Talk:Neural System Development

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Cite this page: Hill, M.A. (2021, April 17) Embryology Neural System Development. Retrieved from

Neural Development Journal -

Draft page - Neural System - Molecular


Micali N, Kim SK, Diaz-Bustamante M, Stein-O'Brien G, Seo S, Shin JH, Rash BG, Ma S, Wang Y, Olivares NA, Arellano JI, Maynard KR, Fertig EJ, Cross AJ, Bürli RW, Brandon NJ, Weinberger DR, Chenoweth JG, Hoeppner DJ, Sestan N, Rakic P, Colantuoni C & McKay RD. (2020). Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates. Cell Rep , 31, 107599. PMID: 32375049 DOI.

Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates

Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons. As human telencephalic NSCs develop from pluripotency in vitro, they transition through organizer states that spatially pattern the cortex before generating glutamatergic precursor fates. NSCs derived from multiple human pluripotent lines vary in these early patterning states, leading differentially to dorsal or ventral telencephalic fates. This work furthers systematic analyses of the earliest patterning events that generate the major neuronal trajectories of the human telencephalon. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. KEYWORDS: BMP; EGFR; FGF2; brain organizer; glutamatergic neurons; human iPSC variation; inhibitory neurons; neural stem cell; neural transcriptional dynamics; neurogenesis; neuronal trajectory variation; patterning of the cortex PMID: 32375049 DOI: 10.1016/j.celrep.2020.107599

UNSW Embryology Links

  • Animal Neural Development - A number of different animal models of neural development, both normal and abnormal, have been established. Mouse | Pig | Rabbit

brain museum - histology images from different species

Human Central Nervous System Development

Joseph Altman and Shirley A. Bayer

Atlas of Human Central Nervous System Development

  • The Spinal Cord from Gestational Week 4 to the 4th Postnatal Month

Shirley A . Bayer and Joseph Altman CRC Press 2002 Print ISBN: 978-0-8493-1420-9 eBook ISBN: 978-1-4200-4018-0

  • The Human Brain During the Third Trimester

Shirley A . Bayer and Joseph Altman CRC Press 2003 Print ISBN: 978-0-8493-1421-6 eBook ISBN: 978-0-203-49494-3

  • The Human Brain During the Second Trimester

Shirley A . Bayer and Joseph Altman CRC Press 2005 Print ISBN: 978-0-8493-1422-3 eBook ISBN: 978-0-203-50748-3

  • The Human Brain During the Late First Trimester

Shirley A . Bayer and Joseph Altman CRC Press 2006 Print ISBN: 978-0-8493-1423-0 eBook ISBN: 978-1-4200-0327-7

  • The Human Brain During the Early First Trimester

Shirley A . Bayer and Joseph Altman CRC Press 2007 Print ISBN: 978-0-8493-1424-7 eBook ISBN: 978-1-4200-0328-4


Zhu Y, Crowley SC, Latimer AJ, Lewis GM, Nash R & Kucenas S. (2019). Migratory Neural Crest Cells Phagocytose Dead Cells in the Developing Nervous System. Cell , 179, 74-89.e10. PMID: 31495570 DOI.

During neural tube closure and spinal cord development, many cells die in both the central and peripheral nervous systems (CNS and PNS, respectively). However, myeloid-derived professional phagocytes have not yet colonized the trunk region during early neurogenesis. How apoptotic cells are removed from this region during these stages remains largely unknown. Using live imaging in zebrafish, we demonstrate that neural crest cells (NCCs) respond rapidly to dying cells and phagocytose cellular debris around the neural tube. Additionally, NCCs have the ability to enter the CNS through motor exit point transition zones and clear debris in the spinal cord. Surprisingly, NCCs phagocytosis mechanistically resembles macrophage phagocytosis and their recruitment toward cellular debris is mediated by interleukin-1β. Taken together, our results reveal a role for NCCs in phagocytosis of debris in the developing nervous system before the presence of professional phagocytes.

Trush O, Liu C, Han X, Nakai Y, Takayama R, Murakawa H, Carrillo JA, Takechi H, Hakeda-Suzuki S, Suzuki T & Sato M. (2019). N-cadherin orchestrates self-organization of neurons within a columnar unit in the Drosophila medulla. J. Neurosci. , , . PMID: 31175213 DOI. neural fly

  • N-cadherin orchestrates self-organization of neurons within a columnar unit in the Drosophila medulla "The columnar structure is a basic unit of the brain, but its developmental mechanism remains unknown. The medulla, the largest ganglion of the fly visual center, provides a unique opportunity to reveal the mechanisms of three-dimensional organization of the columns. We reveal that column formation is initiated by three core neurons that establish distinct concentric domains within a column. We demonstrate the in vivo evidence of N-cadherin-dependent differential adhesion among the core columnar neurons within a column along a two-dimensional layer in the larval medulla. The two-dimensional larval columns evolve to form three distinct layers in the pupal medulla. We propose the presence of mutual interactions among the three layers during formation of the three-dimensional structures of the medulla columns." neural


Caspases and matrix metalloproteases facilitate collective behavior of non-neural ectoderm after hindbrain neuropore closure

BMC Dev Biol. 2018 Jul 31;18(1):17. doi: 10.1186/s12861-018-0175-3.

Shinotsuka N1, Yamaguchi Y2,3, Nakazato K4, Matsumoto Y1, Mochizuki A4,5, Miura M6.

Abstract BACKGROUND: Mammalian brain is formed through neural tube closure (NTC), wherein both ridges of opposing neural folds are fused in the midline and remodeled in the roof plate of the neural tube and overlying non-neural ectodermal layer. Apoptosis is widely observed from the beginning of NTC at the neural ridges and is crucial for the proper progression of NTC, but its role after the closure remains less clear.

RESULTS: Here, we conducted live-imaging analysis of the mid-hindbrain neuropore (MHNP) closure and revealed unexpected collective behavior of cells surrounding the MHNP. The cells first gathered to the closing point and subsequently relocated as if they were released from the point. Inhibition of caspases or matrix metalloproteases with chemical inhibitors impaired the cell relocation.

CONCLUSIONS: These lines of evidence suggest that apoptosis-mediated degradation of extracellular matrix might facilitate the final process of neuropore closure.

