Vertebrate Embryo: Patterning the Neural Crest Lineage


Neural crest (NC) cells form as epithelial progenitors during the process of neurulation, then undergo an epithelial‐to‐mesenchymal transition and become motile. As mesenchymal cells, they migrate through stereotypical pathways, reach their homing sites and differentiate into a large variety of derivatives that are specific and variable along the embryonic axis. These include neurons and glia of the sensory and autonomic nervous system, pigment cells, chromaffin cells of the adrenal gland and mesectoderm in the head region. Given that a few initial progenitors expand and diversify so substantially, the NC provides an excellent model to investigate fundamental questions in Developmental Biology, that is, defining the state of commitment of the different precursors throughout ontogeny, unravelling the nature of cellular interactions among adjacent crest cells and between crest progenitors and their environment, and elucidating the molecular basis of lineage segregation, cell migration and terminal differentiation.

Key Concepts

  • NC progenitors are multipotent at the population level and become differentially restricted during ontogeny.
  • Lineage segregation in the trunk is likely to begin before NC emigration from the neural tube.
  • Epithelial‐to‐mesenchymal transition of NC progenitors is orchestrated by a network of factors (BMP/noggin, Wnt1 and Yap) acting in concert with adhesion molecules, RhoGTPases, extracellular matrix components and cell‐intrinsic determinants.
  • NC cells migrate stereotypically to their homing sites and migration seems to be largely channelled by interactions between inhibitory environmental signals and NC cells expressing their cognate receptors.
  • Specification and subsequent differentiation of NC progenitors into the various phenotypes are regulated by reiterative signals (i.e. BMPs, Wnts) that induce lineage‐specific codes of transcription factors.
  • Schwann cell progenitors residing along peripheral nerves represent a multipotent source for various neuronal and nonneural derivatives
  • In spite of undergoing early fate restrictions in vivo, some NC cells, even following differentiation, retain significant plasticity as evidenced by in vitro analysis.

Keywords: cell fate; cell migration; cell specification; enteric nervous system; epithelial‐to‐mesenchymal conversion; melanocyte; neuron; peripheral nervous system; sensory; Schwann; sympathetic

Figure 1. Pre‐migratory and migrating NC cells revealed by various markers in the chick embryo. (a) In situ hybridisation for Slug messenger ribonucleic acid, a transcription factor expressed in the tips of the closing neural folds (arrowheads) that is likely to mark at least a subset of early pre‐migratory NC cells. (b) The neural primordium (neural tube containing pre‐migratory NC) was transplanted from a quail donor into an equivalent chick host and incubated until the time of NC migration. The micrograph illustrates NC cells expressing the quail marker (condensed nucleolar heterochromatin; arrowheads) migrating through the intersomitic space composed of chick cells (dispersed heterochromatin; light nuclear staining). (c, d) NC cells stained with the HNK‐1 monoclonal antibody (brown colour) at the beginning of migration opposite the somite (c) and at an early post‐migratory stage (d) showing the localisation of immunolabelled cells to the primordia of the dorsal root ganglion (DRG), sympathetic ganglion (SG) and ventral root (VR), where NC cells develop into Schwann cells that line the peripheral nerves.
Figure 2. Segmental migration of NC cells in the trunk depends upon intrinsic differences between rostral and caudal somitic domains. (a, b) Frontal sections of a 3‐day‐old chick embryo through the level of the DRG (a) and ventral roots (b) to illustrate the presence of segmentally organised sensory ganglia and nerves (Schwann cell precursors) stained with the HNK‐1 antibody. Note that ganglia and nerves form within the rostral domain of each somite exclusively. (c–e) Three‐dimensional reconstructions of (c) the normal side of an embryo showing normal segmentation of DRG (yellow), ventral roots (green) and sympathetic ganglia (purple). In (d), the operated side of an embryo in which normal somites were replaced by multiple rostral‐half somites before NC emigration, note the total loss of segmentation of peripheral ganglia and nerves, which are now continuous along the grafted area. (e) The operated side of an embryo that received multiple caudal‐half somites in the place of the normal mesoderm. Note the absence of peripheral neural derivatives along the grafted area. Instead, both NC cells and peripheral nerves circumvent the caudal mesodermal graft and localise to its edges. NT, neural tube; S, somite. In all panels, rostral is to the right.
Figure 3. Early fate restriction of neural progenitors of the NC. (a) and (a′) illustrate the early and late phases of NC migration, respectively. The early phase is characterised by ventral streams of migrating progenitors that yield sensory and sympathetic ganglia and Schwann cells (neural progenitors are coloured red). The late phase is characterised by a dorsolateral migration of progenitors under the ectoderm that generate melanocytes (coloured yellow). (b) Misexpression of DNA encoding the endothelin receptor type B2 (EdnRB2) into neural progenitors diverts their migration towards the dorsolateral pathway, yet they upregulate neural traits even in ectopic locations. (c) When young neural tubes are grafted into a mature host environment conducive to melanogenesis, neural progenitors still migrate ventrally and incorporate into host DRG (not shown and see Krispin et al., ). (d) If transfected with EdnRB2 before grafting, NC cells are diverted into the dorsolateral pathway where they nevertheless upregulate neural markers. DM, dermomyotome; Ect, ectoderm; M, myotome; NT, neural tube.
Figure 4. Two populations of NC‐derived melanocytes. (I) Melanocytes generated from a late emigrating‐early differentiating subset of NC progenitors; these delaminate directly from the NT (arrows), are dorsally located and migrate along the subectodermal pathway to invade the epidermis. (II) A second population derives from Schwann cell progenitors of the spinal nerves (arrows) that comprise an early migrating NC subset. Their differentiation is late when compared to the dorsal melanocytes. Melanocytes are coloured yellow and neural derivatives are in red. DRG, dorsal root ganglion; M, myotome; NO, notochord; NT, neural tube; SG, sympathetic ganglia; SN, spinal nerve.


