Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Induction of the neural crest: a multigene process

Key Points

  • Neural crest cells are a migratory population of cells that originate from the border between the neural plate and the non-neural ectoderm.

  • Induction at the neural plate border is difficult to define; it probably involves many steps and the cells show remarkable plasticity in their cell-fate determination (here, induction of Slug expression is considered to be coincident with the induction of the neural crest).

  • Two models have been proposed for induction of the neural crest: the neural induction model and the two-signal model, both of which involve an interplay between BMP signalling and inhibition, as well as WNT (Wingless-related) and FGF (fibroblast growth factor) signalling.

  • The source of signalling that is required for neural crest induction is still controversial — some experiments indicate that it is the paraxial mesoderm, whereas others indicate that the signals come from the epithelial–neural plate border.

  • Notch signalling, a secreted protein Noelin and zebrafish Narrowminded have also been implicated in neural crest induction.

  • Signals that induce the neural crest turn on the expression of transcription factors such as Slug, Pax, Fox, Zic, Sox and Meis, all of which direct neural crest differentiation.


In the embryo, the neural crest is an important population of cells that gives rise to diverse derivatives, including the peripheral nervous system and the craniofacial skeleton. Evolutionarily, the neural crest is of interest as an important innovation in vertebrates. Experimentally, it represents an excellent system for studying fundamental developmental processes, such as tissue induction. Classical embryologists have identified interactions between tissues that lead to neural crest formation. More recently, geneticists and molecular biologists have identified the genes that are involved in these interactions; this recent work has revealed that induction of the neural crest is a complex multistep process that involves many genes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Regions that form neural crest during neurulation in a hypothetical vertebrate embryo.
Figure 2: Dynamic expression patterns of Wnts and BMPs in the ectoderm of frog and chick.


  1. 1

    Le Douarin, N. M. & Kalcheim, C. The Neural Crest 2nd edn (Cambridge Univ. Press, Cambridge, UK, 1999).

    Book  Google Scholar 

  2. 2

    Selleck, M. A. J. & Bronner-Fraser, M. Origins of the avian neural crest: the role of neural plate–epidermal interactions. Development 121, 525–538 (1995).

    CAS  PubMed  Google Scholar 

  3. 3

    Collazo, A., Bronner-Fraser, M. & Fraser, S. E. Vital dye labelling of Xenopus laevis trunk neural crest reveals multipotency and novel pathways of migration. Development 118, 363–376 (1993).

    CAS  PubMed  Google Scholar 

  4. 4

    Ruffins, S., Artinger, K. B. & Bronner-Fraser, M. Early migrating neural crest cells can form ventral neural tube derivatives when challenged by transplantation. Dev. Biol. 203, 295–304 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Nieto, M. A., Sargent, M. G., Wilkinson, D. G. & Cooke, J. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264, 835–839 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Mayor, R., Morgan, R. & Sargent, M. G. Induction of the prospective neural crest in Xenopus. Development 121, 767–777 (1995).

    CAS  PubMed  Google Scholar 

  7. 7

    Wilson, P. A. & Hemmati-Brivanlou, A. Vertebrate neural induction: inducers, inhibitors, and a new synthesis. Neuron 18, 699–710 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Hogan, B. L. Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev. 6, 432–438 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Streit, A. et al. Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo. Development 125, 507–519 (1998).

    CAS  Google Scholar 

  10. 10

    Faure, S., Santa Barbara, P., Roberts, D. J. & Whitman, M. Endogenous patterns of BMP signaling during early chick development. Dev. Biol. 244, 44–65 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Wilson, S. I., Graziano, E., Harland, R., Jessell, T. M. & Edlund, T. An early requirement for FGF signaling in the acquisition of neural cell fate in the chick embryo. Curr. Biol. 10, 421–429 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Streit, A., Berliner, A. J., Papanayotou, C., Sirulnik, A. & Stern, C. D. Initiation of neural induction by FGF signalling before gastrulation. Nature 406, 74–78 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Storey, K. G. et al. Early posterior neural tissue is induced by FGF in the chick embryo. Development 125, 473–484 (1998).