KEYWORDS: Apoptosis; Caspases; Live-imaging; Matrix metalloproteases; Neural tube closure PMID: 30064364 PMCID: PMC6069860 DOI: 10.1186/s12861-018-0175-3

Nervous System Regionalization Entails Axial Allocation before Neural Differentiation

Cell. 2018 Oct 13. pii: S0092-8674(18)31252-2. doi: 10.1016/j.cell.2018.09.040. [Epub ahead of print]

Metzis V1, Steinhauser S1, Pakanavicius E1, Gouti M2, Stamataki D1, Ivanovitch K1, Watson T1, Rayon T1, Mousavy Gharavy SN1, Lovell-Badge R1, Luscombe NM3, Briscoe J4. Author information Abstract Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This "primary regionalization" allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS. KEYWORDS: ATAC-seq; CDX; WNT signaling; chromatin; computational genomics; embryonic development; gene regulation; neural induction; spinal cord; stem cells and development PMID: 30343898 DOI: 10.1016/j.cell.2018.09.040


Molecular and cellular reorganization of neural circuits in the human lineage

Science. 2017 Nov 24;358(6366):1027-1032. doi: 10.1126/science.aan3456.

Sousa AMM1, Zhu Y1, Raghanti MA2, Kitchen RR3,4, Onorati M1,5, Tebbenkamp ATN1, Stutz B6, Meyer KA1, Li M1, Kawasawa YI1,7, Liu F1, Perez RG8, Mele M8, Carvalho T8, Skarica M1, Gulden FO1, Pletikos M1, Shibata A1, Stephenson AR2, Edler MK2, Ely JJ9, Elsworth JD4, Horvath TL1,6, Hof PR10, Hyde TM11, Kleinman JE11, Weinberger DR11, Reimers M12, Lifton RP13,14,15, Mane SM16, Noonan JP13, State MW17, Lein ES18, Knowles JA19, Marques-Bonet T8,20,21, Sherwood CC22, Gerstein MB3, Sestan N23,4,6,13,24.

Abstract To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease. PMID: 29170230

Mouse Fgf8-Cre-LacZ lineage analysis defines the territory of the postnatal mammalian isthmus

J Comp Neurol. 2017 Aug 15;525(12):2782-2799. doi: 10.1002/cne.24242. Epub 2017 May 30.

Watson C1, Shimogori T2, Puelles L3.


The isthmus is recognized as the most rostral segment of the hindbrain in non-mammalian vertebrates. In mammalian embryos, transient Fgf8 expression defines the developing isthmic region, lying between the midbrain and the first rhombomere, but there has been uncertainty about the existence of a distinct isthmic segment in postnatal mammals. We attempted to find if the region of early embryonic Fgf8 expression (which is considered to involve the entire extent of the prospective isthmus initially) might help to identify the boundaries of the isthmus in postnatal animals. By creating an Fgf8-Cre-LacZ lineage in mice, we were able to show that Fgf8-Cre reporter expression in postnatal mice is present in the same nuclei that characterize the isthmic region in birds. The 'signature' isthmic structures in birds include the trochlear nucleus, the dorsal raphe nucleus, the microcellular tegmental nuclei, the pedunculotegmental nucleus, the vermis of the cerebellum, rostral parts of the parabrachial complex and locus coeruleus, and the caudal parts of the substantia nigra and VTA. We found that all of these structures were labeled with the Fgf8-Cre reporter in the mouse brain, and we conclude that the isthmus is a distinct segment of the mammalian brain lying caudal to the midbrain and rostral to rhombomere 1 of the hindbrain. © 2017 Wiley Periodicals, Inc.

KEYWORDS: Fgf8; Isthmus; RRID:AB_2313764; cerebellum; midbrain; rhombomere PMID: 28510270 DOI: 10.1002/cne.24242


First trimester size charts of embryonic brain structures

Hum Reprod. 2014 Feb;29(2):201-7. doi: 10.1093/humrep/det406. Epub 2013 Nov 28.

Gijtenbeek M1, Bogers H, Groenenberg IA, Exalto N, Willemsen SP, Steegers EA, Eilers PH, Steegers-Theunissen RP.


STUDY QUESTION: Can reliable size charts of human embryonic brain structures be created from three-dimensional ultrasound (3D-US) visualizations? SUMMARY ANSWER: Reliable size charts of human embryonic brain structures can be created from high-quality images. WHAT IS KNOWN ALREADY: Previous studies on the visualization of both the cavities and the walls of the brain compartments were performed using 2D-US, 3D-US or invasive intrauterine sonography. However, the walls of the diencephalon, mesencephalon and telencephalon have not been measured non-invasively before. Last-decade improvements in transvaginal ultrasound techniques allow a better visualization and offer the tools to measure these human embryonic brain structures with precision. STUDY DESIGN, SIZE, DURATION: This study is embedded in a prospective periconceptional cohort study. A total of 141 pregnancies were included before the sixth week of gestation and were monitored until delivery to assess complications and adverse outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the analysis of embryonic growth, 596 3D-US scans encompassing the entire embryo were obtained from 106 singleton non-malformed live birth pregnancies between 7(+0) and 12(+6) weeks' gestational age (GA). Using 4D View (3D software) the measured embryonic brain structures comprised thickness of the diencephalon, mesencephalon and telencephalon, and the total diameter of the diencephalon and mesencephalon. MAIN RESULTS AND THE ROLE OF CHANCE: Of 596 3D scans, 161 (27%) high-quality scans of 79 pregnancies were eligible for analysis. The reliability of all embryonic brain structure measurements, based on the intra-class correlation coefficients (ICCs) (all above 0.98), was excellent. Bland-Altman plots showed moderate agreement for measurements of the telencephalon, but for all other measurements the agreement was good. Size charts were constructed according to crown-rump length (CRL). LIMITATIONS, REASONS FOR CAUTION: The percentage of high-quality scans suitable for analysis of these brain structures was low (27%). WIDER IMPLICATIONS OF THE FINDINGS:

The size charts of human embryonic brain structures can be used to study normal and abnormal development of brain development in future. Also, the effects of periconceptional maternal exposures, such as folic acid supplement use and smoking, on human embryonic brain development can be a topic of future research.

STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Obstetrics and Gynaecology of the Erasmus University Medical Center. M.G. was supported by an additional grant from the Sophia Foundation for Medical Research (SSWO grant number 644). No competing interests are declared. KEYWORDS: embryo development; embryology; pregnancy; prenatal diagnosis; ultrasound

PMID 24287820

Cell cycle regulation of proliferation versus differentiation in the central nervous system

Cell Tissue Res. 2015 Jan;359(1):187-200. doi: 10.1007/s00441-014-1895-8. Epub 2014 May 25.

Hardwick LJ1, Ali FR, Azzarelli R, Philpott A.


Formation of the central nervous system requires a period of extensive progenitor cell proliferation, accompanied or closely followed by differentiation; the balance between these two processes in various regions of the central nervous system gives rise to differential growth and cellular diversity. The correlation between cell cycle lengthening and differentiation has been reported across several types of cell lineage and from diverse model organisms, both in vivo and in vitro. Furthermore, different cell fates might be determined during different phases of the preceding cell cycle, indicating direct cell cycle influences on both early lineage commitment and terminal cell fate decisions. Significant advances have been made in the last decade and have revealed multi-directional interactions between the molecular machinery regulating the processes of cell proliferation and neuronal differentiation. Here, we first introduce the modes of proliferation in neural progenitor cells and summarise evidence linking cell cycle length and neuronal differentiation. Second, we describe the manner in which components of the cell cycle machinery can have additional and, sometimes, cell-cycle-independent roles in directly regulating neurogenesis. Finally, we discuss the way that differentiation factors, such as proneural bHLH proteins, can promote either progenitor maintenance or differentiation according to the cellular environment. These intricate connections contribute to precise coordination and the ultimate division versus differentiation decision. PMID 24859217

Genes expressed in mouse cortical progenitors are enriched in Pax, Lhx, and Sox transcription factor putative binding sites

Brain Res. 2015 Dec 23. pii: S0006-8993(15)00961-0. doi: 10.1016/j.brainres.2015.12.022. [Epub ahead of print]

Bery A1, Mérot Y2, Rétaux S3.


Considerable progress has been made in the understanding of molecular and cellular mechanisms controlling the development of the mammalian cortex. The proliferative and neurogenic properties of cortical progenitors located in the ventricular germinal zone start being understood. Little is known however on the cis-regulatory control that finely tunes gene expression in these progenitors. Here, we undertook an in silico-based approach to address this question, followed by some functional validation. Using the Eurexpress database, we established a list of 30 genes specifically expressed in the cortical germinal zone, we selected mouse/human conserved non-coding elements (CNEs) around these genes and we performed motif-enrichment search in these CNEs. We found an over-representation of motifs corresponding to binding sites for Pax, Sox, and Lhx transcription factors, often found as pairs and located within 100bp windows. A small subset of CNEs (n=7) was tested for enhancer activity, by ex-vivo and in utero electroporation assays. Two showed strong enhancer activity in the germinal zone progenitors. Mutagenesis experiments on a selected CNE showed the functional importance of the Pax, Sox, and Lhx TFBS for conferring enhancer activity to the CNE. Overall, from a cis-regulatory viewpoint, our data suggest an input from Pax, Sox and Lhx transcription factors to orchestrate corticogenesis. These results are discussed with regards to the known functional roles of Pax6, Sox2 and Lhx2 in cortical development. Copyright © 2015 Elsevier B.V. All rights reserved. KEYWORDS: Enhancer activity; Lhx2; Motif search; Mutagenesis; Non-coding regulatory element; in vivo electroporation

PMID 26721689

Development of the vertebrate tailbud

Wiley Interdiscip Rev Dev Biol. 2015 Jan-Feb;4(1):33-44. doi: 10.1002/wdev.163. Epub 2014 Nov 10.

Beck CW1.


The anatomical tailbud is a defining feature of all embryonic chordates, including vertebrates that do not end up with a morphological tail. Due to its seamless continuity with trunk tissues, the tailbud is often overlooked as a mere extension of the body axis; however, the formation of the tail from the tailbud undoubtedly involves unique and distinct mechanisms for forming axial tissues, such as the secondary neurulation process that generates the tailbud-derived spinal cord. Tailbud formation in the frog Xenopus laevis has been demonstrated to involve interaction of three posterior regions of the embryo that first come into alignment at the end of gastrulation, and molecular models for tailbud outgrowth and patterning have been proposed. While classical studies of other vertebrate models, such as the chicken, initially appeared to draw incompatible conclusions, molecular studies have subsequently shown the involvement of at least some similar genetic pathways. Finally, there is an emerging consensus that at least some vertebrate tailbud cells are multipotent progenitors with the ability to form tissues normally derived from different germ layers- a trait normally associated with regeneration of complex appendages, or stem-like cells. © 2014 Wiley Periodicals, Inc.

PMID 25382697

Cellular basis of neuroepithelial bending during mouse spinal neural tube closure

Dev Biol. 2015 Aug 15;404(2):113-24. doi: 10.1016/j.ydbio.2015.06.003. Epub 2015 Jun 12.

McShane SG1, Molè MA1, Savery D1, Greene ND1, Tam PP2, Copp AJ3.


Bending of the neural plate at paired dorsolateral hinge points (DLHPs) is required for neural tube closure in the spinal region of the mouse embryo. As a step towards understanding the morphogenetic mechanism of DLHP development, we examined variations in neural plate cellular architecture and proliferation during closure. Neuroepithelial cells within the median hinge point (MHP) contain nuclei that are mainly basally located and undergo relatively slow proliferation, with a 7h cell cycle length. In contrast, cells in the dorsolateral neuroepithelium, including the DLHP, exhibit nuclei distributed throughout the apico-basal axis and undergo rapid proliferation, with a 4h cell cycle length. As the neural folds elevate, cell numbers increase to a greater extent in the dorsolateral neural plate that contacts the surface ectoderm, compared with the more ventromedial neural plate where cells contact paraxial mesoderm and notochord. This marked increase in dorsolateral cell number cannot be accounted for solely on the basis of enhanced cell proliferation in this region. We hypothesised that neuroepithelial cells may translocate in a ventral-to-dorsal direction as DLHP formation occurs, and this was confirmed by vital cell labelling in cultured embryos. The translocation of cells into the neural fold, together with its more rapid cell proliferation, leads to an increase in cell density dorsolaterally compared with the more ventromedial neural plate. These findings suggest a model in which DLHP formation may proceed through 'buckling' of the neuroepithelium at a dorso-ventral boundary marked by a change in cell-packing density. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. KEYWORDS: Cell proliferation; Embryo; Mouse; Neural tube closure; Neurulation

PMID 26079577

A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply

J Stroke. 2015 May;17(2):144-58. doi: 10.5853/jos.2015.17.2.144. Epub 2015 May 29.

