Cellular and Molecular Life Sciences

, Volume 76, Issue 10, pp 1919–1934 | Cite as

From neural crest cells to melanocytes: cellular plasticity during development and beyond

  • Niels Vandamme
  • Geert BerxEmail author


Here, we review melanocyte development and how the embryonic melanoblast, although specified to become a melanocyte, is prone to cellular plasticity and is not fully committed to the melanocyte lineage. Even fully differentiated and pigment-producing melanocytes do not always have a stable phenotype. The gradual lineage restriction of neural crest cells toward the melanocyte lineage is determined by both cell-intrinsic and extracellular signals in which differentiation and pathfinding ability reciprocally influence each other. These signals are leveraged by subtle differences in timing and axial positioning. The most extensively studied migration route is the dorsolateral path between the dermomyotome and the prospective epidermis, restricted to melanoblasts. In addition, the embryonic origin of the skin dermis through which neural crest derivatives migrate may also affect the segregation between melanogenic and neurogenic cells in embryos. It is widely accepted that, irrespective of the model organism studied, the immediate precursor of both melanoblast and neurogenic populations is a glial-melanogenic bipotent progenitor. Upon exposure to different conditions, melanoblasts may differentiate into other neural crest-derived lineages such as neuronal cells and vice versa. Key factors that regulate melanoblast migration and patterning will regulate melanocyte homeostasis during different stages of hair cycling in postnatal hair follicles.


