MULTIPLE ROLES FOR ENDOTHELIN IN MELANOCYTE DEVELOPMENT - REGULATION OF PROGENITOR NUMBER AND STIMULATION OF DIFFERENTIATION

Melanocytes in the skin are derived from the embryonic neural crest, R ecently, mutations in endothelin 3 and the endothelin receptor B genes have been shown to result in gross pigment defects, indicating that t his signalling pathway is required for melanocyte development. We have examined the effects of endothelins on melanocyte progenitors in cult ures of mouse neural crest. Firstly, they stimulate an increase in pro genitor number and act synergistically with another factor, Steel fact or, in the survival and proliferation of the progenitors. These findin gs are consistent with findings from mice with natural mutations in th e endothelin receptor B gene, which show an early loss of melanocyte p rogenitors. Secondly, endothelins induce differentiation of the progen itors into fully mature pigmented melanocytes. This finding is consist ent with the expression of endothelins in the skin of mice at the init iation of pigmentation. The melanocytes generated in endothelin-treate d cultures also become responsive to alpha melanocyte-stimulating horm one, which then acts to regulate the activity of the pigmentation path way. These findings indicate two key roles for endothelin in melanocyt e development: regulation of expansion of the progenitor pool and diff erentiation of progenitors into mature melanocytes.