Menshawi K1, Mohr JP1, Gutierrez J1.


The anatomy of the arterial system supplying blood to the brain can influence the development of arterial disease such as aneurysms, dolichoectasia and atherosclerosis. As the arteries supplying blood to the brain develop during embryogenesis, variation in their anatomy may occur and this variation may influence the development of arterial disease. Angiogenesis, which occurs mainly by sprouting of parent arteries, is the first stage at which variations can occur. At day 24 of embryological life, the internal carotid artery is the first artery to form and it provides all the blood required by the primitive brain. As the occipital region, brain stem and cerebellum enlarge; the internal carotid supply becomes insufficient, triggering the development of the posterior circulation. At this stage, the posterior circulation consists of a primitive mesh of arterial networks that originate from projection of penetrators from the distal carotid artery and more proximally from carotid-vertebrobasilar anastomoses. These anastomoses regress when the basilar artery and the vertebral arteries become independent from the internal carotid artery, but their persistence is not uncommon in adults (e.g., persistent trigeminal artery). Other common remnants of embryological development include fenestration or duplication (most commonly of the basilar artery), hypoplasia (typically of the posterior communicating artery) or agenesis (typically of the anterior communicating artery). Learning more about the hemodynamic consequence that these variants may have on the brain territories they supply may help understand better the underlying physiopathology of cerebral arterial remodeling and stroke in patients with these variants. KEYWORDS: Arterial variants; Cerebral arteries; Circle of willis; Embryology; Remodeling; Stroke

PMID 26060802

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


A conserved role for non-neural ectoderm cells in early neural development

Development. 2014 Nov;141(21):4127-38. doi: 10.1242/dev.107425. Epub 2014 Oct 1.

Cajal M1, Creuzet SE2, Papanayotou C1, Sabéran-Djoneidi D1, Chuva de Sousa Lopes SM3, Zwijsen A4, Collignon J1, Camus A5.


During the early steps of head development, ectodermal patterning leads to the emergence of distinct non-neural and neural progenitor cells. The induction of the preplacodal ectoderm and the neural crest depends on well-studied signalling interactions between the non-neural ectoderm fated to become epidermis and the prospective neural plate. By contrast, the involvement of the non-neural ectoderm in the morphogenetic events leading to the development and patterning of the central nervous system has been studied less extensively. Here, we show that the removal of the rostral non-neural ectoderm abutting the prospective neural plate at late gastrulation stage leads, in mouse and chick embryos, to morphological defects in forebrain and craniofacial tissues. In particular, this ablation compromises the development of the telencephalon without affecting that of the diencephalon. Further investigations of ablated mouse embryos established that signalling centres crucial for forebrain regionalization, namely the axial mesendoderm and the anterior neural ridge, form normally. Moreover, changes in cell death or cell proliferation could not explain the specific loss of telencephalic tissue. Finally, we provide evidence that the removal of rostral tissues triggers misregulation of the BMP, WNT and FGF signalling pathways that may affect telencephalon development. This study opens new perspectives on the role of the neural/non-neural interface and reveals its functional relevance across higher vertebrates. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Apoptosis; Chick; Embryo; Forebrain patterning; Mouse; Signalling centre; Telencephalon; Vertebrates

PMID 25273086

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Development. 2013 Jul;140(14):3008-17. doi: 10.1242/dev.091173. Epub 2013 Jun 12.

Escobedo N1, Contreras O, Muñoz R, Farías M, Carrasco H, Hill C, Tran U, Pryor SE, Wessely O, Copp AJ, Larraín J.


Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2(Lp) compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2(Lp) mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2(Lp/+) enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2(Lp/+) embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2(Lp/Lp)) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos. KEYWORDS: Neural tube defects; Proteoglycans; Wnt planar cell polarity

PMID 23760952

Open Access

Secondary neurulation of human embryos: morphological changes and the expression of neuronal antigens

Childs Nerv Syst. 2014 Jan;30(1):73-82. doi: 10.1007/s00381-013-2192-7. Epub 2013 Jun 13.

Yang HJ, Lee DH, Lee YJ, Chi JG, Lee JY, Phi JH, Kim SK, Cho BK, Wang KC. Author information

Abstract PURPOSE: The morphological changes and expression patterns of neuronal antigens of human embryos, obtained from the therapeutic termination of pregnancy or from surgical procedures, were analyzed in order to characterize the secondary neurulation. METHODS: A total of 21 human embryos from Carnegie stages 12 to 23 and two fetuses in early stages were studied. The markers used for immunohistochemical study were neural cell adhesion molecule (N-CAM), neuronal nuclear antigen (NeuN), neurofilament-associated protein (3A10), synaptophysin, and glial fibrillary acidic protein (GFAP). RESULTS: The formation of the caudal neural tube to the tip of the caudal portion of the embryo was finished at stage 17. The postcloacal gut had completely disappeared at stage 18, and multiple cavities of the caudal neural tube were clearly visible. The caudal portion of the neural tube showed findings suggestive of involution at stage 19. The expression patterns of neuronal antigens were as follows: N-CAM and NeuN showed immunoreactivity at the germinal layer of the spinal cord at stages 17 and 18. Neurofilament-associated protein (3A10) showed persistent immunoreactivity at the caudal cell mass and notochord during the observation period, along with the spinal cord, and the positive reactions were mainly located at the dorsal white matter at stage 17. Synaptophysin showed a weak positive reaction at the caudal cell mass and notochord at stages 13 and 14, evident by staining observed at the spinal cord at stages 15 and 16. There was no definite positive reaction for GFAP. CONCLUSIONS: These characteristic patterns might be helpful for the understanding of human congenital anomalies involving secondary neurulation processes. PMID 23760472


The longitudinal growth of the neuromeres and the resulting brain in the human embryo

O'Rahilly R. and Müller F. The longitudinal growth of the neuromeres and the resulting brain in the human embryo. (2013) Cells Tissues Organs. 197(3):178-95. doi: 10.1159/000343170. PMID 23183269.

