds well developed. With exception of large allantois and wider tail gut, quite similar to Model C.
|-
| 9 || {{CE80}} || [[Carnegie stage 14|14]] || 5.0 mm|| transverse || 10|| Good|| [[:File:Pohlman1911 plate2C.jpg|Model C]]. x 100. About the same as the foregoing stage. Tail gut undergoing degenerative changes.
|-
| 10 || 371|| [[Carnegie stage 15|15]] || 6.6 mm|| sagittal || 10|| Good|| Tail gut rudimentary. Development of cloaca and renal buds about the same as in no. 12.
|-
| 11 || 116|| [[Carnegie stage 13|13]] || 5.0 mm || sagittal || 20|| Good|| x 100. Intracloacal epithelial plug well marked. Stage about the same as that found in no. 12.
|-
| 12 || {{CE2}} || [[Carnegie stage 15|15]] || 7.0 mm|| transverse|| 15|| Good|| [[:File:Pohlman1911 plate2D.jpg|Model D]] x 100. Marked development of renal buds. Kidney and ureter segments evident. Ventral cloacal segment much widened. Allantois of narrow lumen. Intracloacal epithelial plug marked. Tail gut maximum in length and slightly widened at caudal end.
|-
| 13 || {{CE241}} || [[Carnegie stage 15|15]] || 6.0mm|| transverse|| 10|| Goo(l|| Tailgutmore rudimentary than in no. 12. Cloacal membrane wide and shows intracloacal epithelial plug. Otherwise about the same as in no. 12.
|-
| 14 || {{CE383}} || [[Carnegie stage 16|16]] || 7.0 mm|| transverse || 10|| Good|| State similar to no. 12. Cloacal membrane intact.
|-
| 15 || {{CE397}} || [[Carnegie stage 16|16]] || 8.0 nma.|| transverse|| 10|| Good|| Similar to foregoing.
|-
| 16 || {{CE113}} || [[Carnegie stage 15|15]] || 8.0 mm|| sagittal|| 10 || Fair|| x 100. Stage of cloacal division between than found in no. 12 and that found in no. 19. Cloacal membrane intact. Division of ureteral pelvis. Ureter segment elongated.
|-
| 17 || {{CE114}} || || 10.0 mm|| sagittal|| 10|| Fair|| x 100. Stage of cloacal division about the same as the foregoing. Cloacal membrane intact. Kidney a little higher up. Upper and lower pelvis evident.
|-
| 18 || {{CE109}} || [[Carnegie stage 18|18]] || 11.0 mm|| transverse|| 20|| Good|| Sections directly through lower part of cloacal region somewhat damaged. Otherwise about the same as no. 19.
|-
| 19 || {{CE221}} || [[Carnegie stage 16|16]] || 12.0 mm|| sagittal || 20|| Good|| [[:File:Pohlman1911 plate3E.jpg|Model E]] x 100. All traces of tail gut lost. Cloacal membrane somewhat depressed from surface. Cloacal segment of Wolffian duct shortened and opening of ureter and duct common into ventral cloacal segment. Beginning formation of genital eminence and lengthening of the ventral cloacal wall. Cloacal membrane intact.
|-
| 20 || {{CE175}} || || 13.0 mm|| transverse|| 20|| Good|| x 100. Cloaca about divided. Complete double ureter. Orifices of lateral, and medial ureter and Wolffian duct at same level into cloaca.
|-
| 21 || {{CE353}} || [[Carnegie stage 17|17]] || 11.0 mm|| transverse || 10|| Good|| Cloaca completely divided. Anal and urogenital membranes intact. Ureteral orifice independent and on level with Wolffian opening.
|-
| 22 || {{CE317}} || [[Carnegie stage 18|18]] || 15.0 mm|| coronal || 20|| Good|| About the same stage as in no. 21.
|-
| 23 || {{CE350}} || [[Carnegie stage 19|19]] || 15.0 mm|| coronal || 10|| Good|| About the same as the foregoing, and no. 24.
|-
| 24 || {{CE43}} || [[Carnegie stage 19|19]] || 16.0mm|| sagittal || 50|| Good|| [[:File:Pohlman1911 plate3F.jpg|Model F]] . x 50. Anal and urogenital membranes separated. Genital eminence more marked. Ectodermic inclusion in furrow on caudal surface. Ureteral orifice on same level but some distance lateral to Wolffian orifice.
|-
| 25 || {{CE256}} || [[Carnegie stage 20|20]] || 16.0 mm|| sagittal || 50|| Good|| Urogenital sinus open to outside through rupture of urogenital membrane. Kidney nearly up to normal position and rotated.
|-
| 26 || {{CE296}} || [[Carnegie stage 18|18]] || 7.0mm|| coronal|| 20|| Good|| Slightly older than above. Appearance of secondary genital folds at the sides of the phallus.
|-
| 27 || {{CE128}} || [[Carnegie stage 21|21]] || 20.0 mm|| coronal|| 50|| Good|| About same as above.
|-
| 28 || {{CE240}} || [[Carnegie stage 20|20]] || 20.0 mm|| coronal|| 20|| Good||
|-
| 29 || {{CE22}} || [[Carnegie stage 21|21]] || 20.0 mm|| transverse|| 50|| Good|| One Mullerian duct has reached the urogenital sinus.
|-
| 30 || Embryo KP|| || 22.0 mm|| transverse|| 15|| Good|| X 66. Both Mullerian ducts at sinus.
|}

