Talk:Neural - Spinal Cord Development

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Cite this page: Hill, M.A. (2020, October 21) Embryology Neural - Spinal Cord Development. Retrieved from


Gray de Cristoforis A, Ferrari F, Clotman F & Vogel T. (2020). Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression. Mol Brain , 13, 85. PMID: 32471461 DOI.

Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression

Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2.


Iulianella A & Stanton-Turcotte D. (2019). The Hedgehog receptor Patched1 regulates proliferation, neurogenesis, and axon guidance in the embryonic spinal cord. Mech. Dev. , 160, 103577. PMID: 31634536 DOI.

The Hedgehog receptor Patched1 regulates proliferation, neurogenesis, and axon guidance in the embryonic spinal cord.

Abstract The formation of the vertebrate nervous system depends on the complex interplay of morphogen signaling pathways and cell cycle progression to establish distinct cell fates. The Sonic hedgehog (Shh) signaling pathway is well understood to promote ventral cell fates in the developing spinal cord. A key regulator of Shh signaling is its receptor Patched1 (Ptch1). However, because the Ptch1 null mutation is lethal early in mouse embryogenesis, its role in controlling cell cycle progression, neurogenesis, and axon guidance in the developing spinal cord is not fully understood. An allele of Ptch1 called Wiggable (Ptch1Wig), which was previously shown to enhance Shh signaling, was used to test its ability to regulate neurogenesis and proliferation in the developing spinal cord. Ptch1Wig/Wig mutants displayed enhanced ventral proneural gene activation, and aberrant proliferation of the neural tube and floor plate cells, the latter normally being a quiescent population. The expression of the cell cycle regulators p27Kip1 and p57Kip2 were expanded in Ptch1Wig/Wig mutant spinal cords, as was the number of mitotic and S-phase nuclei, suggesting enhanced cell cycle progression. However, Ptch1Wig/Wig mutants also showed enhanced apoptosis in the ventral embryonic spinal cord, which resulted in thinner spinal cords at later embryonic stages. Commissural axons largely failed to cross the floor plate of Ptch1Wig/Wig mutant embryos, suggesting enhanced Shh signaling in these mutants led to a dorsal expansion of the chemoattraction front. These findings are consistent with a role of Ptch1 in regulating neurogenesis and proliferation of neural progenitors, and in restricting the influence of Shh signaling in commissural axon guidance to the floor plate. Copyright © 2019 Elsevier B.V. All rights reserved.

PMID: 31634536 DOI: 10.1016/j.mod.2019.103577


Species-specific Posture of Human Foetus in Late First Trimester

Sci Rep. 2018 Jan 8;8(1):27. doi: 10.1038/s41598-017-18384-w.

Ohmura Y1, Morokuma S2,3, Kato K3, Kuniyoshi Y4.

Abstract The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation. PMID: 29311655 PMCID: PMC5758525 DOI: 10.1038/s41598-017-18384-w


The Multiple Roles of FGF Signaling in the Developing Spinal Cord

Front Cell Dev Biol. 2017 Jun 2;5:58. doi: 10.3389/fcell.2017.00058. eCollection 2017.

Diez Del Corral R1,2, Morales AV1.


During vertebrate embryonic development, the spinal cord is formed by the neural derivatives of a neuromesodermal population that is specified at early stages of development and which develops in concert with the caudal regression of the primitive streak. Several processes related to spinal cord specification and maturation are coupled to this caudal extension including neurogenesis, ventral patterning and neural crest specification and all of them seem to be crucially regulated by Fibroblast Growth Factor (FGF) signaling, which is prominently active in the neuromesodermal region and transiently in its derivatives. Here we review the role of FGF signaling in those processes, trying to separate its different functions and highlighting the interactions with other signaling pathways. Finally, these early functions of FGF signaling in spinal cord development may underlay partly its ability to promote regeneration in the lesioned spinal cord as well as its action promoting specific fates in neural stem cell cultures that may be used for therapeutical purposes. KEYWORDS: FGF; caudal extension; neural stem cells; neurogenesis; neuromesodermal progenitors; patterning; spinal cord; spinal cord injury PMID: 28626748 PMCID: PMC5454045 DOI: 10.3389/fcell.2017.00058


Coordination of progenitor specification and growth in mouse and chick spinal cord

Science. 2014 Sep 26;345(6204):1254927. doi: 10.1126/science.1254927.