Cells Tissues Organs. 2013;197(3):178-95. doi: 10.1159/000343170. Epub 2012 Nov 24.

O'Rahilly R, Müller F. Author information


The growth of the human brain during the embryonic period was assessed in terms of longitudinal measurements in staged embryos. Precise graphic reconstructions prepared by the onerous point-plotting method were considered to be the most reliable, and 23 were examined in detail. A distinction is necessary between measurements of the brain (cerebral diameters) and those of the skull (osseous diameters), and also between those of the folded brain in situ, studied here, and the later relatively straightened brain. Longitudinal measurements were made of individual neuromeres and their successors in steps (neuromeric lengths). The sum of the neuromeric measurements at any given stage provides the total neuromeric length (TNL) of the folded brain in situ at that stage and it increases in keeping with the greatest length (GL) of the embryo. At stages 16-19, however, the neuromeric length of the brain may exceed the GL. From stage 20 onwards the body length increases more rapidly compared with the length of the brain. The most cephalic neuromere is the telencephalon medium, abbreviated T1 here. The cerebral hemispheres are derived from it, although they are not neuromeres. The hemispheres soon extend rostrally beyond the limit of T1 by an amount that is here designated T2, and that indicates the growth of the telencephalon rostral to the commissural plate, which is the site of the future corpus callosum. Further laterally, the hemispheric length (future fronto-occipital diameter) increases rapidly, as does also the bitemporal (biparietal) diameter. At the end of the embryonic period these diameters are one fourth to one fifth of the head circumference. Additional neuromeric information becomes manifest when the measurements are calculated as percentages of the total length of the brain. The rhombencephalon decreases considerably, diencephalon 2 increases greatly, whereas diencephalon 1 diminishes, and the cerebral hemispheres enlarge massively. In addition, specific neuromeres or subdivisions come to occupy relatively more or relatively less of the total. Three periods were found during which individual neuromeres acquire their maximal or minimal lengths: the maximal absolute lengths were in period 3, whereas the maximal and minimal percentage lengths were in periods 1 and 3. The various neuromeric changes are considered to be related to alterations in functional development. Finally, in furtherance of establishing continuity in prenatal data, comparisons were effected between embryonic and fetal measurements. Copyright © 2012 S. Karger AG, Basel.

PMID 23183269

Neural induction and early patterning in vertebrates

Wiley Interdiscip Rev Dev Biol. 2013 Jul;2(4):479-98. doi: 10.1002/wdev.90. Epub 2012 Oct 15.

Ozair MZ, Kintner C, Brivanlou AH. Source Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY, USA.


In vertebrates, the development of the nervous system is triggered by signals from a powerful 'organizing' region of the early embryo during gastrulation. This phenomenon--neural induction--was originally discovered and given conceptual definition by experimental embryologists working with amphibian embryos. Work on the molecular circuitry underlying neural induction, also in the same model system, demonstrated that elimination of ongoing transforming growth factor-β (TGFβ) signaling in the ectoderm is the hallmark of anterior neural-fate acquisition. This observation is the basis of the 'default' model of neural induction. Endogenous neural inducers are secreted proteins that act to inhibit TGFβ ligands in the dorsal ectoderm. In the ventral ectoderm, where the signaling ligands escape the inhibitors, a non-neural fate is induced. Inhibition of the TGFβ pathway has now been demonstrated to be sufficient to directly induce neural fate in mammalian embryos as well as pluripotent mouse and human embryonic stem cells. Hence the molecular process that delineates neural from non-neural ectoderm is conserved across a broad range of organisms in the evolutionary tree. The availability of embryonic stem cells from mouse, primates, and humans will facilitate further understanding of the role of signaling pathways and their downstream mediators in neural induction in vertebrate embryos. Copyright © 2012 Wiley Periodicals, Inc.

PMID 24014419

Developmental mechanisms directing early anterior forebrain specification in vertebrates

Cell Mol Life Sci. 2013 Oct;70(20):3739-52. doi: 10.1007/s00018-013-1269-5. Epub 2013 Feb 9.

Andoniadou CL, Martinez-Barbera JP. Source Birth Defects Research Centre, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. Abstract Research from the last 15 years has provided a working model for how the anterior forebrain is induced and specified during the early stages of embryogenesis. This model relies on three basic processes: (1) induction of the neural plate from naive ectoderm requires the inhibition of BMP/TGFβ signaling; (2) induced neural tissue initially acquires an anterior identity (i.e., anterior forebrain); (3) maintenance and expansion of the anterior forebrain depends on the antagonism of posteriorizing signals that would otherwise transform this tissue into posterior neural fates. In this review, we present a historical perspective examining some of the significant experiments that have helped to delineate this molecular model. In addition, we discuss the function of the relevant tissues that act prior to and during gastrulation to ensure proper anterior forebrain formation. Finally, we elaborate data, mainly obtained from the analyses of mouse mutants, supporting a role for transcriptional repressors in the regulation of cell competence within the anterior forebrain. The aim of this review is to provide the reader with a general overview of the signals as well as the signaling centers that control the development of the anterior neural plate.

PMID 23397132

Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice

Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):E1045-54. doi: 10.1073/pnas.1219563110. Epub 2013 Feb 21.

Ponti G, Obernier K, Guinto C, Jose L, Bonfanti L, Alvarez-Buylla A. Source Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.


Proliferating neural stem cells and intermediate progenitors persist in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain. This extensive germinal layer in the walls of the lateral ventricles is the site of birth of different types of interneurons destined for the olfactory bulb. The cell cycle dynamics of stem cells (B1 cells), intermediate progenitors (C cells), and neuroblasts (A cells) in the V-SVZ and the number of times these cells divide remain unknown. Using whole mounts of the walls of the lateral ventricles of adult mice and three cell cycle analysis methods using thymidine analogs, we determined the proliferation dynamics of B1, C, and A cells in vivo. Achaete-scute complex homolog (Ascl)1(+) C cells were heterogeneous with a cell cycle length (T(C)) of 18-25 h and a long S phase length (T(S)) of 14-17 h. After C cells, Doublecortin(+) A cells were the second-most common dividing cell type in the V-SVZ and had a T(C) of 18 h and T(S) of 9 h. Human glial fibrillary acidic protein (hGFAP)::GFP(+) B1 cells had a surprisingly short Tc of 17-18 h and a T(S) of 4 h. Progenitor population analysis suggests that following the initial division of B1 cells, C cells divide three times and A cells once, possibly twice. These data provide essential information on the dynamics of adult progenitor cell proliferation in the V-SVZ and how large numbers of new neurons continue to be produced in the adult mammalian brain. PMID 23431204



Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13776-81. Epub 2011 Jul 27.