Neural crest Cellular plasticity Migration Melanocytes EMT ZEB proteins 



B-cell lymphoma 2


Bone morphognetic protein


Selective EDNRB antagonist


Collagen type XVII alpha 1


cAMP-responsive element binding protein


Dopachrome tautomerase




Extracellular matrix


Endothelin 1


Endothelin receptor type B


Endothelin 3


Fibroblast growth factor


Forkhead box D3


Human embryonic stem cells


Junctional adhesion molecules


c-kit/Kit ligand


Kit proto-oncogene


Melanocortin 1 receptor


Microphthalmia-associated transcription factor


Malignant peripheral nerve sheath tumor


Migration staging area


Msh homeobox 1/2


Neurofibromin 1b


Nerve growth factor receptor


Paired Box 3


Proteolipid protein


Schwann cell precursor


Snail family transcription factor 2


Mother against decapentaplegic homolog


Snail family transcription factor 1


(Sex determining region Y)-box 10


Transforming growth factor beta




Tyrosinase-related protein 1/2


Wingless-type MMTV integration site family


Zinc finger of the cerebellum 1/2


Zinc finger E-box binding homeobox 1/2



G.B.’s laboratory is supported by the Fonds Wetenschappelijk Onderzoek (3G050217W), the Geconcerteerde Onderzoeksacties Ghent University (GOA-01GB1013W), Vlaamse Liga tegen Kanker (365U8914U) and the Stichting tegen Kanker (FAF-F/2016/814).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Huang X, Saint-Jeannet JP (2004) Induction of the neural crest and the opportunities of life on the edge. Dev Biol 275(1):1–11Google Scholar
  2. 2.
    Le Douarin NM, Kalcheim C (1999) The neural crest. Cambridge University Press, CambridgeGoogle Scholar
  3. 3.
    Knecht AK, Bronner-Fraser M (2002) Induction of the neural crest: a multigene process. Nat Rev Genet 3(6):453–461Google Scholar
  4. 4.
    Milet C, Monsoro-Burq AH (2012) Neural crest induction at the neural plate border in vertebrates. Dev Biol 366(1):22–33Google Scholar
  5. 5.
    Duband JL (2010) Diversity in the molecular and cellular strategies of epithelium-to-mesenchyme transitions: insights from the neural crest. Cell Adh Migr 4(3):458–482Google Scholar
  6. 6.
    Locascio A et al (2002) Modularity and reshuffling of Snail and Slug expression during vertebrate evolution. Proc Natl Acad Sci USA 99(26):16841–16846Google Scholar
  7. 7.
    del Barrio MG, Nieto MA (2002) Overexpression of Snail family members highlights their ability to promote chick neural crest formation. Development 129(7):1583–1593Google Scholar
  8. 8.
    Perez-Losada J et al (2002) Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. Blood 100(4):1274–1286Google Scholar
  9. 9.
    Sanchez-Martin M et al (2002) SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum Mol Genet 11(25):3231–3236Google Scholar
  10. 10.
    Sanchez-Martin M et al (2003) Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Med Genet A 122A(2):125–132Google Scholar
  11. 11.
    De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110Google Scholar
  12. 12.
    Skrypek N et al (2018) ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition. Epigenet Chromatin 11(1):70Google Scholar
  13. 13.
    Vandewalle C, Van Roy F, Berx G (2009) The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 66(5):773–787Google Scholar
  14. 14.
    Theveneau E, Mayor R (2012) Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration. Dev Biol 366(1):34–54Google Scholar
  15. 15.
    Le Douarin N (1973) A biological cell labeling technique and its use in experimental embryology. Dev Biol 30(1):217–222Google Scholar
  16. 16.
    Creuzet S et al (2004) Reciprocal relationships between Fgf8 and neural crest cells in facial and forebrain development. Proc Natl Acad Sci USA 101(14):4843–4847Google Scholar
  17. 17.
    Klymkowsky MW, Rossi CC, Artinger KB (2010) Mechanisms driving neural crest induction and migration in the zebrafish and Xenopus laevis. Cell Adh Migr 4(4):595–608Google Scholar
  18. 18.
    Sauka-Spengler T et al (2007) Ancient evolutionary origin of the neural crest gene regulatory network. Dev Cell 13(3):405–420Google Scholar
  19. 19.
    Aybar MJ, Mayor R (2002) Early induction of neural crest cells: lessons learned from frog, fish and chick. Curr Opin Genet Dev 12(4):452–458Google Scholar
  20. 20.
    Sommer L (2011) Generation of melanocytes from neural crest cells. Pigment Cell Melanoma Res 24(3):411–421Google Scholar
  21. 21.
    Larue L, de Vuyst F, Delmas V (2013) Modeling melanoblast development. Cell Mol Life Sci 70(6):1067–1079Google Scholar
  22. 22.
    Mort RL, Jackson IJ, Patton EE (2015) The melanocyte lineage in development and disease. Development 142(7):1387Google Scholar
  23. 23.
    Wehrle-Haller B, Weston JA (1995) Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development 121(3):731–742Google Scholar
  24. 24.
    Simoes-Costa M, Bronner ME (2015) Establishing neural crest identity: a gene regulatory recipe. Development 142(2):242–257Google Scholar
  25. 25.
    Ernfors P (2010) Cellular origin and developmental mechanisms during the formation of skin melanocytes. Exp Cell Res 316(8):1397–1407Google Scholar
  26. 26.
    Krispin S et al (2010) Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest. Development 137(4):585–595Google Scholar
  27. 27.
    Harris ML, Erickson CA (2007) Lineage specification in neural crest cell pathfinding. Dev Dyn 236(1):1–19Google Scholar