Adameyko I, Lallemend F, Aquino JB, et al. (2009) Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139: 366–379.

Adameyko I and Lallemend F (2010) Glial versus melanocyte cell fate choice: Schwann cell precursors as a cellular origin of melanocytes. Cellular and Molecular Life Sciences 67: 3037–3055.

Adameyko I, Lallemend F, Furlan A, et al. (2012) Sox2 and Mitf cross‐regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest. Development 139: 397–410.

Basch ML, Bronner‐Fraser M and Garcia‐Castro MI (2006) Specification of the neural crest occurs during gastrulation and requires Pax7. Nature 441: 218–222.

Britsch S, Li L, Kirchhoff S, et al. (1998) The ErbB2 and ErbB3 receptors and their ligand, neuregulin‐1, are essential for development of the sympathetic nervous system. Genes & Development 12: 1825–1836.

Burstyn‐Cohen T and Kalcheim C (2002) Association between the cell cycle and neural crest delamination through specific regulation of G1/S Transition. Developmental Cell 3: 383–395.

Burstyn‐Cohen T, Stanleigh J, Sela‐Donenfeld D and Kalcheim C (2004) Canonical Wnt activity regulates trunk neural crest delamination linking BMP/noggin signaling with G1/S transition. Development 131: 5327–5339.

Colas JF and Schoenwolf GC (2001) Towards a cellular and molecular understanding of neurulation. Developmental Dynamics 221: 117–145.

Coles EG, Taneyhill LA and Bronner‐Fraser M (2007) A critical role for Cadherin6B in regulating avian neural crest emigration. Developmental Biology 312: 533–544.

Curran K, Raible DW and Lister JA (2009) Foxd3 controls melanophore specification in the zebrafish neural crest by regulation of Mitf. Developmental Biology 332: 408–417.

Debby‐Brafman A, Burstyn‐Cohen T, Klar A and Kalcheim C (1999) F‐spondin is expressed in somite regions avoided by neural crest cells and mediates the inhibition of distinct somitic domains to neural crest migration. Neuron 22: 475–488.

Duband JL, Monier F, Delannet M and Newgreen D (1995) Epithelium‐mesenchyme transition during neural crest development. Acta Anatomica (Basel) 154: 63–78.

Dupin E, Real C, Glavieux Pardanaud C, Vaigot P and Le Douarin N (2003) Reversal of developmental restrictions in neural crest lineages: transition from Schwann cells to glial‐melanocytic precursors in vitro. Proceedings of the National Academy of Sciences of the USA 100: 5229–5233.

Dyachuk V, Furlan A, Shahidi MK, et al. (2014) Neurodevelopment. Parasympathetic neurons originate from nerve‐associated peripheral glial progenitors. Science 345: 82–87.

Eickholt BJ, Mackenzie SL, Graham A, Walsh FS and Doherty P (1999) Evidence for collapsin‐1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development 126: 2181–2189.

Espinosa‐Medina I, Outin E, Picard CA, et al. (2014) Neurodevelopment. Parasympathetic ganglia derive from Schwann cell precursors. Science 345: 87–90.

Furlan A, Dyachuk V, Kastriti ME, et al. (2017) Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science 357.

Gammill LS, Gonzalez C and Bronner‐Fraser M (2007) Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation. Developmental Neurobiology 67: 47–56.

Gammill LS and Roffers‐Agarwal J (2010) Division of labor during trunk neural crest development. Developmental Biology 344: 555–565.

