Biology of Melanocytes at a Glance
- derive from the neural crest. Their migration/survival in the epidermis is influenced by numerous factors.
- populate the epidermis, hair follicle, eye, cochlea, and meninges.
- synthesize melanin, an indole derivative of 3,4 di-hydroxy-phenylalanine (DOPA) that is stored in melanosomes.
- are influenced by endocrine, paracrine, and autocrine factors and by ultraviolet (UV) irradiation.
- display four maturation stages.
- contain structural matrix proteins, melanogenic enzymes, pH-maintaining proteins, and free-radical scavengers.
- are transported to melanocyte dendrite tips and transferred to epidermal keratinocytes.
- in skin, absorb UV radiation and protect against photodamage.
Melanocytes are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos1 (eFig. 72-0.1). They derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia, smooth muscle, craniofacial bone, cartiledge, and melanocytes.2,3 Progenitor melanoblasts migrate dorsolaterally between the mesodermal and ectodermal layers to reach their final destinations in the hair follicles and the skin as well as inner ear cochlea, choroids, ciliary body, and iris.2,4 Pigment-producing cells can be found in fetal epidermis as early as the 50th day of gestation.
Migration of melanoblast precursors. Migrating melanoblasts in an E11.5 transgenic mouse embryo expressing the Lac Z reporter gene under the control of the melanocyte-specific Dct (DOPAchrome tautomerase) promoter. The melanoblasts are visualized by staining for β-galactosidase. (Used with permission from Ian Jackson and Alison Wilkie, Medical Research Council, Human Genetics Unit, Western General Hospital, Edinburgh, Scotland.)
Melanoblast migration and differentiation into melanocytes are influenced by a number of signaling molecules produced by neighboring cells. These include Wnt, endothelin (ET)-3, bone morphogenetic proteins (BMPs), steel factor (SF) (stem cell factor, c-Kit ligand), and hepatocyte growth factor (HGF/scatter factor).5–10 By interacting with their specific cell surface receptors, these molecules induce intracellular and intranuclear signaling to influence gene transcription and protein synthesis. Genetic defects in some of these molecules are associated with human genetic diseases: ETs (Waardenburg syndrome and Hirschsprung disease) and c-Kit and stell factor with piebaldism. Detailed discussion of each signaling molecule is available online.
Wnt is expressed in the dorsal neural tube during neural crest cell migration and directs the maturation of pluripotent neural crest cells into melanoblasts.
The Wnt family is composed of 16 different secreted glycoproteins. They bind and activate Frizzled, a transmembrane heptahelical G protein-linked receptor,11 and induce the accumulation of β-catenin (eFig. 72-0.2A). Under baseline conditions, when Wnt does not bind Frizzled, cytosolic β-catenin is complexed with the enzyme glycogen synthase kinase 3β (GSK3β) that induces rapid ubiquitin-mediated degradation of β-catenin by cellular proteosomes. Binding of Wnt to its receptor Frizzled inhibits GSK3β activity, leading to β-catenin accumulation in the cytosol followed by its ...