The last six embryos of this series have been introduced merely to carry out the idea of a brief arrangement according to the development of the tract in so far as it was possible and to indicate the position of Model of no. 30 referred to in reference to the measurements on the inter-ureteral and inter- Wolffian widths mentioned in the discussion of the anlage for the trigonum. Embryo no. 30 has additional interest in that it like no. 20 has a complete duplication of the ureter on one side.

The description of the models has been made in as brief a manner as feasible, and a discussion of the various points in question will be brought up after they have been described. All of these models represent epithelial casts, and all of them with the exception of Model F. are X 100.

{|
| [[:File:Pohlman1911 plate1A.jpg|'''Model A''']]. {No. 3; Mall no. 164; 3.5 mm.) This model shows the cloaca to be a sort of conical sac receiving the wider lumened hind gut dorsally, and the narrow lumened allantois ventrally. The latter joining the cloaca at about a right angle. The cloaca is much wider dorsally and is somewhat wedged-shaped in section. Ventrally, it is limited for about one-half of its extent by the epithelial cloacal membrane which is indicated by a surface contact. The right wall of the cloaca is concaved from before backwards while the left side (shown) is correspondingly convex, and presents a well marked furrow extending from the saddle between the allantois and hind gut to about the mid area of the cloacal membrane. This furrow is interesting because while it indicates the probable line of the later division, it was found in but two embryos of the series examined. The part of the cloaca caudal to the cloacal membrane - the tail gut - is quite short and cone-shaped. The model with the exception of the furrow conforms to Keibel's model of the His embryo EB (3 mm.)
| [[File:Pohlman1911 plate1A.jpg|thumb|200px|Model A]]
|}
{|
| [[:File:Pohlman1911 plate1B.jpg|'''Model B''']] {No. 5; Mall no. {{CE186}}; 3.5 mm.) This model, although made from an embryo of the same length as the above, shows a distinctly older stage in the development of the tract. The allantois has a much wider lumen and the angle between it and the hind gut is much more acute. The Wolffian ducts have reached the cloaca, and attach but do not open into it ventrally near the upper limit of the cloacal membrane. The tail gut is much larger both in length and in thickness, and terminates in an undifferentiated cell mass formed by itself, the chorda and the neural tube (shown as a knob-like ending). The cloaca is wider dorsally than ventrally. A stage similar to the one described was found in two other embryos (nos. 7 and 8), in both of which the allantois was wide at its apparent opening into the cloaca. The possibility of some minor degree of development abnormality suggested itself but on careful study, it was decided that the first evidences of cloacal division were at hand.