Garcia‐Castro MI, Marcelle C and Bronner‐Fraser M (2002) Ectodermal Wnt function as a neural crest inducer. Science 297: 848–851.

Gershon MD (1997) Genes and lineages in the formation of the enteric nervous system. Current Opinion in Neurobiology 7: 101–109.

Hari L, Brault V, Kleber M, et al. (2002) Lineage‐specific requirements of beta‐catenin in neural crest development. Journal of Cell Biology 159: 867–880.

Harris ML and Erickson CA (2007) Lineage specification in neural crest cell pathfinding. Developmental Dynamics 236: 1–19.

Harris ML, Hall R and Erickson CA (2008) Directing pathfinding along the dorsolateral path – the role of EDNRB2 and EphB2 in overcoming inhibition. Development 135: 4113–4122.

Hrabe de Angelis M, McIntyre JII and Gossler A (1997) Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386: 717–721.

Joseph NM, Mukouyama YS, Mosher JT, et al. (2004) Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 131: 5599–5612.

Kalcheim C and Kumar D (2017) Cell fate decisions during neural crest ontogeny. The International Journal of Developmental Biology 61: 195–203.

Knecht AK and Bronner‐Fraser M (2002) Induction of the neural crest: a multigene process. Nature Reviews Genetics 3: 453–461.

Kos R, Reedy MV, Johnson RL and Erickson CA (2001) The winged‐helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 128: 1467–1479.

Krispin S, Nitzan E, Kassem Y and Kalcheim C (2010) Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest. Development 137: 585–595.

Krull CE, Lansford R, Gale NW, et al. (1997) Interactions of Eph‐related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Current Biology 7: 571–580.

Kulesa PM, Bailey CM, Kasemeier‐Kulesa JC and McLennan R (2010) Cranial neural crest migration: new rules for an old road. Developmental Biology 344: 543–554.

Kumar D, Nitzan E and Kalcheim C (2019) YAP promotes neural crest emigration through interactions with BMP and Wnt activities. Cell Communication and Signaling: CCS 17: 69.

Kuo BR and Erickson CA (2010) Regional differences in neural crest morphogenesis. Cell Adhesion & Migration 4: 567–585.

Kuo BR and Erickson CA (2011) Vagal neural crest cell migratory behavior: a transition between the cranial and trunk crest. Developmental Dynamics 240: 2084–2100.

Le Douarin NM (1982) The Neural Crest. Cambridge University Press: New York.

Le Douarin NM (1990) Cell lineage segregation during neural crest ontogeny. Annals of the New York Academy of Sciences 599: 131–140.

Le Douarin NM and Kalcheim C (1999) The Neural Crest. Cambridge University Press: New York.

Le Douarin NM and Dupin E (2003) Multipotentiality of the neural crest. Current Opinion in Genetics & Development 13: 529–536.

Le Lievre CS, Schweizer GG, Ziller CM and Le Douarin NM (1980) Restriction of developmental capabilities in neural crest cell derivatives as tested by in vivo transplantation experiments. Developmental Biology 77: 362–378.

Ma QF, Fode C, Guillemot F and Anderson DJ (1999) NEUROGENIN1 and NEUROGENIN2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes & Development 13: 1717–1728.

Marmigere F and Ernfors P (2007) Specification and connectivity of neuronal subtypes in the sensory lineage. Nature Reviews Neuroscience 8: 114–127.

Minoux M and Rijli FM (2010) Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137: 2605–2621.

Nakagawa S and Takeichi M (1998) Neural crest emigration from the neural tube depends on regulated cadherin expression. Development 125: 2963–2971.

Nitzan E, Pfaltzgraff ER, Labosky PA and Kalcheim C (2013) Neural crest and Schwann cell progenitor‐derived melanocytes are two spatially segregated populations similarly regulated by Foxd3. Proceedings of the National Academy of Sciences of the United States of America 110: 12709–12714.

Osorio L, Teillet MA, Palmeirim I and Catala M (2009) Neural crest ontogeny during secondary neurulation: a gene expression pattern study in the chick embryo. International Journal of Developmental Biology 53: 641–648.

Perris R (1997) The extracellular matrix in neural crest‐cell migration. Trends in Neurosciences 20: 23–31.

Raible DW and Eisen JS (1994) Restriction of neural crest cell fate in the trunk of the embryonic zebrafish. Development 120: 495–503.

Raible DW and Eisen JS (1996) Regulative interactions in zebrafish neural crest. Development 122: 501–507.

Reissmann E, Ernsberger U, Francis‐West PH, et al. (1996) Involvement of bone morphogenetic protein‐4 and bone morphogenetic protein‐7 in the differentiation of the adrenergic phenotype in developing sympathetic neurons. Development 122: 2079–2088.