Spatial and temporal second messenger codes for growth cone turning

Nicol X, Hong KP, Spitzer NC. Source Neurobiology Section, Division of Biological Sciences, Kavli Institute for Brain and Mind, University of California at San Diego, La Jolla, CA 92093, USA.


Cyclic AMP (cAMP) and calcium are ubiquitous, interdependent second messengers that regulate a wide range of cellular processes. During development of neuronal networks they are critical for the first step of circuit formation, transducing signals required for axon pathfinding. Surprisingly, the spatial and temporal cAMP and calcium codes used by axon guidance molecules are unknown. Here, we identify characteristics of cAMP and calcium transients generated in growth cones during Netrin-1-dependent axon guidance. In filopodia, Netrin-1-dependent Deleted in Colorectal Cancer (DCC) receptor activation induces a transient increase in cAMP that causes a brief increase in calcium transient frequency. In contrast, activation of DCC in growth cone centers leads to a transient calcium-dependent cAMP increase and a sustained increase in frequency of calcium transients. We show that filopodial cAMP transients regulate spinal axon guidance in vitro and commissural axon pathfinding in vivo. These growth cone codes provide a basis for selective activation of specific downstream effectors.

PMID 21795610

The Zagreb Collection of human brains: a unique, versatile, but underexploited resource for the neuroscience community

Ann N Y Acad Sci. 2011 May;1225 Suppl 1:E105-30. doi: 10.1111/j.1749-6632.2011.05993.x.

Judaš M, Šimić G, Petanjek Z, Jovanov-Milošević N, Pletikos M, Vasung L, Vukšić M, Kostović I. Source University of Zagreb School of Medicine, Croatian Institute for Brain Research, Zagreb, Croatia. Abstract The Zagreb Collection of developing and adult human brains was founded in 1974 by Ivica Kostović and consists of 1,278 developing and adult human brains, including 610 fetal, 317 children, and 359 adult brains. It is one of the largest collections of developing human brains. The collection serves as a key resource for many focused research projects and has led to several seminal contributions on mammalian cortical development, such as the discovery of the transient fetal subplate zone and of early bilaminar synaptogenesis in the embryonic and fetal human cerebral cortex, and the first description of growing afferent pathways in the human fetal telencephalon. The Zagreb Collection also serves as a core resource for ever-growing networks of international collaboration and represents the starting point for many young investigators who now pursue independent research careers at leading international institutions. The Zagreb Collection, however, remains underexploited owing to a lack of adequate funding in Croatia. Funding could establish an online catalog of the collection and modern virtual microscopy scanning methods to make the collection internationally more accessible.

© 2011 New York Academy of Sciences.

PMID: 21599691

Plxdc2 is a mitogen for neural progenitors

PLoS One. 2011 Jan 21;6(1):e14565.

Miller-Delaney SF, Lieberam I, Murphy P, Mitchell KJ. Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.


The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify Plxdc2 as a novel regulator of these processes, using in ovo electroporation and in vitro cultures of mammalian cells. Plxdc2 is a type I transmembrane protein with some homology to nidogen and to plexins. It is expressed in a highly discrete and dynamic pattern in the developing nervous system, with prominent expression in various patterning centres. In the chick neural tube, where Plxdc2 expression parallels that seen in the mouse, misexpression of Plxdc2 increases proliferation and alters patterns of neurogenesis, resulting in neural tube thickening at early stages. Expression of the Plxdc2 extracellular domain alone, which can be cleaved and shed in vivo, is sufficient for this activity, demonstrating a cell non-autonomous function. Induction of proliferation is also observed in cultured embryonic neuroepithelial cells (ENCs) derived from E9.5 mouse neural tube, which express a Plxdc2-binding activity. These experiments uncover a direct molecular activity of Plxdc2 in the control of proliferation, of relevance in understanding the role of this protein in various cancers, where its expression has been shown to be altered. They also implicate Plxdc2 as a novel component of the network of signalling molecules known to coordinate proliferation and differentiation in the developing nervous system.

PMID: 21283688

Plxdc2 transmembrane protein Plexin domain-containing 2. mouse Plxdc2 gene encodes a type I transmembrane protein of 530 amino acids, characterised by an extracellular region of weak nidogen homology and a plexin repeat or PSI domain, a domain found in several known axon guidance molecules.

Plxdc1 In the human, mouse and chick Plxdc2 has this one related gene.

Molecular Patterning "The midbrain-hindbrain boundary (MHB), which expresses Wnt1 and Fgf8, is one of several local signalling centres in the neuroepithelium which refines AP specification of the brain. DV patterning is influenced by the floor plate, which expresses ventralising factors including sonic hedgehog (Shh) and nodal and the roof plate at the dorsal midline, which expresses members of the BMP and Wnt families. Differential dorsal and ventral growth of the brain is also co-ordinated via a signalling cascade of Shh, FGF and Wnt activity."


Developmental changes in cerebral grey and white matter volume from infancy to adulthood.

Int J Dev Neurosci. 2010 Oct;28(6):481-9. Epub 2010 Jun 30. Groeschel S, Vollmer B, King MD, Connelly A.