[[:File:Pohlman1911 plate1B.jpg|'''Model B''']], other than a better developed tail gut, a slightly higher position of the Wolffian ducts and a shorter cloacal membrane agrees with Keibel's model of the 4.2 mm. embryo. Keibel's model shows this same evidence of division; a frontal septum between the allantois and hind gut slipping down to a level approaching the upper limit of the cloacal membrane. The writer has found no embryo where the cloacal membrane approaches the level of the dermal navel, and will consider this point later.
| [[File:Pohlman1911 plate1B.jpg|thumb|200px|Model B]]
|}
{|
| [[:File:Pohlman1911 plate2C.jpg|'''Model C''']]. {No. 9; Mall no. 80; 5.0 mm..) This model shows marked degeneration of the tail gut. The allantois is narrow lumened, while the widely lumened ventral cloacal segment lies ventral to the hind gut and dorsal segment, and is separated from them by peritoneum. The Wolffian ducts open in the same situation as in the foregoing model, and present dorsal diverticulae, the renal buds. The ventral portion of the cloaca, especially the area above the cloacal membrane, is markedly widened and flattened. The lateral furrow of Model A was not present. This model conforms to the Keibel model of a 6.5 mm. embryo (a considerably older stage if we go by the greatest length rule). The cloaca has lost its more or less even width and attains its greatest lateral diameter at the level of the Wolffian orifices. There is no evidence of displacement of the Wolffian ducts from their primitive position in relation with the upper limit of the cloacal membrane.
| [[File:Pohlman1911 plate2C.jpg|thumb|200px|Model C]]
|}
{|
| [[:File:Pohlman1911 plate2D.jpg|'''Model D''']] {No. 12; Mall no. 2; 7.0 mm.) This model fills in a gap in the Keibel series which may be considered quite an important one. The hind gut and all that pertains to the dorsal segment of the cloaca has retained an even caliber, while the ventral segment has widened progressively. The division of the cloaca may be traced to the level of the Wolffian orifices. The Wolffian ducts are much better developed and the renal anlage has resolved itself into distinct ureter and kidney segments. The segment of Wolffian duct between the orifice of the ureter and the cloaca is relatively shorter. The renal anlagen have assumed the position of dorsal convergence (mentioned by Keibel) but this is only a relative matter (see later). The tail gut has undergone further degeneration and has lost its lumen in part.
| [[File:Pohlman1911 plate2D.jpg|thumb|200px|Model D]]
|}
{|
| [[:File:Pohlman1911 plate3E.jpg|'''Model E''']]. {No. 19; Mall no. 221; 12.0 mm.) This stage shows the cloaca about half divided along the furrow line indicated in Model A. The cloacal membrane has thickened but mostly through addition of ectodermal cells, and has been displaced through development of the ' precloacal mesoderm' from its primitive position parallel to the dorsal line of the cloaca to one more nearly at right angles to it. In so far as it was possible to ascertain, this downward displacement of the cloacal membrane in no way affects its caudal limit. The dorsal segment has retained the original proportions while the ventral segment has widened - most marked again at the level of the Wolffian orifices. The further development of the kidney and ureter will be noted and the gradual approach of the ureteral orifice to the cloaca proper is evident. The ureter shows signs of shifting from its primitive dorsal position on the Wolffian duct to a more lateral one. The peritoneum has descended to the level of the ducts while the cloacal division is relatively far advanced. The model agrees with Keibel's model of an 11.5 mm. embryo.
| [[File:Pohlman1911 plate3E.jpg|thumb|200px|Model E]]
|}
{|
| [[:File:Pohlman1911 plate3F.jpg|'''Model F''']]. {No. 24; Mall no. 43; 16.0 mm. X 50.) Unfortunately this embryo was cut too thick for minute reconstruction. The stage however fills in another gap in the Keibel series. Here the cloaca and the cloacal membrane are completely divided - the ventral segment limited by the urogenital plate and the dorsal segment by the anal plate. The ureter is displaced from its dorso-lateral position on the Wolffian duct to a supero-lateral one and opens distinctly into the ventral cloacal segment. The marked increase in precloacal tissue has resulted not only in the large genital eminence, but the urogenital plate has been dislocated deeper into the base of the phallus and a marked heaping up of ectodermal cells has occurred in the furrow on the caudal surface of the eminence. The two resultant segments of the cloacal membrane, the urogenital and anal plates are apparently no longer than they were in much younger stages; a point that will be brought out in greater detail later.
| [[File:Pohlman1911 plate3F.jpg|thumb|200px|Model F]]
|}

