Key Discoveries in Melanocyte Development

Abstract

Melanocytes are melanin pigment-producing cells. Mammalian melanocytes are categorized as ‘‘cutaneous’’ (follicular and epidermal) and ‘‘extracutaneous’’ (e.g., choroidal, cochlear). Epidermal melanocytes contribute to photoprotection and thermoregulation by packaging melanin pigment into melanosomes and delivering them to neighboring keratinocytes. Melanocytes are derived from the neural crest that is a migratory multipotent population that gives rise to multiple cell lineages, including neurons, glial cells, medullary secretory cells, smooth muscle cells, and bone and cartilage cells. Coat color mutants in different species have been useful for identifying genes involved in melanocyte development. Embryonic transplantation experiments played a significant role in early efforts to investigate melanocyte development. Rawles (1947) conducted a series of elegant transplantation experiments, which revealed that melanocytes originate from the neural crest. The investigator transplanted various axial levels of the embryonic central nervous system, adjacent tissues of the somite and lateral plate, and limb-bud regions, separately and in combination, from various developmental stages of black mouse embryos, to the coelom of White Leghorn chick embryos. Only tissues containing the neural crest or cells migrating from the neural crest were found to produce melanophores. In addition, Rawles found that the portions of embryo that produce pigment cells vary at different developmental stages of donor embryos. The quail nucleus exhibits condensed heterochromatin, which could serve as a marker to distinguish quail cells from chick cells. Teillet and Le Douarin (1970) studied melanoblast migration from the neural crest using a quail-chick xenograft transplantation model. The investigators transplanted different axial levels of quail neural tube and neural crest to White Leghorn chick embryos. They found that (1) at embryonic days E4 and E5, the transplanted quail cells localize mainly in the mesenchyme; (2) at E6 when the dermis and the epidermis are formed, quail cells (melanoblasts) begin to migrate into the epidermis; (3) at E9 quail cells (melanoblasts) increase their cytoplasmic volume and start producing melanin pigments; (4) at E10 and E11 quail cells (melanoblasts) localize in the basal layer of epidermis and become dendritic. Cell type-specific markers are useful tools to study the development of certain cell types. However, it is challenging to identify these markers. Steel et al. (1992) found Tyrp-2/Dct to be a specific marker of melanoblasts, the precursors of melanocytes. Using in situ hybridization, the investigators found that Tyrp-2 expression was detectable in melanoblasts as early as 10 days post coitum. The finding of a marker for early melanoblasts enabled scientists to look for the mechanisms of coat color mutations. Steel and W mutants exhibited a white spotting color pattern. W and Steel encode, respectively, a receptor tyrosine kinase, Kit, and its ligand, which is known by several different names: steel factor, stem cell factor, mast cell growth factor, and Kit ligand. The mutation Steel-dickie (Sl) is a deletion of its transmembrane and cytoplasmic domains so that only a secreted form of stem cell factor is produced. Steel et al. (1992) found that the number of melanoblasts in (Sl/ Sl) mutants began to decrease at around 11 days post coitum. They also found that the melanoblasts caudal of the optic vesicle failed to migrate toward the vesicle. These results suggested that the cell surface form of stem cell factor is important for both the survival and migration of melanoblasts. Wehrle-Haller and Weston (1995) performed in situ hybridization with Kit, Tyrp-2, and stem cell factor probes in Sl (null) and Sl mutants to examine the early dispersal and fate of melanoblasts in order to elucidate the function of stem cell factor in more detail. They concluded that soluble stem cell factor is sufficient for responsive melanoblast precursors to initiate their dispersal onto the lateral migration pathway, and that cell-bound stem cell factor was necessary for the survival of melanoblasts in the newly formed dermal mesenchyme. Dorsky et al. (1998) found that cranial neural crest cells destined to encode pigment cells were located adjacent to the Wnt-1 and Wnt-3a expression domain, whereas neurons were far from the Wnt-expressing domain in zebrafish. Most lateral cells, which become neurons when forcibly overexpressing an activated form of b-catenin, adopted a pigment-cell fate. Conversely, when the investigators overexpressed a mutant form of Tcf-3 or a dominant-negative Wnt-1 to inhibit Wnt signaling in medial neural crest cells, the number of pigment cells decreased dramatically. Thus, Dorsky et al. provided key evidence that Wnt signaling plays an essential early role in pigment cell formation.