Radiology and Physics Unit, UCL Institute of Child Health, London, UK. Abstract

In order to quantify human brain development in vivo, high resolution magnetic resonance images of 158 normal subjects from infancy to young adulthood were studied (age range 3 months-30 years, 71 males, 87 females). Data were analysed using algorithms based on voxel-based morphometry (VBM) (an objective whole brain processing technique) to generate global volume measures of whole brain, grey matter (GM) and white matter (GM). Gender-specific development of WM and GM volumes is characterised using a piecewise polynomial growth curve model to account for the non-linear nature of human brain development, implemented using Markov chain Monte Carlo simulation. The statistical method employed in this study proved to be successful and robust in the characterisation of brain development. The resulting growth curve parameter estimates lead to the following observations: total brain volume is demonstrated to undergo an initial rapid spurt. The total GM volume peaks during childhood and decreases thereafter, whereas total WM volume increases up to young adulthood. Relative to brain size, GM decreases and WM increases markedly over this age range in a non-linear manner, resulting in an increasing WM-to-GM ratio over much of the observed age range. In addition, significant gender differences are found. In general, brain volume and total white and grey matter volume are larger in males than in females, with a time-dependent difference over the age range studied. Over part of the observed age range females tend to have more GM volume relative to brain size and lower WM-to-GM ratio than males. The presented findings should be taken into account when investigating physiological and pathological changes during brain development.


Heterogeneity in subcortical brain development: A structural magnetic resonance imaging study of brain maturation from 8 to 30 years.

J Neurosci. 2009 Sep 23;29(38):11772-82.

Ostby Y, Tamnes CK, Fjell AM, Westlye LT, Due-Tønnessen P, Walhovd KB.

Center for the Study of Human Cognition, Department of Psychology, University of Oslo, Norway. Abstract Brain development during late childhood and adolescence is characterized by decreases in gray matter (GM) and increases in white matter (WM) and ventricular volume. The dynamic nature of development across different structures is, however, not well understood, and the present magnetic resonance imaging study took advantage of a whole-brain segmentation approach to describe the developmental trajectories of 16 neuroanatomical volumes in the same sample of children, adolescents, and young adults (n = 171; range, 8-30 years). The cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens area, hippocampus, amygdala, thalamus, brainstem, cerebellar GM, cerebellar WM, lateral ventricles, inferior lateral ventricles, third ventricle, and fourth ventricle were studied. The cerebral cortex was further analyzed in terms of lobar thickness and surface area. The results revealed substantial heterogeneity in developmental trajectories. GM decreased nonlinearly in the cerebral cortex and linearly in the caudate, putamen, pallidum, accumbens, and cerebellar GM, whereas the amygdala and hippocampus showed slight, nonlinear increases in GM volume. WM increased nonlinearly in both the cerebrum and cerebellum, with an earlier maturation in cerebellar WM. In addition to similarities in developmental trajectories within subcortical regions, our results also point to differences between structures within the same regions: among the basal ganglia, the caudate showed a weaker relationship with age than the putamen and pallidum, and in the cerebellum, differences were found between GM and WM development. These results emphasize the importance of studying a wide range of structural variables in the same sample, for a broader understanding of brain developmental principles.


Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development

Eur J Neurosci. 2008 Oct;28(8):1449-56.

Bayatti N, Sarma S, Shaw C, Eyre JA, Vouyiouklis DA, Lindsay S, Clowry GJ. Source Institute of Neuroscience, Newcastle University, Newcastle-upon-Tyne, UK.


The transcription factors Emx2 and Pax6 are expressed in the proliferating zones of the developing rodent neocortex, and gradients of expression interact in specifying caudal and rostral identities. Pax6 is also involved in corticoneurogenesis, being expressed by radial glial progenitors that give rise to cells that also sequentially express Tbr2, NeuroD and Tbr1, genes temporally downstream of Pax6. In this study, using in situ hybridization, we analysed the expression of EMX2, PAX6, TBR2, NEUROD and TBR1 mRNA in the developing human cortex between 8 and 12 postconceptional weeks (PCW). EMX2 mRNA was expressed in the ventricular (VZ) and subventricular zones (SVZ), but also in the cortical plate, unlike in the rodent. However, gradients of expression were similar to that of the rodent at all ages studied. PAX6 mRNA expression was limited to the VZ and SVZ. At 8 PCW, PAX6 was highly expressed rostrally but less so caudally, as has been seen in the rodent, however this gradient disappeared early in corticogenesis, by 9 PCW. There was less restricted compartment-specific expression of TBR2, NEUROD and TBR1 mRNA than in the rodent, where the gradients of expression were similar to that of PAX6 prior to 9 PCW. The gradient disappeared for TBR2 by 10 PCW, and for NEUROD and TBR1 by 12 PCW. These data support recent reports that EMX2 but not PAX6 is more directly involved in arealization, highlighting that analysis of human development allows better spatio-temporal resolution than studies in rodents.

PMID 18973570

A structural MRI study of human brain development from birth to 2 years.

Knickmeyer RC, Gouttard S, Kang C, Evans D, Wilber K, Smith JK, Hamer RM, Lin W, Gerig G, Gilmore JH. J Neurosci. 2008 Nov 19;28(47):12176-82. PMID 19020011


3 dimensional modelling of early human brain development using optical projection tomography

BMC Neurosci. 2004 Aug 6;5:27.

Kerwin J, Scott M, Sharpe J, Puelles L, Robson SC, Martínez-de-la-Torre M, Ferran JL, Feng G, Baldock R, Strachan T, Davidson D, Lindsay S. Source Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.


BACKGROUND: As development proceeds the human embryo attains an ever more complex three dimensional (3D) structure. Analyzing the gene expression patterns that underlie these changes and interpreting their significance depends on identifying the anatomical structures to which they map and following these patterns in developing 3D structures over time. The difficulty of this task greatly increases as more gene expression patterns are added, particularly in organs with complex 3D structures such as the brain. Optical Projection Tomography (OPT) is a new technology which has been developed for rapidly generating digital 3D models of intact specimens. We have assessed the resolution of unstained neuronal structures within a Carnegie Stage (CS)17 OPT model and tested its use as a framework onto which anatomical structures can be defined and gene expression data mapped. RESULTS: Resolution of the OPT models was assessed by comparison of digital sections with physical sections stained, either with haematoxylin and eosin (H&E) or by immunocytochemistry for GAP43 or PAX6, to identify specific anatomical features. Despite the 3D models being of unstained tissue, peripheral nervous system structures from the trigeminal ganglion (approximately 300 microm by approximately 150 microm) to the rootlets of cranial nerve XII (approximately 20 microm in diameter) were clearly identifiable, as were structures in the developing neural tube such as the zona limitans intrathalamica (core is approximately 30 microm thick). Fourteen anatomical domains have been identified and visualised within the CS17 model. Two 3D gene expression domains, known to be defined by Pax6 expression in the mouse, were clearly visible when PAX6 data from 2D sections were mapped to the CS17 model. The feasibility of applying the OPT technology to all stages from CS12 to CS23, which encompasses the major period of organogenesis for the human developing central nervous system, was successfully demonstrated. CONCLUSION: In the CS17 model considerable detail is visible within the developing nervous system at a minimum resolution of approximately 20 microm and 3D anatomical and gene expression domains can be defined and visualised successfully. The OPT models and accompanying technologies for manipulating them provide a powerful approach to visualising and analysing gene expression and morphology during early human brain development.