  28. 28.
    Beauvais-Jouneau A et al (1999) A novel model to study the dorsolateral migration of melanoblasts. Mech Dev 89(1–2):3–14Google Scholar
  29. 29.
    Adameyko I, Lallemend F (2010) Glial versus melanocyte cell fate choice: schwann cell precursors as a cellular origin of melanocytes. Cell Mol Life Sci 67(18):3037–3055Google Scholar
  30. 30.
    Adameyko I et al (2009) Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139(2):366–379Google Scholar
  31. 31.
    Rizvi TA et al (2002) A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. J Neurosci 22(22):9831–9840Google Scholar
  32. 32.
    Nataf V, Le Douarin NM (2000) Induction of melanogenesis by tetradecanoylphorbol-13 acetate and endothelin 3 in embryonic avian peripheral nerve cultures. Pigment Cell Res 13(3):172–178Google Scholar
  33. 33.
    Nichols DH, Weston JA (1977) Melanogenesis in cultures of peripheral nervous tissue. I. The origin and prospective fate of cells giving rise to melanocytes. Dev Biol 60(1):217–225Google Scholar
  34. 34.
    Nichols DH, Kaplan RA, Weston JA (1977) Melanogenesis in cultures of peripheral nervous tissue. II. Environmental factors determining the fate of pigment-forming cells. Dev Biol 60(1):226–237Google Scholar
  35. 35.
    Dupin E et al (2003) Reversal of developmental restrictions in neural crest lineages: transition from Schwann cells to glial-melanocytic precursors in vitro. Proc Natl Acad Sci USA 100(9):5229–5233Google Scholar
  36. 36.
    Colombo S et al (2012) Transcriptomic analysis of mouse embryonic skin cells reveals previously unreported genes expressed in melanoblasts. J Invest Dermatol 132(1):170–178Google Scholar
  37. 37.
    Hari L et al (2012) Temporal control of neural crest lineage generation by Wnt/beta-catenin signaling. Development 139(12):2107–2117Google Scholar
  38. 38.
    Leone DP et al (2003) Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol Cell Neurosci 22(4):430–440Google Scholar
  39. 39.
    Nitzan E et al (2013) Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3. Proc Natl Acad Sci USA 110(31):12709–12714Google Scholar
  40. 40.
    Candille SI et al (2004) Dorsoventral patterning of the mouse coat by Tbx15. PLoS Biol 2(1):E3Google Scholar
  41. 41.
    Lowe LA, Yamada S, Kuehn MR (2000) HoxB6-Cre transgenic mice express Cre recombinase in extra-embryonic mesoderm, in lateral plate and limb mesoderm and at the midbrain/hindbrain junction. Genesis 26(2):118–120Google Scholar
  42. 42.
    Schartl M et al (2016) What is a vertebrate pigment cell? Pigment Cell Melanoma Res 29(1):8–14Google Scholar
  43. 43.
    Kuo BR, Erickson CA (2010) Regional differences in neural crest morphogenesis. Cell Adh Migr 4(4):567–585Google Scholar
  44. 44.
    Colombo S, Berlin I, Larue L (2011) Classical and nonclassical melanocytes in vertebrates. In: Boranovsky J, Riley PA (eds) Melanins and melanosomes. Wiley, Weinheim, p 407Google Scholar
  45. 45.
    Thomas AJ, 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(11):1849–1858Google Scholar
  46. 46.
    Shibahara S et al (2001) Microphthalmia-associated transcription factor (MITF): multiplicity in structure, function, and regulation. J Investig Dermatol Symp Proc 6(1):99–104Google Scholar
  47. 47.
    Moore KJ (1995) Insight into the microphthalmia gene. Trends Genet 11(11):442–448Google Scholar
  48. 48.
    Watanabe A et al (1998) Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nat Genet 18(3):283–286Google Scholar
  49. 49.
    Verastegui C et al (2000) Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. J Biol Chem 275(40):30757–30760Google Scholar
  50. 50.
    Kos R et al (2001) The winged-helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 128(8):1467–1479Google Scholar
  51. 51.
    Bertolotto C et al (1998) Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J Cell Biol 142(3):827–835Google Scholar
  52. 52.
    Kawakami A (2017) DE Fisher, The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest 97:649Google Scholar
  53. 53.
    Nishikawa-Torikai S, Osawa M, Nishikawa S (2011) Functional characterization of melanocyte stem cells in hair follicles. J Invest Dermatol 131(12):2358–2367Google Scholar
  54. 54.
    Nishimura EK (2011) Melanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res 24(3):401–410Google Scholar
  55. 55.
    Nishimura EK, Granter SR, Fisher DE (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307(5710):720–724Google Scholar
  56. 56.
    Nishimura EK et al (2010) Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell 6(2):130–140Google Scholar
  57. 57.
    King R, Busam K, Rosai J (1999) Metastatic malignant melanoma resembling malignant peripheral nerve sheath tumor: report of 16 cases. Am J Surg Pathol 23(12):1499–1505Google Scholar
  58. 58.
    Luo C et al (2015) Expression of oncogenic BRAFV600E in melanocytes induces Schwannian differentiation in vivo. Pigment Cell Melanoma Res 28(5):603–606Google Scholar
  59. 59.
    Marsh Durban V et al (2013) Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. J Clin Invest 123(12):5104–5118Google Scholar
  60. 60.
    Damsky W et al (2015) mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 27(1):41–56Google Scholar
  61. 61.
    Aoki H et al (2009) Two distinct types of mouse melanocyte: differential signaling requirement for the maintenance of non-cutaneous and dermal versus epidermal melanocytes. Development 136(15):2511–2521Google Scholar