==The Cloacal Membrane==

While authorities seem to agree that the cloacal membrane arises from the primitive streak, or at least that portion which has been displaced ventrally in the formation of the tailfold, they disagree on the point whether this part of the primitive streak consists in applied layers of ecto- and entoderm, or whether it is composed of all three germ layers. Stated in an simple manner, is the cloacal membrane formed dorsally as an epithelial membrane or is it formed ventrally through disappearance of intervening mesodermal tissue? One of the earliest stages in the formation of the tail fold is found in the Spee reconstruction ('96) of [[:Category:Glaevecke Embryo|embryo Gle]] (2.0 mm.). A schematic sagittal section is presented in his fig. 1, and emphasis is laid on the point that the primitive streak is composed of all three germ layers. No. 1 of the present tabulation was reconstructed by Mall ('97), and while a slightly older stage in the development, shows the cloacal sac limited ventrally by all three germ layers. No. 2 presents a similar condition. The first embryo of this series to show a cloacal membrane is no. 3 (3.5 mm.) which is quite a little farther advanced in the development than no. 2; unfortunately the transition stages are wanting. It is the writer's opinion therefore that the view held by Keibel is the correct one, and that while the cloacal membrane is derived from the primitive streak area, it is formed in situ as an epithelial membrane on the ventral cloacal surface, naturally after the formation of the tail fold.

The sagittal width of the cloacal membrane varies somewhat with the stage in the development. Born's statement that it extends as far cephalward as the dermal navel is based on Keibel's model of a 4.2 mm. embryo ('88). A somewhat similar condition is noted in two of the embryos of this series. The writer does not believe this to be the normal relation, but rather one which through persistence may have a decided bearing on bladder exstrophy and epispadias. The epithelial plate, if it extends to the dermal navel, and persists in this relation, separates the precloacal tissue into two lateral halves, and accounts quite satisfactorily for the deficience in the abdominal wall and for the gutter on the upper surface of the phallus. In practically all of the embrj'os exam- ined, the cloacal membrane did not extend higher than the level of the Wolffian orifices. The membrane is normally shortest in length at the time of its formation but attains its greatest length in Model C. (0.29 mm.); in Model D (0.27 mm.); in Model E (0.34 mm.). This increase is not marked when we consider that these stages represent 5, 7 and 12 mm. embryos respectively.

The width of the cloacal membrane is a rather indefinite quantity to measure ; it widens progressively however with the widening of the ventral cloacal segment, and in the proportion of 5 in B to 8 in C to 12 in D or in other words in proportion to the greatest length measurement of the embryo.

The position of the cloacal membrane is about parallel to the long axis of the embryo in Models A, B and C. With the development of the precloacal tissue, the cloacal membrane is displaced so that its upper end is pushed caudalward â€” beginning in D; more marked in E ; and culminating in F where the upper end of the membrane has been displaced through practically 90° with the caudal end as the fixed point of the radius. The displacement is probably due to the active lengthening of the ventral cloacal wall and to the development of the genital eminence. The membrane is divided into two parts in Model F â€” a ventral or urogenital membrane and a dorsal or anal membrane; both of which have been displaced from the surface in the manner suggested by Born. The anal membrane persists beyond the stages described in this paper, and is dealt with in sufficient detail in Keibels' article. The urogenital membrane ruptures with its formation and is of particular interest in its relation to the position of the bulbovestibular glands ; a point to be brought in a paper which is to appear shortly. It may be noted that in Model D the cloacal membrane is much thicker in its midarea, and not infrequently one finds a heaping up of cells in this region and a corresponding eminence on the inner surface of the cloacal (intracloacal epithelial plug) . The significance of this is not understood but it may be due to the more active proliferation of the ectodermal cells which contribute to the formation of the cloacal membrane.