Kicheva A1, Bollenbach T2, Ribeiro A1, Valle HP3, Lovell-Badge R4, Episkopou V5, Briscoe J6.


Development requires tissue growth as well as cell diversification. To address how these processes are coordinated, we analyzed the development of molecularly distinct domains of neural progenitors in the mouse and chick neural tube. We show that during development, these domains undergo changes in size that do not scale with changes in overall tissue size. Our data show that domain proportions are first established by opposing morphogen gradients and subsequently controlled by domain-specific regulation of differentiation rate but not differences in proliferation rate. Regulation of differentiation rate is key to maintaining domain proportions while accommodating both intra- and interspecies variations in size. Thus, the sequential control of progenitor specification and differentiation elaborates pattern without requiring that signaling gradients grow as tissues expand. Copyright © 2014, American Association for the Advancement of Science. Comment in Developmental Biology. Managing patterns and proportions over time. [Science. 2014] PMID 25258086

Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord

Development. 2014 Jul;141(14):2875-84. doi: 10.1242/dev.105387. Epub 2014 Jun 19.

Li X1, Liu Z2, Qiu M3, Yang Z1.


Progenitor cells are segregated into multiple domains along the dorsoventral axis of the vertebrate neural tube, and each progenitor domain generates particular types of neurons. Selective cross-repressive interactions between pairs of class I and class II transcription factors play important roles in patterning neural progenitors into domains with clear boundaries. Here, we provide evidence that the zinc-finger protein Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary through mutually repressive interactions with the class II protein Nkx2-2. The ventral limit of Sp8 expression is complementary to the dorsal limit of Nkx2-2 expression at the pMN/p3 boundary. Sp8 and Nkx2-2 exert cross-repressive interactions, and changing the expression of Sp8 and Nkx2-2 is coupled with pMN and p3 progenitor fate conversion. Sp8 exerts its neural patterning activities by acting as a transcriptional activator. The expression of a repressive form of Sp8 results in the selective inhibition of motor neuron generation and the ectopic induction of Nkx2-2 expression. Sp8 expression is positively regulated by, but not completely dependent on, Pax6. Furthermore, whereas loss of Pax6 function alone results in disruption of the pMN/p3 domain boundary only in the rostral levels of the spinal cord, loss of both Sp8 and Pax6 functions results in disruption of the pMN/p3 domain boundary along the whole rostrocaudal axis of the spinal cord. We conclude that Sp8 plays a supplementary role to Pax6 in specifying the pMN over p3 progenitor fate through cross-repressive interactions with Nkx2-2. © 2014. Published by The Company of Biologists Ltd. KEYWORDS: Chick; Motor neuron; Mouse; Nkx2-2; Pax6; Sp8; Ventral patterning

PMID 24948600


Fasciculation and Guidance of Spinal Motor Axons in the Absence of FGFR2 Signaling

During development, fibroblast growth factors (FGF) are essential for early patterning events along the anterior-posterior axis, conferring positional identity to spinal motor neurons by activation of different Hox codes. In the periphery, signaling through one of four fibroblast growth factor receptors supports the development of the skeleton, as well as induction and maintenance of extremities. In previous studies, FGF receptor 2 (FGFR2) was found to interact with axon bound molecules involved in axon fasciculation and extension, thus rendering this receptor an interesting candidate for the promotion of proper peripheral innervation. However, while the involvement of FGFR2 in limb bud induction has been extensively studied, its role during axon elongation and formation of distinct nervous projections has not been addressed so far. We show here that motor neurons in the spinal cord express FGFR2 and other family members during the establishment of motor connections to the forelimb and axial musculature. Employing a conditional genetic approach to selectively ablate FGFR2 from motor neurons we found that the patterning of motor columns and the expression patterns of other FGF receptors and Sema3A in the motor columns of mutant embryos are not altered. In the absence of FGFR2 signaling, pathfinding of motor axons is intact, and also fasciculation, distal advancement of motor nerves and gross morphology and positioning of axonal projections are not altered. Our findings therefore show that FGFR2 is not required cell-autonomously in motor neurons during the formation of initial motor projections towards limb and axial musculature.