PMID 15298700


The timing and sequence of appearance of neuromeres and their derivatives in staged human embryos

Acta Anat (Basel). 1997;158(2):83-99.

Müller F, O'Rahilly R. Author information


Serial sections of 215 human embryos from Carnegie stages 6-17 were investigated, and 85 graphic reconstructions were prepared. It is proposed that neuromeres be defined as morphologically identifiable transverse subdivisions perpendicular to the longitudinal axis of the embryonic brain and extending onto both sides of the body. It is proposed further that primary neuromeres be redefined as the early-appearing larger divisions of the open neural folds, and secondary neuromeres as the smaller subdivisions that are found both before and after closure of the neural tube. In the light of these definitions, 6 primary neuromeres can be detected in the human brain at stage 9, and a maximum of 16 secondary neuromeres at stage 14. The relationships of the 8 rhombomeres to the associated neural crest, as well as to the pharyngeal arches and the exits of the cranial nerves, are tabulated. Rhombomere 8 (Rh. 8) is intermediate between the more rostral neuromeres and the spinal cord, and its neural relationships indicate that the four occipital somitic pairs do not impress a strictly repetitive pattern as in the spinal cord. Hence, it is suggested that Rh. 8 depends on both intrinsic and extrinsic factors. The synencephalon, parencephalon, and isthmic neuromere can be distinguished in stage 13. In stage 14, rostral and caudal portions of the parencephalon are recognizable, and the full complement of 16 neuromeres is now present. The medial ventricular eminence appears in the diencephalon (D1). A longitudinal organisation begins to be superimposed on the neuromeres, as now indicated by the appearance of the hypothalamic cell cord. This continues in stage 15, when the hypothalamic sulcus develops. That groove, however, is not continuous with the sulcus limitans. In the diencephalon, five longitudinal zones can be discerned. In stage 16, fibre tracts, such as the habenulo-interpeduncular (fasciculus retroflexus) and the tract of the posterior commissure, outline the boundaries of the synencephalon. In stage 17, the tract of the zona limitans intrathalamica (along the marginal ridge in the parencephalon) is an important landmark. This is the last stage in which all the neuromeres can be distinguished. The supramamillary recess becomes defined and is the termination of the sulcus limitans: the alar/basal distinction is inappropriate in the human forebrain. The number and identity of the neuromeres in the human brain, their precise sequence of appearance, and the stages at which they appear are here clarified for the first time. The results of various studies of domains of gene expression indicate that, although in some instances such territories follow the morphological neuromeres, in others they may cross interneuromeric boundaries. It is concluded that the precise morphological study of neuromeres in any given species is necessary for correlative investigations of gene expression. PMID 9311417


Neurulation in the normal human embryo

Ciba Found Symp. 1994;181:70-82; discussion 82-9.

O'Rahilly R, Müller F. Source Institut für Anatomie und Spezielle Embryologie, Universität Freiburg, Switzerland.


The neural groove and folds are first seen during stage 8 (about 18 postovulatory days). Two days later (stage 9) the three main divisions of the brain, which are not cerebral vesicles, can be distinguished while the neural groove is still completely open. Two days later (stage 10) the neural folds begin to fuse near the junction between brain and spinal cord, when neural crest cells are arising mainly from the neural ectoderm. The rostral (or cephalic) neuropore closes within a few hours during stage 11 (about 24 days). The closure is bidirectional; it takes place from the dorsal and terminal lips and may occur in several areas simultaneously. The two lips, however, behave differently. The caudal neuropore takes a day to close during stage 12 (about 26 days) and the level of final closure is approximately at future somitic pair 31, which corresponds to the level of sacral vertebra 2. At stage 13 (4 weeks) the neural tube is normally completely closed. Secondary neurulation, which begins at stage 12, is the differentiation of the caudal part of the neural tube from the caudal eminence (or end-bud) without the intermediate phase of a neural plate.

PMID 8005032

Neural Development Table

Neural Tube Primary Vesicles Secondary Vesicles Adult Structures
Brain Prosencephalon Telencephalon Rhinencephalon, Amygdala, Hippocampus, Neocortex, Basal Ganglia, Lateral Ventricles
Diencephalon Epithalamus, Thalamus, Hypothalamus, Subthalamus, Pituitary, Pineal, Third ventricle
Mesencephalon Mesencephalon Tectum, Cerebral peduncle, Pretectum, Cerebral aqueduct
Rhombencephalon Metencephalon Pons, Cerebellum
Myelencephalon Medulla oblongata
Spinal Cord

Neural Table Linked

Neural Tube Primary Vesicles Secondary Vesicles Adult Structures
Brain Prosencephalon Telencephalon Rhinencephalon, Amygdala, Hippocampus, Neocortex, Basal Ganglia, lateral ventricles
Diencephalon Epithalamus, Thalamus, Hypothalamus, Subthalamus, Pituitary, Pineal, third ventricle
Mesencephalon Mesencephalon Tectum, Cerebral peduncle, Pretectum, cerebral aqueduct
Rhombencephalon Metencephalon Pons, Cerebellum
Myelencephalon Medulla Oblongata
Spinal Cord
Neural Parts: neural | prosencephalon | telencephalon cerebrum | amygdala | hippocampus | basal ganglia | diencephalon | epithalamus | thalamus | hypothalamus‎ | pituitary | pineal | mesencephalon | tectum | rhombencephalon | metencephalon | pons | cerebellum | myelencephalon | medulla oblongata | spinal cord | neural vascular | ventricular | lateral ventricles | third ventricle | cerebral aqueduct | fourth ventricle | central canal | meninges | Category:Ventricular System | Category:Neural