Rothman TP, Le Douarin NM, Fontaine‐Perus JC and Gershon MD (1990) Developmental potential of neural crest‐derived cells migrating from segments of developing quail bowel back‐grafted into younger chick host enbryos. Development 109: 411–423.

Sauka‐Spengler T and Bronner‐Fraser M (2008) A gene regulatory network orchestrates neural crest formation. Nature Reviews Molecular Cell Biology 9: 557–568.

Savagner P (2004) Leaving the neighborhood: molecular mechanisms involved during epithelial‐mesenchymal transition. BioEssays 23: 912–923.

Scarpa E and Mayor R (2016) Collective cell migration in development. The Journal of Cell Biology 212: 143–155.

Schneider C, Wicht H, Enderich J, Wegner M and Rohrer H (1999) Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron 24: 861–870.

Schoenwolf GC and Delongo J (1980) Ultrastructure of secondary neurulation in the chick embryo. American Journal of Anatomy 158: 43–63.

Schwarz Q, Maden CH, Davidson K and Ruhrberg C (2009) Neuropilin‐mediated neural crest cell guidance is essential to organise sensory neurons into segmented dorsal root ganglia. Development 136: 1785–1789.

Schweizer GG, Ayer‐Le Lièvre C and Le Douarin NM (1983) Restrictions of developmental capabilities in the dorsal root ganglia in the course of development. Cell Differentiation 13: 191–200.

Sela‐Donenfeld D and Kalcheim C (1999) Regulation of the onset of neural crest migration by coordinated activity of BMP4 and noggin in the dorsal neural tube. Development 126: 4749–4762.

Sela‐Donenfeld D and Kalcheim C (2000) Inhibition of noggin expression in the dorsal neural tube by somitogenesis: a mechanism for coordinating the timing of neural crest emigration. Development 127: 4845–4854.

Sela‐Donenfeld D and Kalcheim C (2002) Localized BMP4–noggin interactions generate the dynamic patterning of noggin expression in somites. Developmental Biology 246: 311–328.

Shoval I, Ludwig A and Kalcheim C (2007) Antagonistic roles of full‐length N‐cadherin and its soluble BMP cleavage product in neural crest delamination. Development 134: 491–501.

Stanke M, Junghans D, Geissen M, et al. (1999) The Phox2 homeodomain proteins are sufficient to promote the development of sympathetic neurons. Development 126: 4087–4094.

Stanke M, Stubbusch J and Rohrer H (2004) Interaction of Mash1 and Phox2b in sympathetic neuron development. Molecular and Cellular Neuroscience 25: 374–382.

Taneyhill LA, Coles EG and Bronner‐Fraser M (2007) Snail2 directly represses cadherin6B during epithelial‐to‐mesenchymal transitions of the neural crest. Development 134: 1481–1490.

Theveneau E and Mayor R (2012) Neural crest delamination and migration: from epithelium‐to‐mesenchyme transition to collective cell migration. Developmental Biology 366: 34–54.

Thomas AJ and Erickson CA (2008) The making of a melanocyte: the specification of melanoblasts from the neural crest. Pigment Cell & Melanoma Research 21: 598–610.

Thomas AJ and Erickson CA (2009) FOXD3 regulates the lineage switch between neural crest‐derived glial cells and pigment cells by repressing MITF through a non‐canonical mechanism. Development 136: 1849–1858.

Tsarovina K, Pattyn A, Stubbusch J, et al. (2004) Essential role of Gata transcription factors in sympathetic neuron development. Development 131: 4775–4786.

Wang HU and Anderson DJ (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18: 383–396.

Wu J, Saint Jeannet J and Klein P (2003) Wnt‐frizzled signaling in neural crest formation. Trends in Neurosciences 26: 40–45.

Xie M, Kamenev D, Kaucka M, et al. (2019) Schwann cell precursors contribute to skeletal formation during embryonic development in mice and zebrafish. Proceedings of the National Academy of Sciences of the United States of America.

Further Reading

Betancur P, Bronner‐Fraser M and Sauka‐Spengler T (2010) Assembling neural crest regulatory circuits into a gene regulatory network. Annual Review of Cell and Developmental Biology 26: 581–603.

Hall BK (2008) The neural crest and neural crest cells: discovery and significance for theories of embryonic organization. Journal of Biosciences 33: 781–793.

Kalcheim C and Kumar D (2017) Cell fate decisions during neural crest ontogeny. The International Journal of Developmental Biology 61: 195–203.

Minoux M and Rijli FM (2010) Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137: 2605–2621.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kalcheim, Chaya(Dec 2019) Vertebrate Embryo: Patterning the Neural Crest Lineage. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000738.pub4]