Cell type specific, traceable gene silencing for functional gene analysis during vertebrate neural development

Nucleic Acids Res. 2011 Nov 1;39(20):e133. Epub 2011 Aug 8.

Wilson NH, Stoeckli ET. Source Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Abstract Many genes have several, sometimes divergent functions during development. Therefore, timing of gene knockdown for functional analysis during development has to be done with precise temporal control, as loss of a gene's function at early stages prevents its analysis later in development. RNAi, in combination with the accessibility of chicken embryos, is an effective approach for temporally controlled analysis of gene function during neural development. Here, we describe novel plasmid vectors that contain cell type-specific promoters/enhancers to drive the expression of a fluorescent marker, followed directly by a miR30-RNAi transcript for gene silencing. These vectors allow for direct tracing of cells experiencing gene silencing by the bright fluorescence. The level of knockdown is sufficient to reproduce the expected pathfinding defects upon perturbation of genes with known axon guidance functions. Mixing different vectors prior to electroporation enables the simultaneous knockdown of multiple genes in independent regions of the spinal cord. This permits complex cellular and molecular interactions to be examined during development, in a fast and precise manner. The advancements of the in ovo RNAi technique that we describe will not only markedly enhance functional gene analysis in the chicken, but also could be adapted to other organisms in developmental studies.

PMID 21824915

Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons

Development. 2011 Dec;138(23):5121-34.

England S, Batista MF, Mich JK, Chen JK, Lewis KE. Source Biology Department, Syracuse University, 107 College Place, Syracuse, NY 13244, USA. Abstract In mouse, Hedgehog (Hh) signalling is required for most ventral spinal neurons to form. Here, we analyse the spinal cord phenotype of zebrafish maternal-zygotic smoothened (MZsmo) mutants that completely lack Hh signalling. We find that most V3 domain cells and motoneurons are lost, whereas medial floorplate still develops normally and V2, V1 and V0v cells form in normal numbers. This phenotype resembles that of mice that lack both Hh signalling and Gli repressor activity. Ventral spinal cord progenitor domain transcription factors are not expressed at 24 hpf in zebrafish MZsmo mutants. However, pMN, p2 and p1 domain markers are expressed at early somitogenesis stages in these mutants. This suggests that Gli repressor activity does not extend into zebrafish ventral spinal cord at these stages, even in the absence of Hh signalling. Consistent with this, ectopic expression of Gli3R represses ventral progenitor domain expression at these early stages and knocking down Gli repressor activity rescues later expression. We investigated whether retinoic acid (RA) signalling specifies ventral spinal neurons in the absence of Hh signalling. The results suggest that RA is required for the correct number of many different spinal neurons to form. This is probably mediated, in part, by an effect on cell proliferation. However, V0v, V1 and V2 cells are still present, even in the absence of both Hh and RA signalling. We demonstrate that Gli1 has a Hh-independent role in specifying most of the remaining motoneurons and V3 domain cells in embryos that lack Hh signalling, but removal of Gli1 activity does not affect more dorsal neurons.

PMID 22069186

Motor neuron position and topographic order imposed by β- and γ-catenin activities

Cell. 2011 Oct 28;147(3):641-52.

Demireva EY, Shapiro LS, Jessell TM, Zampieri N. Source Department of Neuroscience, Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA. Abstract

Neurons typically settle at positions that match the location of their synaptic targets, creating topographic maps. In the spinal cord, the organization of motor neurons into discrete clusters is linked to the location of their muscle targets, establishing a topographic map of punctate design. To define the significance of motor pool organization for neuromuscular map formation, we assessed the role of cadherin-catenin signaling in motor neuron positioning and limb muscle innervation. We find that joint inactivation of β- and γ-catenin scrambles motor neuron settling position in the spinal cord but fails to erode the predictive link between motor neuron transcriptional identity and muscle target. Inactivation of N-cadherin perturbs pool positioning in similar ways, albeit with reduced penetrance. These findings reveal that cadherin-catenin signaling directs motor pool patterning and imposes topographic order on an underlying identity-based neural map. Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 22036570

Isl1 is required for multiple aspects of motor neurone development

Mol Cell Neurosci. 2011 Jul;47(3):215-22. Epub 2011 May 4.