    CAS  Google Scholar 

  14. 14

    Wilson, S. et al. The status of Wnt signalling regulates neural and epidermal fates in the chick embryo. Nature 411, 325–330 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Mayor, R. & Aybar, M. J. Induction and development of neural crest in Xenopus laevis. Cell Tissue Res. 305, 203–209 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Streit, A. & Stern, C. D. Establishment and maintenance of the border of the neural plate in the chick: involvement of FGF and BMP activity. Mech. Dev. 82, 51–66 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Nguyen, V. H. et al. Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by a bmp2b/swirl pathway of genes. Dev. Biol. 199, 93–110 (1998).

    CAS  Article  Google Scholar 

  18. 18

    LaBonne, C. & Bronner-Fraser, M. Neural crest induction in Xenopus: evidence for a two-signal model. Development 125, 2403–2414 (1998).

    CAS  PubMed  Google Scholar 

  19. 19

    Wilson, P. A. & Hemmati-Brivanlou, A. Induction of epidermis and inhibition of neural fate by Bmp-4. Nature 376, 331–333 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Knecht, A. K. & Harland, R. M. Mechanisms of dorsal–ventral patterning in noggin-induced neural tissue. Development 124, 2477–2488 (1997).

    CAS  PubMed  Google Scholar 

  21. 21

    Essex, L. J., Mayor, R. & Sargent, M. A. Expression of Xenopus snail in mesoderm and prospective neural fold ectoderm. Dev. Dyn. 198, 108–122 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Bang, A. G., Papalopulu, N., Kintner, C. & Goulding, M. D. Expression of Pax-3 is initiated in the early neural plate by posteriorizing signals produced by the organizer and by posterior non-axial mesoderm. Development 124, 2075–2085 (1997).

    CAS  PubMed  Google Scholar 

  23. 23

    Linker, C., Bronner-Fraser, M. & Mayor, R. Relationship between gene expression domains of Xsnail, Xslug, and Xtwist and cell movement in the prospective neural crest of Xenopus. Dev. Biol. 224, 215–225 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Marchant, L., Linker, C., Ruiz, P., Guerrero, N. & Mayor, R. The inductive properties of mesoderm suggest that the neural crest cells are specified by a BMP gradient. Dev. Biol. 198, 319–329 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Villanueva, S., Glavic, A., Ruiz, P. & Mayor, R. Posteriorization by FGF, Wnt, and retinoic acid is required for neural crest induction. Dev. Biol. 241, 289–301 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Saint-Jeannet, J.-P., He, X., Varmus, H. E. & Dawid, I. B. Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a. Proc. Natl Acad. Sci. USA 94, 13713–13718 (1997).

    CAS  Article  Google Scholar 

  27. 27

    Chang, C. & Hemmati-Brivanlou, A. Neural crest induction by Xwnt7B in Xenopus. Dev. Biol. 194, 129–134 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Isaacs, H. V., Tannahill, D. & Slack, J. M. W. Expression of a novel FGF in the Xenopus embryo. A new candidate inducing factor for mesoderm formation and anteroposterior specification. Development 114, 711–720 (1992).

    CAS  PubMed  Google Scholar 

  29. 29

    Christian, J. L., McMahon, J. A., McMahon, A. P. & Moon, R. T. XWnt-8, a Xenopus Wnt-1/int-1 related gene responsive to mesoderm-inducing growth factors, may play a role in ventral mesodermal patterning during embryogenesis. Development 111, 1045–1055 (1991).

    CAS  PubMed  Google Scholar 

  30. 30

    Deardorff, M. A., Tan, C., Saint-Jeannet, J.-P. & Klein, P. A role for frizzled 3 in neural crest development. Development 128, 3655–3663 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Papalopulu, N. & Kintner, C. A posteriorising factor, retinoic acid, reveals that anteroposterior patterning controls the timing of neuronal differentiation in Xenopus neuroectoderm. Development 122, 3409–3418 (1996).

