title: Biological and mathematical modeling of melanocyte development.
abstract: 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.
authors.affiliation: Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Luciani
authors.forename: Delphine
authors.initials: D
authors.lastname: Champeval
authors.forename: Aurélie
authors.initials: A
authors.lastname: Herbette
authors.forename: Laurence
authors.initials: L
authors.lastname: Denat
authors.forename: Bouchra
authors.initials: B
authors.lastname: Aylaj
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinozzi
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Rolf
authors.initials: R
authors.lastname: Kemler
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Florian
authors.initials: F
authors.lastname: De Vuyst
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.forename: Véronique
authors.initials: V
authors.lastname: Delmas
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000196:embryology; D004622:Embryo, Mammalian; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D048788:Growth and Development / Q000502:physiology*; D006801:Humans; D008544:Melanocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008962:Models, Theoretical