==The Ectodermal Cloaca==

An ectodermal cloaca has been stated by Keibel to be present only in traces, if at all. None of the embryos examined showed a surface depression, and we may therefore critically examine Nagel's fig. 1 and his contention concerning the cloacal membrane. It will be seen that in fig. 1, while the embryo shows a cloacal division comparable to our Model E; the phallus is developed to the extent of that found in Model F ; while the cloacal membrane is ruptured. None of the embryos of this stage, or younger than this stage, showed rupture of the cloacal membrane, and we may therefore agree with Keibel that the cloacal membrane remains intact normally as long as it persists as such. Nagel believes that the rupture of the membrane is essential or where would the secretion of the mesonephros be passed? We may answer this question. The ventral cloacal segment and the allantois do not show the degree of widening necessary to accommodate the urinary excretion, and we call to mind Hill's work on the pig embryo ('04) and our own ('04) on the human embrj'o, in both of which it is conclusively shown that the mesonephros is actively degenerate long before the kidney is developmentally fitted to take up a urinary function. Cases of atresia urethrae commonly occur without bladder distension ; monstrosities may go to term without kidneys and with no undue persistence of the mesonephros; and experimentally, it has been shown that there is no evidence of urinary excretion into the amniotic fluid even in term children. We do not believe it necessary to assume that the mesonephros functionates as an organ of excretion in the placental mammals, and do not consider Nagel's contention for a functional rupture of the cloacal membrane as a serious one.

==The Tail Gut==

The tail gut is that portion of the enteron that lies caudal to the lower limit of the cloacal membrane and before the formation of the cloacal membrane has no definite line of demarkation from the cloaca proper. The tail gut is represented by a conical sac in Model A and attains its largest proportions in Model B or at about the time that the Wolffian ducts reach the cloaca. Its relation to the neural tube and to the chorda is most marked at this stage in the development but the histogenesis of this region (shown in ]\Iodel B as a terminal knob) together with its possible connection with the ano-coccygeal body is not definitely known. The degenerative changes have already set in in Model C and are more apparent in Model D. The shrinkage in size does not affect the tail gut evenly throughout its length, but is less marked at the caudal extremity where a cord of cells may be found even after all traces of the primitive connection with the cloaca have disappeared. In general, the tail gut arises with the tail and accompanies the tail in its development and resorbtion. It appears at a 3.5 mm. stage and has almost completely disappeared in an 8.0 mm. embryo. The comparative embryology of this rudimentary and transient segment of the gut deserves careful study.

==The Cloaca==

Morphologically, we may hardly consider that portion of the gut caudal to the orifices of the allantois and hind gut as cloaca until the arrival of the Wolffian ducts contribute a connection with. the urogenital system, and practically we may not consider the sac as such until the formation of the cloacal membrane indicates how much is cloaca and how much is tail gut. The condition in the development which antedates these structures might be termed the precloacal stage.

Born states that the allantois arises ventrally in the human embryo and in close relation to the yolk sac, and that the allantois is displaced caudalward through growth in the intervening mesoderm. We may agree with the first part of this statement from the relations demonstrated in the Spee embryo and in Mall's reconstruction of no. 1. The last point, the downward displacement of the allantois, may be seriously questioned. In the formation of the hind gut, either the allantois is displaced caudalward, or the yolk sac is pushed upward on the gut. A comparison of embryos 1 and 3 favors the latter view. The development of the hind gut does not seem to take place at the expense of the cloaca, but the allantois appears to occupy a relatively fixed position at the lower border of the dermal navel. This argument is strengthened by the active increase in length of the hind gut, and by such conditions of strictly pathological nature such as bladder exstrophy. The line of demarkation however between what is allantois and what is ventral cloacal segment is largely a matter of topography, but is after all of some importance in a definite determination of the anlage for the urinary bladder.

==The Division Of The Cloaca==

The division of the cloaca manifests itself in a separation into ventral and a dorsal segment. According to Tourneux, the division is accomplished through the downgrowth of a single mesodermic fold (the saddle between the allantois and hindgut), while Retterer maintains that two lateral mesodermic folds encroach upon the lumen of the cloaca and pinch it off, as it were, into the two resulting segments. Minot ('97) and Keibel hold the manner of division to be of little moment, and even Fleischmann ('07) appears to have given up hope of solving the question from the standpoint of comparative embryology. Tourneux's idea is, according to the writer, a much better description of the process than that of Retterer.

Taking the Wolffian ducts as a fixed point, it is easily seen that a coronal septum grows down dorsal to the Wolffian orifices until finally the entoderm covering the septum comes into relation with the entoderm of the cloacal membrane. With the disappearance of the epithelium in this fused area, the mesoderm of the setpum touches the ectoderm of the surface and the cloacal membrane is split into its two resulting segments. While this division of the cloaca results in two segments that are about of equal size as far as their antero-posterior measurements are concerned, and inasmuch as the cloacal membrane does not materially increase in length, it may be assumed that the cloacal membrane is split into about equal parts in its transformation into the urogenital and anal membranes. This would mean that the increase in the apparent length of the urogenital membrane is due to proliferation of the ectodermal cells or to inclusion of the surface ectoderm as Born states it. The difference in opinion on this point will be brought out in a later article.

