Biological and mathematical modeling of melanocyte development

Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France.
Development (Impact Factor: 6.46). 09/2011; 138(18):3943-54. DOI: 10.1242/dev.067447
Source: PubMed


We aim to evaluate environmental and genetic effects on the expansion/proliferation of committed single cells during embryonic development, using melanoblasts as a paradigm to model this phenomenon. Melanoblasts are a specific type of cell that display extensive cellular proliferation during development. However, the events controlling melanoblast expansion are still poorly understood due to insufficient knowledge concerning their number and distribution in the various skin compartments. We show that melanoblast expansion is tightly controlled both spatially and temporally, with little variation between embryos. We established a mathematical model reflecting the main cellular mechanisms involved in melanoblast expansion, including proliferation and migration from the dermis to epidermis. In association with biological information, the model allows the calculation of doubling times for melanoblasts, revealing that dermal and epidermal melanoblasts have short but different doubling times. Moreover, the number of trunk founder melanoblasts at E8.5 was estimated to be 16, a population impossible to count by classical biological approaches. We also assessed the importance of the genetic background by studying gain- and loss-of-function β-catenin mutants in the melanocyte lineage. We found that any alteration of β-catenin activity, whether positive or negative, reduced both dermal and epidermal melanoblast proliferation. Finally, we determined that the pool of dermal melanoblasts remains constant in wild-type and mutant embryos during development, implying that specific control mechanisms associated with cell division ensure half of the cells at each cell division to migrate from the dermis to the epidermis. Modeling melanoblast expansion revealed novel links between cell division, cell localization within the embryo and appropriate feedback control through β-catenin.

Download full-text


Available from: Lionel Larue,
  • Source
    • "However, not all melanoblasts cross the dermal/epidermal junction and a dermal population also persists. This process is clearly regulated and, although dermal melanoblasts are proliferating, their numbers remain unchanged, indicating a constant and controlled dermal-to-epidermal movement (Luciani et al., 2011). Furthermore, in mice with mutations that cause an expansion of the early melanoblast population, the number of melanocytes reaching the epidermis appears to be unchanged whilst the number of dermal melanocytes increases, thereby resulting in dark skin (Van Raamsdonk et al., 2004), suggesting a mechanism for controlling the size of the epidermal melanoblast population. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):620-632. DOI:10.1242/dev.106567 · 6.46 Impact Factor
  • Source
    • "Mice with a conditional deletion of the Ecad gene (Cdh1) were generated by mating Tyr::Cre transgenic mice with animals homozygous for a floxed allele of Ecad (DEcad) (Boussadia et al., 2002; Delmas et al., 2003). Wild-type and DEcad mice were crossed with Dct::LacZ mice to visualize melanocytes in skin sections by Xgal coloration as previously described (Luciani et al., 2011). Melanoblast proliferation was analyzed by BrdU labeling in vivo as described previously (Berlin et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes as well as oxidative and mechanical stress. It is important to identify early events in vitiligo, to clarify pathogenesis, improve diagnosis and inform therapy. Here, we show that E-cadherin, which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from, or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective E-cadherin expression in melanocytes we demonstrated that E-cadherin is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/pre-clinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness, which under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.Journal of Investigative Dermatology accepted article preview online, 29 January 2015. doi:10.1038/jid.2015.25.
    Journal of Investigative Dermatology 01/2015; 135(7). DOI:10.1038/jid.2015.25 · 7.22 Impact Factor
  • Source
    • "Melanoblast specification from NC precursors is governed primarily by Wnt and BMP signaling molecules; BMP can suppress both Wnt-induced sensory neurogenesis in mouse [14] and Wnt-induced melanocyte generation in quail neural crest cells [15]. Wnt/b-catenin plays a dual stage-dependent role in neural crest stem cell lineage decisions: at an early stage (presumably in the premigratory neural crest), canonical Wnt controls sensory neurogenesis; at a somewhat later stage, it might regulate melanocyte formation, although this remains to be confirmed [2]. Wnt signals that influence NC formation and melanocyte lineage specification act through the stabilization of b-catenin and its regulation of transcription by binding to Tcf/Lef transcription factors [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnt3a and Frizzled-3 are both expressed in the dorsal neural tube that gives rise to the neural crest in Xenopus, zebrafish and mice. Melanocytes originate from the neural crest (NC) and postnatally, melanocyte stem cells reside in the hair follicle bulge and in the dermis. However, the roles of Wnt3a and Frizzled-3 in melanocyte development have not been clarified. The aim of this study was to delineate the expression of Frizzled-3 in murine melanocyte lineage and human melanocytes, and to study the effects of Wnt3a on melanocyte development at various stages. Murine NC explant cultures and three NC-derived melanocyte lineage cell lines, including NCCmelb4M5 (Kit(-) melanocyte precursors), NCCmelb4 (Kit(+) melanoblasts) and NCCmelan5 (differentiated melanocytes), and human epidermal melanocytes were treated with pure recombinant Wnt3a protein and their cell behaviors were analyzed including their proliferation, Kit expression, tyrosinase (Tyr) activity, melanin production, dendrite formation and migration. Frizzled-3 was expressed in Tyr-related protein (TRP)-1(+) cells in NC explant cultures, in all 3 melanocyte precursor cell lines and in human melanocytes. Wnt3a increased the population of TRP-1(+) cells, the number of L-3,4-dihydroxyphenylalanine (DOPA)(+) cells and dendrite formation in NC explant cultures. Wnt3a stimulated the proliferation of all 3 melanocyte precursor cell lines in a dose-dependent manner and also stimulated human melanocyte proliferation. Moreover, Wnt3a increased Tyr activity and melanin content of differentiated melanocytes, but did not activate Tyr activity in melanoblasts. Wnt3a stimulated dendrite formation in differentiated melanocytes, but not in melanoblasts. Wnt3a did not affect melanoblast or melanocyte migration. Wnt3a did not induce c-Kit expression in Kit(-) NCCmelb4M5 cells and did not affect c-Kit expression in any cell line tested. Frizzled-3 is constitutively expressed in murine melanocyte precursors, melanocytes and human melanocytes. Wnt3a and Frizzled-3 signalings play important roles in regulating the proliferation and differentiation of murine NCCs and various developmental stages of melanocyte precursors. The effect of Wnt3a on human melanocytes is similar to its effects on murine melanocytes. Therefore Wnt3a/Frizzled-3 signaling is a promising target for human melanocyte regeneration.
    Journal of dermatological science 05/2014; 75(2). DOI:10.1016/j.jdermsci.2014.04.012 · 3.42 Impact Factor
Show more