Liang X, Song MR, Xu Z, Lanuza GM, Liu Y, Zhuang T, Chen Y, Pfaff SL, Evans SM, Sun Y. Source Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Abstract The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. Copyright © 2011 Elsevier Inc. All rights reserved. PMID 21569850

In vivo imaging of cell behaviors and F-actin reveals LIM-HD transcription factor regulation of peripheral versus central sensory axon development

Neural Dev. 2011 May 27;6:27.

Andersen EF, Asuri NS, Halloran MC. Source Genetics Training Program, University of Wisconsin, 1117 W, Johnson Street, Madison, WI 53706, USA. Abstract BACKGROUND: Development of specific neuronal morphology requires precise control over cell motility processes, including axon formation, outgrowth and branching. Dynamic remodeling of the filamentous actin (F-actin) cytoskeleton is critical for these processes; however, little is known about the mechanisms controlling motile axon behaviors and F-actin dynamics in vivo. Neuronal structure is specified in part by intrinsic transcription factor activity, yet the molecular and cellular steps between transcription and axon behavior are not well understood. Zebrafish Rohon-Beard (RB) sensory neurons have a unique morphology, with central axons that extend in the spinal cord and a peripheral axon that innervates the skin. LIM homeodomain (LIM-HD) transcription factor activity is required for formation of peripheral RB axons. To understand how neuronal morphogenesis is controlled in vivo and how LIM-HD transcription factor activity differentially regulates peripheral versus central axons, we used live imaging of axon behavior and F-actin distribution in vivo. RESULTS: We used an F-actin biosensor containing the actin-binding domain of utrophin to characterize actin rearrangements during specific developmental processes in vivo, including axon initiation, consolidation and branching. We found that peripheral axons initiate from a specific cellular compartment and that F-actin accumulation and protrusive activity precede peripheral axon initiation. Moreover, disruption of LIM-HD transcriptional activity has different effects on the motility of peripheral versus central axons; it inhibits peripheral axon initiation, growth and branching, while increasing the growth rate of central axons. Our imaging revealed that LIM-HD transcription factor activity is not required for F-actin based protrusive activity or F-actin accumulation during peripheral axon initiation, but can affect positioning of F-actin accumulation and axon formation. CONCLUSION: Our ability to image the dynamics of F-actin distribution during neuronal morphogenesis in vivo is unprecedented, and our experiments provide insight into the regulation of cell motility as neurons develop in the intact embryo. We identify specific motile cell behaviors affected by LIM-HD transcription factor activity and reveal how transcription factors differentially control the formation and growth of two axons from the same neurone.

PMID 21619654


Wnt won the war: antagonistic role of Wnt over Shh controls dorso-ventral patterning of the vertebrate neural tube

Ulloa F, Martí E. Dev Dyn. 2010 Jan;239(1):69-76. Review.

The spinal cord has been used as a model to dissect the mechanisms that govern the patterning of tissues during animal development, since the principles that rule the dorso-ventral patterning of the neural tube are applicable to other systems. Signals that determine the dorso-ventral axis of the spinal cord include Sonic hedgehog (Shh), acting as a bona fide morphogenetic signal to determine ventral progenitor identities, and members of the Bmp and the Wnt families, acting in the dorsal neural tube. Although Wnts have been initially recognized as important in proliferation of neural progenitor cells, their role in the dorso-ventral patterning has been controversial. In this review, we discuss recent reports that show an important contribution of the Wnt canonical pathway in dorso-ventral pattern formation. These data allow building a model by which the ventralizing activity of Shh is antagonized by Wnt activity through the expression of Gli3, a potent inhibitor of the Shh pathway. Therefore, antagonistic interactions between canonical Wnt, promoting dorsal identities, and Shh pathways, inducing ventral ones, would define the dorso-ventral patterning of the developing central nervous system.