    CAS  PubMed  Google Scholar 

  32. 32

    Lamb, T. M. & Harland, R. M. Fibroblast growth factor is a direct neural inducer, which combined with noggin generates anterior–posterior neural pattern. Development 121, 3627–3636 (1995).

    CAS  PubMed  Google Scholar 

  33. 33

    McGrew, L. L., Lai, C. J. & Moon, R. T. Specification of the antero-posterior neural axis through synergistic interaction of the Wnt signaling cascade with noggin and follistatin. Dev. Biol. 172, 337–342 (1995).

    CAS  Article  Google Scholar 

  34. 34

    Ikeya, M., Lee, S. M., Johnson, J. E., McMahon, A. P. & Takada, S. Wnt signaling required for expansion of neural crest and CNS progenitors. Nature 389, 966–970 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Mayor, R., Guerrero, N. & Martinez, C. Role of FGF and noggin in neural crest induction. Dev. Biol. 189, 1–12 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Tan, C. et al. Kermit, a frizzled interacting protein, regulates frizzled 3 signaling in neural crest development. Development 128, 3665–3674 (2001).

    CAS  PubMed  Google Scholar 

  37. 37

    Raven, C. R. & Kloos, J. Induction by medial and lateral pieces of the archenteron roof, with special reference to the determination of neural crest. Acta Neerl. Morphol. 5, 384–362 (1945).

    Google Scholar 

  38. 38

    Bonstein, L., Elias, S. & Frank, D. Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos. Dev. Biol. 193, 156–168 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Rollhäuser-ter Horst, J. Artificial neural crest formation in amphibia. Anat. Embryol. 157, 113–120 (1979).

    Article  Google Scholar 

  40. 40

    Moury, J. D. & Jacobson, A. G. Neural fold formation at newly created boundaries between neural plate and epidermis in the axolotl. Dev. Biol. 133, 44–57 (1989).

    CAS  Article  Google Scholar 

  41. 41

    Woo, K. & Fraser, S. E. Specification of the hindbrain fate in the zebrafish. Dev. Biol. 197, 283–296 (1998).

    CAS  Article  Google Scholar 

  42. 42

    Moury, J. D. & Jacobson, A. G. The origins of neural crest cells in the axolotl. Dev. Biol. 141, 243–253 (1990).

    CAS  Article  Google Scholar 

  43. 43

    Mancilla, A. & Mayor, R. Neural crest formation in Xenopus laevis: mechanisms of Xslug induction. Dev. Biol. 177, 580–589 (1996).

    CAS  Article  Google Scholar 

  44. 44

    Liem, K. F., Tremml, G., Roelink, H. & Jessell, T. M. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 82, 969–979 (1995).

    CAS  Article  Google Scholar 

  45. 45

    Liem, K. F., Tremml, G. & Jessell, T. M. A role for the roof plate and its resident TGFβ-related proteins in neuronal patterning in the dorsal spinal cord. Cell 91, 127–138 (1997).

    CAS  Article  Google Scholar 

  46. 46

    Selleck, M. A. J., García-Castro, M. I., Artinger, K. B. & Bronner-Fraser, M. Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm. Development 125, 4919–4930 (1998).

    CAS  PubMed  Google Scholar 

  47. 47

    García-Castro, M. I., Marcelle, C. & Bronner-Fraser, M. Wnt in the ectoderm functions as a neural crest inducer. Science (in the press).

  48. 48

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

    CAS  PubMed  Google Scholar 

  49. 49

    Coffman, C. R., Skoglund, P., Harris, W. A. & Kintner, C. R. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell 73, 659–671 (1993).

    CAS  Article  Google Scholar 

  50. 50

    Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    CAS  Article  Google Scholar 

  51. 51

    Cornell, R. A. & Eisen, J. S. Delta signaling mediates segregation of neural crest and spinal sensory neurons from zebrafish lateral neural plate. Development 127, 2873–2882 (2000).

