Endothelin 3 induces the reversion of melanocytes to glia through a neural crest-derived glial-melanscytic progenitor

Functional signaling of endothelin 3 (ET3) and its receptor B (ETRB) has been shown to be required for the development of neural crest (NC)-derived pigment cells in mouse, but the precise role of ET3 is not completely understood. Using the avian embryo as a model, we previously reported that ET3 promotes the survival and proliferation of unipotent melanocyte and bipotent glia-melanocyte precursors in trunk NC cultures. Here we investigated whether, at later stages, embryonic pigment cells respond to ET3. Such a possibility is supported by the previous finding that, in vivo, avian melanocytes express endothelin receptor B2 (ETRB2) during migration and after their differentiation in the skin. We found that in vitro ET3 exerts a dose-dependent stimulation of proliferation and melanogenesis in NC cells that had homed to the epidermis of embryonic quail dorsal skin. Moreover, in clonal cultures of skin-derived pigment cells, ET3 induces rapid cell divisions of clonogenic melanocytes that generate a mixed progeny of melanocytes and cells devoid of pigment granules and expressing glial markers in more than 40% of the colonies. It can therefore be concluded that ET3 is strongly mitogenic to embryonic pigment cells and able to alter their differentiation program, leading them to recapitulate the glial-melanocyte bipotentiality of their NC ancestors.