(c) 2009 Wiley-Liss, Inc.

PMID: 19681160


Brachial plexus anatomy: normal and variant

Scientific World Journal. 2009 Apr 28;9:300-12.

Orebaugh SL, Williams BA. Source University of Pittsburgh, UPMC South Side, 2000 Mary Street, Pittsburgh, PA 15203, USA.


Effective brachial plexus blockade requires a thorough understanding of the anatomy of the plexus, as well as an appreciation of anatomic variations that may occur. This review summarizes relevant anatomy of the plexus, along with variations and anomalies that may affect nerve blocks conducted at these levels. The Medline, Cochrane Library, and PubMed electronic databases were searched in order to compile reports related to the anatomy of the brachial plexus using the following free terms: "brachial plexus", "median nerve", "ulnar nerve", "radial nerve", "axillary nerve", and "musculocutanous nerve". Each of these was then paired with the MESH terms "anatomy", "nerve block", "anomaly", "variation", and "ultrasound". Resulting articles were hand searched for additional relevant literature. A total of 68 searches were conducted, with a total of 377 possible articles for inclusion. Of these, 57 were found to provide substantive information for this review. The normal anatomy of the brachial plexus is briefly reviewed, with an emphasis on those features revealed by use of imaging technologies. Anomalies of the anatomy that might affect the conduct of the various brachial plexus blocks are noted. Brachial plexus blockade has been effectively utilized as a component of anesthesia for upper extremity surgery for a century. Over that period, our understanding of anatomy and its variations has improved significantly. The ability to explore anatomy at the bedside, with real-time ultrasonography, has improved our appreciation of brachial plexus anatomy as well.

PMID 19412559

Modeling the spatio-temporal network that drives patterning in the vertebrate central nervous system

Biochim Biophys Acta. 2009 Apr;1789(4):299-305.

Nishi Y, Ji H, Wong WH, McMahon AP, Vokes SA.

Department of Molecular and Cellular Biology, Harvard University , Cambridge, MA 02138, USA. Abstract In this review, we discuss the gene regulatory network underlying the patterning of the ventral neural tube during vertebrate embryogenesis. The neural tube is partitioned into domains of distinct cell fates by inductive signals along both anterior-posterior and dorsal-ventral axes. A defining feature of the dorsal-ventral patterning is the graded distribution of Sonic hedgehog (Shh), which acts as a morphogen to specify several classes of ventral neurons in a concentration-dependent fashion. These inductive signals translate into patterned expressions of transcription factors that define different neural progenitor subtypes. Progenitor boundaries are sharpened by repressive interactions between these transcription factors. The progenitor-expressed transcription factors induce another set of transcription factors that are thought to contribute to neural identities in post-mitotic neural precursors. Thus, the gene regulatory network of the ventral neural tube patterning is characterized by hierarchical expression [inductive signal-->progenitor specifying factors (mitotic)--> precursor specifying factors (post mitotic)--> differentiated neural markers] and cross-repression between progenitor-expressed regulatory factors. Although a number of transcriptional regulators have been identified at each hierarchical level, their precise regulatory relationships are not clear. Here we discuss approaches aimed at clarifying and extending our understanding of the formation and propagation of this network.

PMID 19445894


Development. 2008 Aug;135(15):2489-503. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Dessaud E, McMahon AP, Briscoe J.

Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK. Abstract Neuronal subtype specification in the vertebrate neural tube is one of the best-studied examples of embryonic pattern formation. Distinct neuronal subtypes are generated in a precise spatial order from progenitor cells according to their location along the anterior-posterior and dorsal-ventral axes. Underpinning this organization is a complex network of multiple extrinsic and intrinsic factors. This review focuses on the molecular mechanisms and general strategies at play in ventral regions of the forming spinal cord, where sonic hedgehog-based morphogen signaling is a key determinant. We discuss recent advances in our understanding of these events and highlight unresolved questions.

PMID: 18621990