    CAS  PubMed  Google Scholar 

  52. 52

    Endo, Y., Osumi, N. & Wakamatsu, Y. Bimodal functions of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development 129, 863–873 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Barembaum, M., Moreno, T. A., LaBonne, C., Sechrist, J. & Bronner-Fraser, M. Noelin-1 is a secreted glycoprotein involved in generation of the neural crest. Nature Cell Biol. 2, 219–225 (2000).

    CAS  Article  Google Scholar 

  54. 54

    Artinger, K. B., Chitnis, A. B., Mercola, M. & Driever, W. Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons. Development 126, 3969–3979 (1999).

    CAS  PubMed  Google Scholar 

  55. 55

    LaBonne, C. & Bronner-Fraser, M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev. Biol. 221, 195–205 (2000).

    CAS  Article  Google Scholar 

  56. 56

    Epstein, D. J., Vekemans, M. & Gros, P. splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the Paired homeodomain of Pax-3. Cell 67, 767–774 (1991).

    CAS  Article  Google Scholar 

  57. 57

    Mansouri, A., Stoykova, A., Torres, M. & Gruss, P. Dysgenesis of cephalic neural crest derivatives in Pax7−/− mutant mice. Development 122, 831–838 (1996).

    CAS  PubMed  Google Scholar 

  58. 58

    Dottori, M., Gross, M. K., Labosky, P. & Goulding, M. The winged-helix transcription factor Foxd3 suppresses interneuron differentiation and promotes neural crest cell fate. Development 128, 4127–4138 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Kos, R., Reedy, M. V., Johnson, R. L. & Erickson, C. A. The winged-helix transcription factor Foxd3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 128, 1467–1479 (2001).

    CAS  PubMed  Google Scholar 

  60. 60

    Sasai, N., Mizuseki, K. & Sasai, Y. Requirement of FoxD3 -class signaling for neural crest determination in Xenopus. Development 128, 2525–2536 (2001).

    CAS  Google Scholar 

  61. 61

    Nakata, K., Nagai, T., Aruga, J. & Mikoshiba, K. Xenopus Zic3, a primary regulator both in neural and neural crest development. Proc. Natl Acad. Sci. USA 94, 11980–11985 (1997).

    CAS  Article  Google Scholar 

  62. 62

    Nakata, K., Nagai, T., Aruga, J. & Mikoshiba, K. Xenopus Zic family and its role in neural and neural crest development. Mech. Dev. 75, 43–51 (1998).

    CAS  Article  Google Scholar 

  63. 63

    Kuo, J. S. et al. Opl: a zinc finger protein that regulates neural determination and patterning in Xenopus. Development 125, 2867–2882 (1998).

    CAS  PubMed  Google Scholar 

  64. 64

    Brewster, R., Lee, J. & Ruiz í Altaba, A. Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. Nature 393, 579–583 (1998).

    CAS  Article  Google Scholar 

  65. 65

    Nakata, K., Koyabu, Y., Aruga, J. & Mikoshiba, K. A novel member of the Xenopus Zic family, Zic5, mediates neural crest development. Mech. Dev. 99, 83–91 (2000).

    CAS  Article  Google Scholar 

  66. 66

    Dutton, K. A. et al. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development 128, 4113–4125 (2001).

    CAS  PubMed  Google Scholar 

  67. 67

    Spokony, R. F., Aoki, Y., Saint-Germain, N., Magner-Fink, E. & Saint-Jeannet, J.-P. The transcription factor Sox9 is required for cranial neural crest development in Xenopus. Development 129, 421–432 (2002).

    CAS  PubMed  Google Scholar 

  68. 68

    Maeda, R. et al. Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos. Oncogene 20, 1329–1342 (2001).

    CAS  Article  Google Scholar 

  69. 69

    Reeves, F. C., Burdge, G. C., Fredericks, W. J., Rauscher, F. J. & Lillycrop, K. A. Induction of antisense Pax-3 expression leads to the rapid morphological differentiation of neuronal cells and an altered response to the mitogenic growth factor bFGF. J. Cell Sci. 112, 253–261 (1999).