The development of the ventral cloacal segment interests us because it has to do with the formation of the bladder. Detailed measurements of this region have been suppressed because of the variable size of the cloaca proper, but the union of the allantois to the cloaca seems to be fairly definite in Models C, D and E. In all of these embryos the Wolffian ducts open a little above the center of a line drawn from the caudal extremity of the cloacal membrane to the apparent line of union of allantois with cloaca. We have therefore no material reason for not believing, inasmuch as this is the primitive relation of the Wolffian orifices and there is no evidence of downward displacement of the allantois, that the gradually constricting area above the Wolffian orifices is ventral cloacal segment (see Model B).

The active widening of the ventral cloacal segment, particularly at the level of the Wolffian orifices, is evident to every observer of the cross sections in this region, and in the dorsal convergence of the ureters â€” a fact first noted by Lieberkuhn and Keibel. It is evident also, as suggested by them, that the distal segment of the Wolffian ducts may become incorporated into the anlage for the bladder. This alone does not however account for the lateral rotation of the ureter to gain the position noted in Model F, nor does it explain the later upper displacement of the ureter to its normal position in the bladder.

It is seen in our models that the renal buds appear on the dorsal aspect of the Wolffian ducts at some distance from the cloaca, and the intervening segment of duct may be termed the ' cloacal segment' merely for convenience in the description. It is well known that this gradual shifting of the ureter is not due alone to the resorption of the cloacal segment of the Wolffian duct, for when two ureters arise from the same duct, the one with the orifice nearest the cloaca assumes the more lateral position. In this region we have to deal with the relations as they appear from their topography for it is not possible as yet to differentiate mesodermal epithelium from that of entodermal origin.

The widening of the ventral cloacal segment is made evident from the following measurements. A comparison of the inter-Wolfiian width and the width of the dorsal segment gives a proportion of 20 : 9 in B; 28 : 8 in C ; 36 : 9 in D ; and 46 : 9 in E. This means that the ventral cloacal segment increases markedly in width while the dorsal segment remains about the same. Observed in transverse sections, this active widening gives the impression of two lateral mesodermic folds encroaching upon the cloacal lumen (Retterer's idea.) The widening of the ventral cloacal segment is most marked at the level of the Wolffian orifices and progresses equally both upward and downward giving the idea coronal section of the cloaca in Model E a diamond shape.

In conclusion we may sum up the points that have been investigated in this paper in a review of the development of the cloaca and of the structures in relation with it. The article has been written largely as a check on the earlier stages in the development in order that the writer might have first hand information regarding this important segment of the enteron.

==Summary==

The cloaca is a closed entodermal sac and is never normally opened to the outside (amniotic cavity) through rupture of the cloacal membrane. It represents that portion of the enteron which lies caudal to the opening of the allantois and may not be separated from the tail gut until the formation of the cloacal membrane, when the inferior border of the membrane forms an arbitrary limit between the cloaca and the tail gut. The cloacal membrane arises from the primitive streak area. The primitive streak at the time of its ventral displacement in the formation of the tail fold, is composed of three germ layers, and the cloacal membrane is formed in situ through disappearance of the intervening mesoderm. Normally, the cloacal membrane occupies the caudal half of the ventral cloacal border, but in some cases, the membrane may extend as far cephalward as the dermal navel.. This latter condition has an important bearing on the embryology of bladder exstrophy and epispadias. The increase in width and thickness of the cloacal membrane is concomitant with the corresponding changes in the ventral segment of the cloaca, and is due to ectodermic proliferation. The membrane is displaced in the process of cloacal division through development of the precloacal mesodermic tissue to form the genital eminence, and at the same time, the original membrane comes to lie deeper in the substance of the embryo. The division of the cloaca begins before the arrival of the Wolffian ducts, and is effected by the downgrowth of a coronal septum. The division, when completed, results in a ventral, (or bladder-urogenital sinus,) segment and a dorsal, (or rectal,) segment which are about of equal size as far as their antero-posterior measurements are concerned. The same holds true of the resultants of the division of the cloacal membrane - the urogenital and anal membranes ; both of which are about of the same length and both of which are displaced from the surface through upgrowth of the surrounding mesoderm. The ventral cloacal segment enlarges progressively in length and in width during the division of the cloaca, and as the widening is most marked at the orifices of the Wolffian ducts, the cloacal segment of the ducts may contribute to this active enlargement, or in other words, some of the epithelium of the bladder may be of mesodermic origin. The displacement of the ureter on the Wolffian duct, and the later upward displacement of its orifice from that of the duct, is due in part to the disappearance of the cloacal segment of the duct. The orifices of both ureter and Wolffian duct are however shifted medianward after the completion of the cloacal division, so that the trigonum may be spoken of as distinctly of entodermic origin. The greater part of the bladder and urachus are developed from the ventral segment including the mesodermic contributions from the Wolffian ducts. The allantois probably contributes no part in the formation of the bladder and retains its original relation to the lower border of the dermal navel. The urogenital membrane ruptures normally when the division of the cloaca is completed, or in other words, with its formation, and before the arrival of the Mullerian ducts at the urogenital sinus. The contribution of the entoderm and ectoderm in the formation of the urethra, together with the developmental relations of the bulbovestibular glands, will be considered in a later paper.

Born has stated that the trigonum may be of mesodermic origin. We have measured Model F and compared it wdth Model 30 and find the following: that the inter-ureteral distance (between the orifices) is greater in F (0.55 mm.) than in no. 30 (0.34) ; while the Wolffian ducts in the former are almost twice as far apart as in the latter. This implies that the ureter is not displaced lateral-ward from the duct but that both are displaced medianward, and that if there is any part of the bladder to which the mesoderm has definitely not contributed it is the trigonum.

We are of the opinion that the ventral segment of the cloaca probably forms the anlage for the bladder including the urachus, as was stated in Born's article, and that the cloacal segment of the Wolffian ducts (mesodermic) contributes some part. How much is impossible to determine. When the cloacal membrane extends as far upward as the dermal navel and persists as an epithelial membrane, we have the origin of the cases of complete bladder exstrophy which take in the whole ventral wall of the bladder and urachus. The present champion of the allantoigen origin of the bladder is not supported by our investigations. Rather we agree with Disse ('02) who states that Nagel misunderstood the relations found in the earlier stages through examination of embryos too far advanced in the development.

==Bibliography==

Bonnet, K. 1888 Ucber die Entwickelung der Allantois und die Bildung des Afters bei den Wiederkiiuem. Anat. Anz.

Born, G. 1893 Die Entwickelung der Ableitungswege, etc. Ergebnisse der Anat. und Entwickelungsgesch.

DissE, J. 1902 Harnorgane. In von Bardeleben's Handbuch der Anatomie.

Hill, E. C. 1904 On the first appearance of the renal artery, etc. Johns Hopkins Bull., vol 16, February.

Fleischmann, 1907 Die Stilcharactere am Urodaeum und Phallus. Morph-Jahrbuch, vol. 36.

Keibel, F. 1888 Die Entwickelungsvorgange am hinteren Ende des Meersch" weinchenembryo. Arch. f. Anat. und Entw.

1891 Zur Entwickelungsgeschichte der Harnblase. Anat. Anz.

1896 Zur Entwickelungsgeschichte desmensch. Urogenitalapparates. Arch. f. Anat. und Phys. Anat. Abt.

Kolliker, A. Von 1898 Entwickelungsgeschichte des Menschen.

Lieberkuhn, N. 1882 Qucrschnittc von der Anlage der AUantois und der Harnblase, etc. Marburger Sitzungsberichte.

Mall, F. P. 1893 Early human embryos. Johns Hopkins Bull, (also Anat. Anz.).

1904 Collection of human embryos. Baltimore.

{{Ref-Mall1897}}

Mihaicovics, G. von 1885 Untersuchungen uber die Entw. des Harn- und Geschlechtsapparates der Amnioten. Internat. Monatschrift. f. Anat. u. Hist.

Minot C. S. 1894 Human Embryology.

Nagel, W. 1894 Ueber die Entw. der inneren u. ausseren Genitalien beim mensch lichen Weibe. Arch. f. Gynilkologie.

1896 Zur Entwickelungsgeschichte des Urogenitalsystems beim Menschen. Arch. f. Anat. u. Phys. Anat. Abt.

{{Ref-Pohlman1904}}

Ratuke, 1832 Abhandlungen zur Bildungs- u. Entwickelungsgeschichte des Menschen u. der Thiere. Leipzig.

Reichel, P 1893 Die Entwickelung der Harnblase und Harnrohre. Verhand. d. mod. -phys. Gcsell. zu Wiirzburg.

Retterer, E. 1890 Sur I'origin et de revolution de la region ano-genitale des mammifreres. Jr. de I'anat. et de la phys.

1893-4 Mode de cloisonnement du cloaque chez le cobaye. Bibliog. Anat.

Spee, Graf 1896 Neue Beobachtungen uber sehr friihe Entwickelungsstufen des menschlichen Eies. Arch. f. Anat. u. Phys. Anat. Abt.

Strahl 1886 Zur Bildung der Cloake des Kaninchens. Arch. f. Anat. u. Phys. Anat. Abt.

Tourneux, F. 1893-4 Sur le mode de cloisonnement du cloaque, etc. Bibliog. Anat.

Zuckenkandl 1903 Handbuch der Urologie. Wien, Austria.

==Plates==
===Key to Lettering===

A., Allantois K., Kidney

A.M., Position of anal membrane P.T., Precloacal mesodermic tissue

C, Cloaca R.B., Renal bud

CM., Cloacal membrane T.G., Tail cut

C.S., Cloacal segment of Wolffian duct U., Ureter

G.E., Genital eminence U.G., Urogenital sinus

H.G., Hind gut U.M., Position of urogenital membrane

* Probable position of point where allantois joins cloaca.

All drawings represent 100 diameters enlargement except of Model F which is 50 diameters.

===Plate 1===
[[File:Pohlman1911 plate1.jpg|800px]]

===Plate 2===
[[File:Pohlman1911 plate2.jpg|800px]]

===Plate 3===
[[File:Pohlman1911 plate3.jpg|800px]]

{{Footer}}
[[Category:1910's]][[Category:Renal]][[Category:Gastrointestinal Tract]]
[[Category:Draft]]

Template:Cloacal exstrophy

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Z8600021: Created page with "cloacal exstrophy<noinclude>Category:TemplateCategory:Term LinkCategory:Cloaca Category:Gastrointestinal TractCategory:RenalCategory:GenitalCategory:Abnormal Development</noinclude>"

[[Cloaca_Development#Cloacal_Exstrophy|cloacal exstrophy]]<noinclude>[[Category:Template]][[Category:Term Link]][[Category:Cloaca]]
[[Category:Gastrointestinal Tract]][[Category:Renal]][[Category:Genital]][[Category:Abnormal Development]]</noinclude>

Template:USA 1997-2009 Abnormalities Sex Ratio table

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Z8600021:

{|
|+ '''{{USA}} Abnormalities Sex Ratio (1997-2009)'''
|-bgcolor="CEDFF2"
! Male preponderance
! Female preponderance
|-
|
* {{craniosynostosis}} (2.12)
* {{cleft lip and palate}} (2.01)
* cleft lip without cleft palate (1.78)
|
* {{choanal atresia}} (0.45)
* {{cloacal exstrophy}} (0.46)
* {{holoprosencephaly}} (0.64)
|-bgcolor="F5FAFF"
! colspan=2|Cardiac defects
|-
|
* {{aortic stenosis}} (2.88)
* {{coarctation of the aorta}} (2.51)
* {{transposition of the great vessels}} (2.34)
|
* multiple {{ventricular septal defects}} (0.52)
* {{truncus arteriosus}} (0.63)
* heterotaxia with congenital heart defect (0.64)
|-bgcolor="F5FFFA"
| colspan=2|Table data{{#pmid:25711982|PMID25711982}}   Links: {{abnormal development}} | {{cardiovascular abnormalities}} | {{USA}} | {{Male}} | {{Female}} | {{cleft lip and palate}}
|}<noinclude>[[Category:Template]][[Category:USA]][[Category:Abnormal Development]][[Category:Statistics]][[Category:Heart]]</noinclude>