  62. 62.
    Mackenzie MA et al (1997) Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo. Dev Biol 192(1):99–107Google Scholar
  63. 63.
    Jordan SA, Jackson IJ (2000) A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos. Mech Dev 92(2):135–143Google Scholar
  64. 64.
    Alonso L, Fuchs E (2006) The hair cycle. J Cell Sci 119(Pt 3):391–393Google Scholar
  65. 65.
    Mayer TC (1973) The migratory pathway of neural crest cells into the skin of mouse embryos. Dev Biol 34(1):39–46Google Scholar
  66. 66.
    Cui R et al (2007) Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128(5):853–864Google Scholar
  67. 67.
    Cotsarelis G, Sun TT, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61(7):1329–1337Google Scholar
  68. 68.
    Blanpain C, Fuchs E (2009) Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10(3):207–217Google Scholar
  69. 69.
    Blanpain C, Fuchs E (2006) Epidermal stem cells of the skin. Annu Rev Cell Dev Biol 22:339–373Google Scholar
  70. 70.
    Blanpain C, Horsley V, Fuchs E (2007) Epithelial stem cells: turning over new leaves. Cell 128(3):445–458Google Scholar
  71. 71.
    Jaks V et al (2008) Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet 40(11):1291–1299Google Scholar
  72. 72.
    Nishimura EK et al (2002) Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416(6883):854–860Google Scholar
  73. 73.
    Osawa M et al (2005) Molecular characterization of melanocyte stem cells in their niche. Development 132(24):5589–5599Google Scholar
  74. 74.
    Rabbani P et al (2011) Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell 145(6):941–955Google Scholar
  75. 75.
    Lowry WE et al (2005) Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells. Genes Dev 19(13):1596–1611Google Scholar
  76. 76.
    Bertolotto C (2013) Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo) 2013:635203Google Scholar
  77. 77.
    Latil M et al (2017) Cell-type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition. Cell Stem Cell 20(2):191 e5–204 e5Google Scholar
  78. 78.
    Greco V et al (2009) A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4(2):155–169Google Scholar
  79. 79.
    Zhou L et al (2016) CD133-positive dermal papilla-derived Wnt ligands regulate postnatal hair growth. Biochem J 473(19):3291–3305Google Scholar
  80. 80.
    Botchkareva NV, Ahluwalia G, Shander D (2006) Apoptosis in the hair follicle. J Invest Dermatol 126(2):258–264Google Scholar
  81. 81.
    Botchkareva NV, Botchkarev VA, Gilchrest BA (2003) Fate of melanocytes during development of the hair follicle pigmentary unit. J Investig Dermatol Symp Proc 8(1):76–79Google Scholar
  82. 82.
    Mak SS et al (2006) Indispensable role of Bcl2 in the development of the melanocyte stem cell. Dev Biol 291(1):144–153Google Scholar
  83. 83.
    Tanimura S et al (2011) Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell 8(2):177–187Google Scholar
  84. 84.
    Chang CY et al (2013) NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche. Nature 495(7439):98–102Google Scholar
  85. 85.
    Schouwey K et al (2007) Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner. Dev Dyn 236(1):282–289Google Scholar
  86. 86.
    Kumano K et al (2008) Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis. Pigment Cell Melanoma Res 21(1):70–78Google Scholar
  87. 87.
    Moriyama M et al (2006) Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 173(3):333–339Google Scholar
  88. 88.
    Ito M et al (2005) Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11(12):1351–1354Google Scholar
  89. 89.
    Glover JD et al (2015) Maintenance of distinct melanocyte populations in the interfollicular epidermis. Pigment Cell Melanoma Res 28(4):476–480Google Scholar
  90. 90.
    Gilchrest BA (2011) Molecular aspects of tanning. J Invest Dermatol 131(E1):E14–E17Google Scholar
  91. 91.
    Li L et al (2010) Human dermal stem cells differentiate into functional epidermal melanocytes. J Cell Sci 123(Pt 6):853–860Google Scholar
  92. 92.
    Falabella R (2009) Vitiligo and the melanocyte reservoir. Indian J Dermatol 54(4):313–318Google Scholar
  93. 93.
    Falabella R, Barona MI (2009) Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 22(1):42–65Google Scholar
  94. 94.
    Rusfianti M, Wirohadidjodjo YW (2006) Dermatosurgical techniques for repigmentation of vitiligo. Int J Dermatol 45(4):411–417Google Scholar
  95. 95.
    Watt FM, Jensen KB (2009) Epidermal stem cell diversity and quiescence. EMBO Mol Med 1(5):260–267Google Scholar
  96. 96.
    Topczewska JM et al (2006) Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med 12(8):925–932Google Scholar
  97. 97.
    Hendrix MJ et al (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3(6):411–421Google Scholar
  98. 98.
    Rambow F et al (2018) Toward minimal residual disease-directed therapy in melanoma. Cell 174(4):843 e19–855 e19Google Scholar
  99. 99.
    Fleischman RA et al (1991) Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci USA 88(23):10885–10889Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
  2. 2.DAMBI, VIB Center for Inflammation ResearchGhentBelgium
  3. 3.Department of Applied Mathematics, Computer Science and StatisticsGhent UniversityGhentBelgium
  4. 4.Cancer Research Institute Ghent (CRIG)GhentBelgium

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