    CAS  PubMed  Google Scholar 

  70. 70

    Vallin, J. et al. Cloning and characterization of three Xenopus Slug promoters reveal direct regulation by Lef/β-catenin signaling. J. Biol. Chem. 276, 30353–30358 (2001).

    Article  Google Scholar 

  71. 71

    del Barrio, M. G. & Nieto, M. A. Overexpression of Snail family members highlights their ability to promote chick neural crest formation. Development 129, 1583–1593 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Jiang, R., Lan, Y., Norton, C., Sundberg, J. P. & Gridley, T. The Slug gene is not essential for mesoderm or neural crest development in mice. Dev. Biol. 198, 277–285 (1998).

    CAS  Article  Google Scholar 

  73. 73

    Sefton, M., Sanchez, S. & Nieto, M. A. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125, 3111–3121 (1998).

    CAS  PubMed  Google Scholar 

  74. 74

    Baker, C. V. H. & Bronner-Fraser, M. The origins of the neural crest. II. An evolutionary perspective. Mech. Dev. 69, 13–29 (1997).

    CAS  Article  Google Scholar 

  75. 75

    Maisey, J. G. Heads and tails: a chordate phylogeny. Cladistics 2, 201–256 (1986).

    Article  Google Scholar 

  76. 76

    Peterson, K. J. A phylogenetic test of the calcichordate scenario. Lethaia 28, 25–38 (1995).

    Article  Google Scholar 

  77. 77

    Kuratani, S., Nobusada, Y., Horigome, N. & Shigetani, Y. Embryology of the lamprey and evolution of the vertebrate jaw: insights from molecular and developmental perspectives. Phil. Trans. R. Soc. Lond. B356, 1615–1632 (2001).

    Article  Google Scholar 

  78. 78

    Holland, L. Z. & Holland, N. D. Evolution of neural crest and placodes: amphioxus as a model for the ancestral vertebrate? J. Anat. 199, 85–98 (2001).

    CAS  Article  Google Scholar 

  79. 79

    Neidert, A. H., Panopoulou, G. & Langeland, J. A. Amphioxus goosecoid and the evolution of the head organizer and prechordal plate. Evol. Dev. 2, 303–310 (2000).

    CAS  Article  Google Scholar 

Download references


The authors thank T. Moreno for help with the figures, and M. García-Castro and M. Albrecht for critical reading of the manuscript.

Author information



Corresponding author

Correspondence to Marianne Bronner-Fraser.

Related links

Related links
















Encyclopedia of Life Sciences

Neural crest: origin, migration and differentiation

Vertebrate embryo: patterning the neural crest lineage



A cylindrical structure that runs through the midline of the embryo; it expands in the head to form the brain and in the trunk to form the spinal cord.


Tips of invaginating ectoderm that will close to form the dorsal portion of the neural tube.


Thickenings in the vertebrate cranial ectoderm that invaginate and form parts of cranial sensory ganglia and paired sensory organs.


Nerve cells of the peripheral nervous system that innervate the viscera, smooth muscles and exocrine glands.


Dense structures on the surface of pharyngeal arches of early vertebrates that are thought to be pressure sensitive.


Morphogenetic movement that transforms a single-layered embryo into an embryo with three germ layers.


Stages that describe the age of chick embryos; stage 2 refers to the time before gastrulation.


A term for the embryonic layer in chicks, mice and humans from which the embryo proper arises during gastrulation.


Modified antisense oligonucleotides that are designed to block translation by pairing with the translation start site in the 5′ untranslated region.


Mesoderm that is adjacent to the neural tube and that is destined to form somites.


Mesodermal balls of cells adjacent to the neural tube that will differentiate into the muscle, vertebrae and dermis.


Early-differentiating neurons in the dorsal neural tube of fish and amphibians.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Knecht, A., Bronner-Fraser, M. Induction of the neural crest: a multigene process. Nat Rev Genet 3, 453–461 (2002).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing