Talk:Musculoskeletal System - Axial Skeleton Development

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Cite this page: Hill, M.A. (2021, September 28) Embryology Musculoskeletal System - Axial Skeleton Development. Retrieved from


Okuno K, Ishizu K, Matsubayashi J, Fujii S, Sakamoto R, Ishikawa A, Yamada S, Yoneyama A & Takakuwa T. (2019). Rib Cage Morphogenesis in the Human Embryo: A Detailed Three-Dimensional Analysis. Anat Rec (Hoboken) , 302, 2211-2223. PMID: 31344324 DOI.

Rib Cage Morphogenesis in the Human Embryo: A Detailed Three-Dimensional Analysis.

Abstract Formation of the skeletal structure in the human embryo has important consequences in terms of support, protection, and function of organs and other systems. We aimed to describe the formation of the rib cage during the embryonic period, in order to detect prominent features and identify the possible factors affecting rib cage morphology. We employed high-resolution digitized imaging data (n = 34) obtained in human embryos with Carnegie stage (CS) between 17 and 23. The rib cage became detectable as cartilage formation at CS17, expanding outward from the dorsal side of the chest-abdominal region. Ribs elongated progressively to surround the chest, differentiating into the upper and lower rib cage regions by CS20. The ends of corresponding ribs in the upper region elongated toward each other, leading to their joining and sternum formation between CS21 and CS23, while the lower region of the rib cage remained widely open. The rib cage area with the largest width shifted from the 5th rib pair at CS17 to the 9th pair at CS23. The depth of the rib cage was similar across the upper region at CS17, with the major portion remaining in the middle part after CS20. The heart was located beneath the rib pairs providing the largest depth, while the liver was located beneath the rib pairs providing the largest width. Formation of the sternum, development of spinal kyphosis, and organization of larger internal organs within the thoracic and abdominal cavity are possible factors affecting rib cage morphology. Anat Rec, 302:2211-2223, 2019. © 2019 American Association for Anatomy. KEYWORDS: 3-D reconstructions; MRI; human embryo; phase-contrast X-ray CT; rib cage PMID: 31344324 DOI: 10.1002/ar.24226

Evolutionary selection and morphological integration in the vertebral column of modern humans

Am J Phys Anthropol. 2019 Nov 1. doi: 10.1002/ajpa.23950. [Epub ahead of print]

Arlegi M1,2, Veschambre-Couture C2, Gómez-Olivencia A1,3,4. Author information 1 Departamento de Estratigrafía y Paleontología, Facultad de Ciencia y Tecnología, Universidad del País Vasco-Euskal Herriko Unibertsitatea (UPV/EHU), Leioa, Spain. 2 Université de Bordeaux, PACEA UMR 5199, Pessac, France. 3 IKERBASQUE. Basque Foundation for Science, Bizkaia, Spain. 4 Centro UCM-ISCIII de Investigación sobre Evolución y Comportamiento Humanos, Madrid, Spain. Abstract OBJECTIVES: The main objective is to quantify integration, modularity, and response to selection in the presacral vertebral column of modern humans. MATERIALS AND METHODS: Seventeen linear variables on each presacral vertebra were collected in 108 modern humans producing a total of ~39,000 measurements. Then, we studied patterns and magnitudes of integration at regional, vertebral, and intra-vertebral levels. Additionally, we calculated the ability of vertebrae to respond to selection by quantifying differences in evolvability, flexibility, and constraint throughout the spine. RESULTS: The results indicate that caudal vertebrae are more evolvable than those located more cranially in the presacral vertebral column, following an increasing pattern of evolvability from the cervical to the lumbar region. Additionally, the atlas and fifth lumbar vertebra show the lowest values of integration, while central thoracic vertebrae display the highest magnitudes of integration. DISCUSSION: These results could be related to three main factors: body plan organization expressed by the Hox genes, the strong developmental constraints that determine the number of mammalian vertebrae, and, finally, the functional requirements of an adaptation to bipedal locomotion in the human lineage. © 2019 Wiley Periodicals, Inc. KEYWORDS: adaptation; constraints; evolvability; flexibility; modularity PMID: 31675109 DOI: 10.1002/ajpa.23950


Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype

Kappen C (2016) Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype. PLoS ONE 11(1): e0146019. doi:10.1371/journal.pone.0146019

"The contribution of Hoxb6 to each segment is different either by expression level or functional activity, which is required for proper patterning of the five skeletal elements C6, C7, T1-T3. As it has recently been shown that Hox genes act in presomitic mesoderm [29, 32, 42, 43], and in mesoderm ingression in the primitive streak [44, 45] prior to somitogenesis, temporally different requirements may further modulate the patterning process."


Hox genes control vertebrate body elongation by collinear Wnt repression

Elife. 2015 Feb 26;4. doi: 10.7554/eLife.04379.

Denans N1, Iimura T2, Pourquié O1.


In vertebrates, the total number of vertebrae is precisely defined. Vertebrae derive from embryonic somites that are continuously produced posteriorly from the presomitic mesoderm (PSM) during body formation. We show that in the chicken embryo, activation of posterior Hox genes (paralogs 9-13) in the tail-bud correlates with the slowing down of axis elongation. Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength. This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process. Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size. This ultimately brings the retinoic acid (RA)-producing segmented region in close vicinity to the tail bud, potentially accounting for the termination of segmentation and axis elongation. KEYWORDS: Hox; axis elongation; chicken; developmental biology; gastrulation; morphogenesis; stem cells

PMID 25719209


Embryonic and early fetal period development and morphogenesis of human craniovertebral junction

Clin Anat. 2014 Apr;27(3):337-45. doi: 10.1002/ca.22372. Epub 2014 Feb 5.

Hita-Contreras F1, Roda O, Martínez-Amat A, Cruz-Díaz D, Mérida-Velasco JA, Sánchez-Montesinos I. Author information


Several studies have focused on the cartilaginous, articular, and ligamentous development of the craniovertebral joint (CVJ), but there are no unifying criteria regarding the origin and morphogenetic timetable of the structures that make up the CVJ. In our study, serial sections of 53 human embryonic (n = 27) and fetal (n = 26) specimens from O'Rahilly stages 17-23 and 9-13 weeks, respectively, have been analyzed. Our results demonstrate that the chondrification of the pars basioccipitalis and exoccipitalis becomes observable at stage 19, and all future bones in the CVJ are in their cartilaginous form except for the future odontoid process. In addition, two chondrification centers appear for the body of the axis. From stage 21, the apical, alar, and transverse atlantal ligaments begin to acquire a ligamentous structure and the odontoid process initiates its chondrogenic phase. Stage 22 witnesses the first signs of the articular cavities of the atlanto-occipital joint, and by stage 23 all joints have cavities except for the transverse-odontoid joint, which will wait until week 9. In week 10, the ossification of the basilar part of the occipital bone begins, followed by the rest of the structures except for the odontoid process, which will start at week 13, thus completing the osteogenesis of all bones in the CVJ. The results of this study could help in establishing the anatomical basis of the normally functioning CVJ and for detecting its related pathologies, abnormalities, and malformations. Clin. Anat. 27:337-345, 2014. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc. KEYWORDS: atlas, axis, chondrogenesis, craniovertebral, embryology, fetal, odontoid process

PMID 24497108


Morphometric study of the T6 vertebra and its three ossification centers in the human fetus

Surg Radiol Anat. 2013 Dec;35(10):901-16. doi: 10.1007/s00276-013-1107-3. Epub 2013 Mar 30.

Szpinda M, Baumgart M, Szpinda A, Woźniak A, Mila-Kierzenkowska C, Dombek M, Kosiński A, Grzybiak M. Author information


PURPOSE: Knowledge on the normative growth of the spine is critical in the prenatal detection of its abnormalities. We aimed to study the size of T6 vertebra in human fetuses with the crown-rump length of 115-265 mm. MATERIALS AND METHODS: Using the methods of computed tomography (Biograph mCT), digital image analysis (Osirix 3.9) and statistics, the normative growth of the T6 vertebral body and the three ossification centers of T6 vertebra in 55 spontaneously aborted human fetuses (27 males, 28 females) aged 17-30 weeks were studied. RESULTS: Neither male-female nor right-left significant differences were found. The height, transverse, and sagittal diameters of the T6 vertebral body followed natural logarithmic functions as y = -4.972 + 2.732 × ln(age) ± 0.253 (R (2) = 0.72), y = -14.862 + 6.426 × ln(age) ± 0.456 (R (2) = 0.82), and y = -10.990 + 4.982 × ln(age) ± 0.278 (R (2) = 0.89), respectively. Its cross-sectional area (CSA) rose proportionately as y = -19.909 + 1.664 × age ± 2.033 (R (2) = 0.89), whereas its volumetric growth followed the four-degree polynomial function y = 19.158 + 0.0002 × age(4) ± 7.942 (R (2) = 0.93). The T6 body ossification center grew logarithmically in both transverse and sagittal diameters as y = -14.784 + 6.115 × ln(age) ± 0.458 (R (2) = 0.81) and y = -12.065 + 5.019 × ln(age) ± 0.315 (R (2) = 0.87), and proportionately in both CSA and volume like y = -15.591 + 1.200 × age ± 1.470 (R (2) = 0.90) and y = -22.120 + 1.663 × age ± 1.869 (R (2) = 0.91), respectively. The ossification center-to-vertebral body volume ratio was gradually decreasing with age. On the right and left, the neural ossification centers revealed the following models: y = -15.188 + 6.332 × ln(age) ± 0.629 (R (2) = 0.72) and y = -15.991 + 6.600 × ln(age) ± 0.629 (R (2) = 0.74) for length, y = -6.716 + 2.814 × ln(age) ± 0.362 (R (2) = 0.61) and y = -7.058 + 2.976 × ln(age) ± 0.323 (R (2) = 0.67) for width, y = -5.665 + 0.591 × age ± 1.251 (R (2) = 0.86) and y = -11.281 + 0.853 × age ± 1.653 (R (2) = 0.78) for CSA, and y = -9.279 + 0.849 × age ± 2.302 (R (2) = 0.65) and y = -16.117 + 1.155 × age ± 1.832 (R (2) = 0.84) for volume, respectively. CONCLUSIONS: Neither sex nor laterality differences are found in the morphometric parameters of evolving T6 vertebra and its three ossification centers. The growth dynamics of the T6 vertebral body follow logarithmically for its height, and both sagittal and transverse diameters, linearly for its CSA, and four-degree polynomially for its volume. The three ossification centers of T6 vertebra increase logarithmically in both transverse and sagittal diameters, and linearly in both CSA and volume. The age-specific reference intervals for evolving T6 vertebra present the normative values of potential relevance in the diagnosis of congenital spinal defects.

PMID 23543237

Cross-sectional study of the neural ossification centers of vertebrae C1-S5 in the human fetus

Surg Radiol Anat. 2013 Oct;35(8):701-11. doi: 10.1007/s00276-013-1093-5. Epub 2013 Feb 28.

Szpinda M, Baumgart M, Szpinda A, Woźniak A, Mila-Kierzenkowska C. Author information


PURPOSE: An understanding of the normal evolution of the spine is of great relevance in the prenatal detection of spinal abnormalities. This study was carried out to estimate the length, width, cross-sectional area and volume of the neural ossification centers of vertebrae C1-S5 in the human fetus. MATERIALS AND METHODS: Using the methods of CT (Biograph mCT), digital-image analysis (Osirix 3.9) and statistics (the one-way ANOVA test for paired data, the Kolmogorov-Smirnov test, Levene's test, Student's t test, the one-way ANOVA test for unpaired data with post hoc RIR Tukey comparisons) the size for the neural ossification centers throughout the spine in 55 spontaneously aborted human fetuses (27 males, 28 females) at ages of 17-30 weeks was studied. RESULTS: The neural ossification centers were visualized in the whole pre-sacral spine, in 74.5 % for S1, in 61.8 % for S2, in 52.7 % for S3, and in 12.7 % for S4. Neither male-female nor right-left significant differences in the size of neural ossification centers were found. The neural ossification centers were the longest within the cervical spine. The maximum values referred to the axis on the right, and to C5 vertebra on the left. There was a gradual decrease in length for the neural ossification centers of T1-S4 vertebrae. The neural ossification centers were the widest within the proximal thoracic spine and narrowed bi-directionally. The growth dynamics for CSA of neural ossification centers were found to parallel that of volume. The largest CSAs and volumes of neural ossification centers were found in the C3 vertebra, and decreased in the distal direction. CONCLUSIONS: The neural ossification centers show neither male-female nor right-left differences. The neural ossification centers are characterized by the maximum length for C2-C6 vertebrae, the maximum width for the proximal thoracic spine, and both the maximum cross-sectional area and volume for C3 vertebra. There is a sharp decrease in size of the neural ossification centers along the sacral spine. A decreasing sequence of values for neural ossification centers along the spine from cervical to sacral appears to parallel the same direction of the timing of ossification. The quantitative growth of the neural ossification centers is of potential relevance in the prenatal diagnosis and monitoring of achondrogenesis, caudal regression syndrome, diastematomyelia and spina bifida. PMID 23455365

Ossification of the vertebral column in human foetuses: histological and computed tomography studies

Folia Morphol (Warsz). 2013 Aug;72(3):230-8.

Skórzewska A, Grzymisławska M, Bruska M, Lupicka J, Woźniak W. Author information


There is no agreement in the literature as to the time of the onset and progress of the vertebral column ossification. The aim of the present study was to determine the precise sequence of ossification of the neural arches and vertebral centra.Histological and radiographic studies were performed on 27 human foetuses aged from 9 to 21 weeks. It was found that the ossification of vertebrae commences in foetuses aged 10 and 11 weeks. Ossification centres appear first for neuralarches in the cervical and upper thoracic vertebrae and by the end of 11th week they are present in all thoracic and lumbar neural arches. In the vertebral centrain foetus of 10 weeks ossification was found in the lower 7 thoracic and first lumbar vertebrae. By the end of 11th week ossification is present in the lower 4 cervical, all thoracic, all lumbar and 4 sacral vertebral centra. The study indicates that ossification of the neural arches proceeds in the craniocaudal direction,whereas in the vertebral centra it progresses from the lower thoracic vertebrae into both directions. Different shapes of ossification centres were also described.

PMID 24068685

Foxa1 and foxa2 are required for formation of the intervertebral discs

PLoS One. 2013;8(1):e55528. doi: 10.1371/journal.pone.0055528. Epub 2013 Jan 31.

Maier JA, Lo Y, Harfe BD. Source Molecular Genetics and Microbiology and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, United States of America.


The intervertebral disc (IVD) is composed of 3 main structures, the collagenous annulus fibrosus (AF), which surrounds the gel-like nucleus pulposus (NP), and hyaline cartilage endplates, which are attached to the vertebral bodies. An IVD is located between each vertebral body. Degeneration of the IVD is thought to be a major cause of back pain, a potentially chronic condition for which there exist few effective treatments. The NP forms from the embryonic notochord. Foxa1 and Foxa2, transcription factors in the forkhead box family, are expressed early during notochord development. However, embryonic lethality and the absence of the notochord in Foxa2 null mice have precluded the study of potential roles these genes may play during IVD formation. Using a conditional Foxa2 allele in conjunction with a tamoxifen-inducible Cre allele (ShhcreER(T2)), we removed Foxa2 from the notochord of E7.5 mice null for Foxa1. Foxa1(-/-);Foxa2(c/c);ShhcreER(T2) double mutant animals had a severely deformed nucleus pulposus, an increase in cell death in the tail, decreased hedgehog signaling, defects in the notochord sheath, and aberrant dorsal-ventral patterning of the neural tube. Embryos lacking only Foxa1 or Foxa2 from the notochord were indistinguishable from control animals, demonstrating a functional redundancy for these genes in IVD formation. In addition, we provide in vivo genetic evidence that Foxa genes are required for activation of Shh in the notochord.

PMID 23383217


Embryology and bony malformations of the craniovertebral junction

Childs Nerv Syst. 2011 Apr;27(4):523-64. Epub 2010 Dec 31.

Pang D, Thompson DN. Source Department of Neurological Surgery, University of California, Davis, Sacramento, CA, USA.


BACKGROUND: The embryology of the bony craniovertebral junction (CVJ) is reviewed with the purpose of explaining the genesis and unusual configurations of the numerous congenital malformations in this region. Functionally, the bony CVJ can be divided into a central pillar consisting of the basiocciput and dental pivot and a two-tiered ring revolving round the central pivot, comprising the foramen magnum rim and occipital condyles above and the atlantal ring below. Embryologically, the central pillar and the surrounding rings descend from different primordia, and accordingly, developmental anomalies at the CVJ can also be segregated into those affecting the central pillar and those affecting the surrounding rings, respectively. DISCUSSION: A logical classification of this seemingly unwieldy group of malformations is thus possible based on their ontogenetic lineage, morbid anatomy, and clinical relevance. Representative examples of the main constituents of this classification scheme are given, and their surgical treatments are selectively discussed.

PMID 21193993

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord

Dev Dyn. 2010 Aug;239(8):2141-8.

Risbud MV, Schaer TP, Shapiro IM. Source Department of Orthopedic Surgery and Graduate Program in Tissue Engineering and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.


The goal of this mini-review is to address the long standing argument that the pathogenesis of disc disease is due to the loss and/or the replacement of the notochordal cells by other cell types. We contend that, although cells of different size and morphology exist, there is no strong evidence to support the view that the nucleus pulposus contains cells of distinct lineages. Based on lineage mapping studies and studies of other notochordal markers, we hypothesize that in all animals, including human, nucleus pulposus retains notochordal cells throughout life. Moreover, all cells including chondrocyte-like cells are derived from notochordal precursors, and variations in morphology and size are representative of different stages of maturation, and or, function. Thus, the most critical choice for a suitable animal model should relate more to the anatomical and mechanical characteristics of the motion segment than concerns of cell loss and replacement by non-notochordal cells.

PMID: 20568241

Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc

BMC Dev Biol. 2010 Mar 9;10:29.

Sohn P, Cox M, Chen D, Serra R.

Department of Cell Biology, University of Alabama at Birmingham, Birmingham AL, USA.

Abstract BACKGROUND: Very little is known about how intervertebral disc (IVD) is formed or maintained. Members of the TGF-beta superfamily are secreted signaling proteins that regulate many aspects of development including cellular differentiation. We recently showed that deletion of Tgfbr2 in Col2a expressing mouse tissue results in alterations in development of IVD annulus fibrosus. The results suggested TGF-beta has an important role in regulating development of the axial skeleton, however, the mechanistic basis of TGF-beta action in these specialized joints is not known. One of the hurdles to understanding development of IVD is a lack of known markers. To identify genes that are enriched in the developing mouse IVD and to begin to understand the mechanism of TGF-beta action in IVD development, we undertook a global analysis of gene expression comparing gene expression profiles in developing mouse vertebrae and IVD. We also compared expression profiles in tissues from wild type and Tgfbr2 mutant mice as well as in sclerotome cultures treated with TGF-beta or BMP4.

RESULTS: Lists of IVD and vertebrae enriched genes were generated. Expression patterns for several genes were verified either through in situ hybridization or literature/database searches resulting in a list of genes that can be used as markers of IVD. Cluster analysis using genes listed under the Gene Ontology terms multicellular organism development and pattern specification indicated that mutant IVD more closely resembled vertebrae than wild type IVD. We also generated lists of genes regulated by TGF-beta or BMP4 in cultured sclerotome. As expected, treatment with BMP4 resulted in up-regulation of cartilage marker genes including Acan, Sox 5, Sox6, and Sox9. In contrast, treatment with TGF-beta1 did not regulate expression of cartilage markers but instead resulted in up-regulation of many IVD markers including Fmod and Adamtsl2.

CONCLUSIONS: We propose TGF-beta has two functions in IVD development: 1) to prevent chondrocyte differentiation in the presumptive IVD and 2) to promote differentiation of annulus fibrosus from sclerotome. We have identified genes that are enriched in the IVD and regulated by TGF-beta that warrant further investigation as regulators of IVD development.

PMID: 20214815


Extensive molecular differences between anterior- and posterior-half-sclerotomes underlie somite polarity and spinal nerve segmentation

BMC Dev Biol. 2009 May 22;9:30.

Hughes DS, Keynes RJ, Tannahill D. Source Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB3 2DY, UK. Abstract BACKGROUND: The polarization of somite-derived sclerotomes into anterior and posterior halves underlies vertebral morphogenesis and spinal nerve segmentation. To characterize the full extent of molecular differences that underlie this polarity, we have undertaken a systematic comparison of gene expression between the two sclerotome halves in the mouse embryo. RESULTS: Several hundred genes are differentially-expressed between the two sclerotome halves, showing that a marked degree of molecular heterogeneity underpins the development of somite polarity. CONCLUSION: We have identified a set of genes that warrant further investigation as regulators of somite polarity and vertebral morphogenesis, as well as repellents of spinal axon growth. Moreover the results indicate that, unlike the posterior half-sclerotome, the central region of the anterior-half-sclerotome does not contribute bone and cartilage to the vertebral column, being associated instead with the development of the segmented spinal nerves.

PMID 19463158

Establishment of Hox vertebral identities in the embryonic spine precursors

Curr Top Dev Biol. 2009;88:201-34.

Iimura T, Denans N, Pourquié O. Source Tokyo Medical and Dental University, Tokyo, Japan.


The vertebrate spine exhibits two striking characteristics. The first one is the periodic arrangement of its elements-the vertebrae-along the anteroposterior axis. This segmented organization is the result of somitogenesis, which takes place during organogenesis. The segmentation machinery involves a molecular oscillator-the segmentation clock-which delivers a periodic signal controlling somite production. During embryonic axis elongation, this signal is displaced posteriorly by a system of traveling signaling gradients-the wavefront-which depends on the Wnt, FGF, and retinoic acid pathways. The other characteristic feature of the spine is the subdivision of groups of vertebrae into anatomical domains, such as the cervical, thoracic, lumbar, sacral, and caudal regions. This axial regionalization is controlled by a set of transcription factors called Hox genes. Hox genes exhibit nested expression domains in the somites which reflect their linear arrangement along the chromosomes-a property termed colinearity. The colinear disposition of Hox genes expression domains provides a blueprint for the regionalization of the future vertebral territories of the spine. In amniotes, Hox genes are activated in the somite precursors of the epiblast in a temporal colinear sequence and they were proposed to control their progressive ingression into the nascent paraxial mesoderm. Consequently, the positioning of the expression domains of Hox genes along the anteroposterior axis is largely controlled by the timing of Hox activation during gastrulation. Positioning of the somitic Hox domains is subsequently refined through a crosstalk with the segmentation machinery in the presomitic mesoderm. In this review, we focus on our current understanding of the embryonic mechanisms that establish vertebral identities during vertebrate development.

PMID: 19651306


Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints

BMC Dev Biol. 2007 Jun 17;7:68.

Teppner I, Becker S, de Angelis MH, Gossler A, Beckers J. Source GSF-National Research Center for Environment and Health, GmbH, Institute of Experimental Genetics, Neuherberg, Germany. <>


BACKGROUND: Expression of the mouse Delta-like 1 (Dll1) gene in the presomitic mesoderm and in the caudal halves of somites of the developing embryo is required for the formation of epithelial somites and for the maintenance of caudal somite identity, respectively. The rostro-caudal polarity of somites is initiated early on within the presomitic mesoderm in nascent somites. Here we have investigated the requirement of restricted Dll1 expression in caudal somite compartments for the maintenance of rostro-caudal somite polarity and the morphogenesis of the axial skeleton. We did this by overexpressing a functional copy of the Dll1 gene throughout the paraxial mesoderm, in particular in anterior somite compartments, during somitogenesis in transgenic mice. RESULTS: Epithelial somites were generated normally and appeared histologically normal in embryos of two independent Dll1 over-expressing transgenic lines. Gene expression analyses of rostro-caudal marker genes suggested that over-expression of Dll1 without restriction to caudal compartments was not sufficient to confer caudal identity to rostral somite halves in transgenic embryos. Nevertheless, Dll1 over-expression caused dysmorphologies of the axial skeleton, in particular, in morphological structures that derive from the articular joint forming compartment of vertebrae. Accordingly, transgenic animals exhibited missing or reduced intervertebral discs, rostral and caudal articular processes as well as costal heads of ribs. In addition, the midline of the vertebral column did not develop normally. Transgenic mice had open neural arches and split vertebral bodies with ectopic pseudo-growth plates. Endochondral bone formation and ossification in the developing vertebrae were delayed. CONCLUSION: The mice overexpressing Dll1 exhibit skeletal dysmorphologies that are also evident in several mutant mice with defects in somite compartmentalisation. The Dll1 transgenic mice demonstrate that vertebral dysmorphologies such as bony fusions of vertebrae and midline vertebral defects can occur without apparent changes in somitic rostro-caudal marker gene expression. Also, we demonstrate that the over-expression of the Dll1 gene in rostral epithelial somites is not sufficient to confer caudal identity to rostral compartments. Our data suggest that the restricted Dll1 expression in caudal epithelial somites may be particularly required for the proper development of the intervertebral joint forming compartment.

PMID 17572911 [PubMed - indexed for MEDLINE] PMCID: PMC1924847

Altered axial skeletal development

Birth Defects Res B Dev Reprod Toxicol. 2007 Dec;80(6):451-72.

Tyl RW, Chernoff N, Rogers JM. Center for Life Sciences and Toxicology, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.

Abstract The axial skeleton is routinely examined in standard developmental toxicity bioassays and has proven to be sensitive to a wide variety of chemical agents. Dysmorphogenesis in the skull, vertebral column and ribs has been described in both human populations and in laboratory animals used to assess potential adverse developmental effects. This article emphasizes vertebrae and rib anomalies both spontaneous and agent induced. Topics discussed include the morphology of the more common effects; incidences in both human and experimental animal populations; the types of anomalies induced in the axial skeleton by methanol, boric acid, valproic acid and others; the postnatal persistence of common skeletal anomalies; and the genetic control of the development of the axial skeleton. Tables of the spontaneous incidence of axial anomalies in both humans and animals are provided.

PMID: 18157900


Normal fetal lumbar spine on postmortem MR imaging

AJNR Am J Neuroradiol. 2006 Mar;27(3):553-9.

Widjaja E, Whitby EH, Paley MN, Griffiths PD.

Academic Section of Radiology, University of Sheffield, Sheffield, United Kingdom. Abstract BACKGROUND AND PURPOSE: There is an increasing interest in use of postmortem MR imaging as an adjunct or alternative to autopsy. Before evaluating spinal pathology on postmortem MR imaging, it is important to have knowledge of the normal appearance of the fetal spine at different gestational ages. The aim of this study is to describe the MR imaging appearances of normal development of the fetal spine at different gestational ages.

METHODS: Postmortem MR imaging was performed on 30 fetuses ranging from 14 to 41 gestational weeks. There was no structural abnormality of the spine in these fetuses on MR imaging or at autopsy. Fast spin-echo T2-weighted MR imaging of the lumbar spine was performed in the coronal plane in all cases and supplemented by sagittal and/or axial imaging. The following parameters were measured: height of the L1/2 disk and L2 vertebral body and area of ossification center in L2 vertebral body as well as area of vertebral body. The signal intensity of the disk space and the vertebral level of conus termination were also assessed.

RESULTS: The height and area of the vertebral body increased linearly with gestational age (P <.01). The increase in disk space was proportionally greater than the increase in vertebral body height as gestational age increased (P <.01). The disk space appeared as a linear low-signal-intensity area in fetuses < or = 21 weeks gestation but increasingly developed high signal intensity in the disk after 21 weeks. The size of the ossification center increased with gestational age (P <.01), and the ratio of ossification center to the overall size of the vertebral body also increased with gestational age (P <.01). In fetuses less than 35 weeks of age, the conus lay between L2 and L5 level, whereas in fetuses more than 35 weeks of age, the conus lay between L1/2 and L2/3 level.

CONCLUSION: Understanding the normal growth and signal-intensity characteristics of the fetal spine on postmortem MR imaging is essential before studying abnormal fetal spine.

PMID: 16551992


Three-dimensional sonographic evaluation of the fetal lumbar spinal canal

J Anat. 2002 May;200(5):439-43.

Wallny T, Schild RL, Fimmers R, Hansmann ME.

Department of Orthopaedics, University of Bonn, Germany. Abstract In a prospective cross-sectional ultrasound study the size of the fetal lumbar spinal canal was evaluated to determine reference values for the lumbar part of the vertebral canal. One hundred and sixty-seven pregnant women undergoing routine obstetric ultrasound were studied between 16 and 41 weeks of gestation. Exclusion criteria consisted of structural fetal anomalies or growth restriction. Area and volume of the vertebral canal at L1, L3 and L5 were calculated by three-dimensional (3D) ultrasound. Length of the lumbar spine was also determined. The size of the spinal canal and spinal length correlated well with gestational age. No gestational-age-dependent differences in area and volume measurements between upper and lower lumbar spine were found. The results provide an in vivo assessment of the spinal canal by 3D ultrasound over the entire gestation period.

PMID: 12090390


The development of the avian vertebral column

Anat Embryol (Berl). 2000 Sep;202(3):179-94.

Christ B, Huang R, Wilting J.

Institute of Anatomy, University of Freiburg, Germany. Abstract Segmentation of the paraxial mesoderm leads to somite formation. The underlying molecular mechanisms involve the oscillation of "clock-genes" like c-hairy-1 and lunatic fringe indicative of an implication of the Notch signaling pathway. The cranio-caudal polarity of each segment is already established in the cranial part of the segmental plate and accompanied by the expression of genes like Delta1, Mesp1, Mesp2, Ulicx-1, and EphA4 which are restricted to one half of the prospective somite. Dorsoventral compartmentalization of somites leads to the development of the dermomyotome and the sclerotome, the latter forming as a consequence of an epithelio-to-mesenchymal transition of the ventral part of the somite. The sclerotome cells express Pax-1 and Pax-9, which are induced by notochordal signals mediated by sonic hedgehog (Shh) and noggin. The craniocaudal somite compartmentalization that becomes visible in the sclerotomes is the prerequisite for the segmental pattern of the peripheral nervous system and the formation of the vertebrae and ribs, whose boundaries are shifted half a segment compared to the sclerotome boundaries. Sclerotome development is characterized by the formation of three subcompartments giving rise to different parts of the axial skeleton and ribs. The lateral sclerotome gives rise to the laminae and pedicles of the neural arches and to the ribs. Its development depends on signals from the notochord and the myotome. The ventral sclerotome giving rise to the vertebral bodies and intervertebral discs is made up of Pax-1 expressing cells that have invaded the perinotochordal space. The dorsal sclerotome is formed by cells that migrate from the dorso-medial angle of the sclerotome into the space between the roof plate of the neural tube and the dermis. These cells express the genes Msx1 and Msx2, which are induced by BMP-4 secreted from the roof plate, and they later form the dorsal part of the neural arch and the spinous process. The formation of the ventral and dorsal sclerotome requires directed migration of sclerotome cells. The regionalization of the paraxial mesoderm occurs by a combination of functionally Hox genes, the Hox code, and determines the segment identity. The development of the vertebral column is a consequence of a segment-specific balance between proliferation, apoptosis and differentiation of cells.

PMID: 10994991


The human vertebral column at the end of the embryonic period proper. 4. The sacrococcygeal region

J Anat. 1990 Feb;168:95-111.

O'Rahilly R, Müller F, Meyer DB.

Department of Human Anatomy, University of California, Davis 95616. Abstract The sacral and coccygeal vertebrae at 8 postovulatory weeks (the end of the embryonic period proper) have been studied by means of graphic reconstructions. The cartilaginous sacrum is now a definitive unit composed of five separable vertebrae, each of which consists of a future centrum and bilateral neural processes. The base of each neural process consists of an anterolateral or alar element, not present in the lumbar region, and a posterolateral part, which includes costal and transverse elements. The usual illustrations, in which the costal component is placed in the alar element, are incorrect. The future dorsal foramina (containing dorsal rami) face laterally in the embryo and are in line with the thoracicolumbar intervertebral foramina. Considerable differential growth is required to change the dorsal openings from a lateral to a dorsal positions. The intervertebral foramina transmit ventral rami, but pelvic foramina are not yet present. The lumbosacral plexus is completed by S.N.1-3; S.N.4, 5 and Co.N.1 form the pelvic plexus. The inferior hypogastric plexus and the hypogastric nerves are present. The sacrum takes part in the spina bifida occulta that characterises the entire length of the embryonic vertebral column. The coccygeal vertebrae, which are variable, were 4-6 in number in the present series. The first is the best developed. The ventriculus terminalis ends usually at the level of Co.V.1 and the spinal cord generally at Co.V.5. The coccygeal notochord ends commonly in bifurcation or trifurcation. 'Haemal arches' were not observed.

PMID: 2182589

The human vertebral column at the end of the embryonic period proper. 3. The thoracicolumbar region

J Anat. 1990 Feb;168:81-93.

O'Rahilly R, Müller F, Meyer DB.

Department of Human Anatomy, University of California, Davis 95616. Abstract The present study of the thoracicolumbar region continues an investigation of the vertebral column at 8 postovulartory weeks (the end of the embryonic period proper) by means of graphic reconstructions. The cartilaginous vertebrae have short neural processes associated with the normal spina bifida occulta present at this time. The separate cartilaginous centres that several authors believe to exist in the cervical and lumbar costal elements, but which have not been observed by the present authors, have been thought to be the forerunners of extrathoracic ribs. A distinction needs to be made, however, between such centres and ribs. Similarly, in the fetal period, ossific loci in the costal elements of CV 7 are very frequent, whereas cervical ribs in the adult are relatively rare. The neurocentral joints, and hence the boundaries between neural arches and centra, are unclear before ossification has begun and has progressed during the fetal period. The sternal bands are almost completely united and the scapula is high in position. Neural relationships aid in the determination of homologous parts within the vertebral column, but clarification of corresponding parts has not previously been possible within the embryonic period. Areas ventral to the dorsal rami are ribs in the thoracic region and costal elements in other regions. Areas underlying the dorsal rami are transverse processes in the thoracic region and minute 'true' transverse elements in the cervical and lumbar regions. Thus, the descriptive lumbar transverse processes correspond to the true transverse processes and the ribs in the thoracic region. The dorsal rami of the thoracic nerves pass between the transverse processes and the tubercles of the ribs and then divide. The ventral rami of lumbar Nerves 1 and 2 resemble the thoracic in their course, whereas those of Nerves 3-5 are similar to the sacral. The thoracic dorsal roots are sloping and, associated with the greater height of the lumbar centra, the lumbar roots even more so. The directions of the various dorsal roots reflect differences in growth gradients between vertebral column and spinal cord. The thoracic and lumbar portions of the column change little in proportion during the embryonic period proper.

PMID: 2323997


The human vertebral column at the end of the embryonic period proper. 2. The occipitocervical region

J Anat. 1983 Jan;136(Pt 1):181-95. O'Rahilly R, Müller F, Meyer DB.

Abstract The present investigation of the cervical region of the vertebral column at eight post-ovulatory weeks is the first such study based on precise reconstructions of staged embryos. At the end of the embryonic period proper, a typical vertebra is a U-shaped piece of cartilage characterized by spina bifida occulta. The notochord ascends through the centra and leaves the dens to enter the basal plate of the skull. The median column of the axis comprises three parts (designated X, Y, Z) which persist well into the fetal period. They are related to the first, second and third cervical nerves, respectively. Part X may project into the foramen magnum and form an occipito-axial joint. Part Z appears to be the centrum of the axis. The articular columns of the cervical vertebrae are twofold, as in the adult: an anterior (atlanto-occipital and atlanto-axial) and a posterior (from the lower aspect of the axis downwards). Alar and transverse ligaments are present. Cavitation is not found in the embryonic period in either the atlanto-occipital or zygapophysial joints, and is generally not present in the median atlanto-axial joint either. Most of the transverse processes exhibit anterior and posterior tubercles. An 'intertubercular lamella' may or may not be present, i.e. the foramina transversaria are being formed around the vertebral artery. The spinal ganglia are generally partly in the vertebral canal and partly on the neural arches, medial to the articular processes. During the fetal period, the articular processes shift to a coronal position and this alteration appears to be associated with a corresponding change in the location of the spinal ganglia.

PMID: 6833119


The human vertebral column at the end of the embryonic period proper. 1. The column as a whole

J Anat. 1980 Oct;131(Pt 3):565-75.

O'Rahilly R, Muller F, Meyer DB.

Abstract The present investigation of the vertebral column at 8 post-ovulatory weeks, the first such study based on precise reconstructions, has revealed 33 or 34 cartilaginous vertebrae arranged in flexion and approximately 20--33 mm in total length. At the end of the embryonic period proper, a typical vertebra, such as TV6, consists of a centrum that is continuous with two neural processes. Pedicles, articular and transverse processes, but no spinous processes, are identifiable. The tips of the neural processes, which are formed by the laminae, are connected by fibrous tissue and resemble the condition of total rachischisis. The union of the laminae, the onset of ossification, and the appearance of articular cavities are characteristic of the early fetal period. The variations encountered within a single developmental stage were noted. They were mostly minor, e.g. the number of coccygeal elements and the extent of the dorsal growth of the neural processes.

PMID: 7216919


A radiographic study of the human fetal spine. 3. Longitudinal growth

J Anat. 1979 Jun;128(Pt 4):777-87.

Bagnall KM, Harris PF, Jones PR.

Abstract Regression equations are presented which describe the growth in length of the various regions of the vertebral column in the human fetus. From 8 weeks on the thoracic is always the longest region and the sacral the shortest, while the lumbar region is longer than the cervical. From the regression equations predictions of fetal vertebral length can be made from fetal age: this should be useful in obstetric practice when diagnostic ultrasound techniques are being employed for the diagnosis of growth disorders and skeletal abnormalities. A different developmental pattern emerges when average 'vertebral units' for each region are compared. The lumbar vertebrae are always the largest with the thoracic, cervical and sacral vertebrae being progressively smaller.

PMID: 489466


The development of vertebral bone marrow of human fetuses

Blood. 1975 Sep;46(3):389-408.

Chen LT, Weiss L.

Abstract The development of the bone marrow of the thoracic vertebrae in seven human fetuses ranging from 95 to 150 mm in crown-rump length (CRL) was studied using light and electron microscopy. In the 95-mm CRL, hypertrophy of the chondrocytes occurred in the central region of the vertebrae, and blood vessels penetrated there from dorsal and ventral sides of the vertebral body. The primary marrow was represented by liberated cartilage lacunnae, occupied by the thin-walled blood vessels and a few mesenchymal cells and mononuclear cells containing granules or vacuoles (GMC). In the 99-mm CRL, chondroclasts were active in removing the cartilage near the central region of the vertebrae. Consequently, a large cavity was formed and occupied by a dilated sinus. GMC were numerous. Osteoblasts and osteocytes were increased in number. Reticular cells with long processes containing large amounts of glycogen began to appear in the extravascular space and formed the loosely arranged cellular meshwork of the hematopoietic compartment. Bundles of collagen fibrils were scattered in the meshwork. Hematopoietic cells were recognizable only in the 105-mm-CRL fetus and increased in number in the 120-mm-CRL fetus. The sinus endothelium was very thin and continuous without apertures except where blood cells crossed the wall. The developing blood cells lying against the outside of the sinus endothelium indented it. At points, collagen fibrils attached to the outside of endothelial cells and appeared to function as the anchoring filaments of lymphatics. The physiologic implications of the association of stromal cells, vascular sinuses, and hematopoietic cells are discussed in relationship to the microhematopoietic environment of the bone marrow.

PMID: 1097001