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

Abstract

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.epidermis ͉ quail embryo ͉ clonal cultures ͉ transdifferentiation ͉ Schwann cell myelin protein T he pigment cells of the body are one of the numerous derivatives of the neural crest (NC), a pluripotent structure of the vertebrate embryo that forms from the lateral ridges of the dorsal neural primordium. In addition to the melanocytes, the NC is the source of the neurons and glia of the peripheral nervous system, of endocrine cells and, at the cephalic level, of mesenchymal cells (the mesectoderm) that differentiate into connective tissues and smooth muscles and form most of the head skeleton (see refs. 1 and 2 for reviews). These multiple cell types arise from multipotent precursors, whose existence was demonstrated in avian and rodent NC at the premigratory and migratory stages (3-9). The population of migratory NC cells also includes lineage-restricted precursors, which increase in number as development proceeds (5, 10-15). Finally, the phenotype of the various NC derivatives is controlled by exposure of the cells to environmental signals during their migration and at their homing sites. A number of these signals have been characterized in mice by analyzing spontaneous mutations or by gene targeting (see refs. 16-18 for reviews).Thus the spontaneous or experimental inactivation of the murine genes encoding endothelin 3 (ET3) and its receptor (endothelin receptor B) (ETRB) causes defects of body pigmentation and posterior gut innervation (19,20). To understand the role for ET3͞ETRB signaling in the development of NC-derived cells, we have studied these ligand͞receptor system in avian NC ontogeny. Avian ETRB and ET3 genes were shown to have complementary expression patterns in...

Self-renewal capacity is a widespread property of various types of neural crest precursor cells

“…Such dependency is consistent with our findings (26) that GM precursors of trunk origin are a privileged target for the survival-and proliferation-promoting effects of ET3 in vitro. The strong potential of ET3 to trigger expansion of GM stem cells may also underlie the capacity of differentiated glial cells and melanocytes to reverse their phenotypic program and transdifferentiate reciprocally in vitro (36,37,53). GM cells isolated from the cephalic NC showed a delayed response to ET3 because they were unaffected by treatment during the first cloning.…”

Gene Duplication of endothelin 3 Is Closely Correlated with the Hyperpigmentation of the Internal Organs (Fibromelanosis) in Silky Chickens

“…Numerous in vitro studies using quail and mouse embryos have reported that EDN3 affects the melanocyte lineage population by increasing their number in a dose-dependent manner (Lahav et al 1996(Lahav et al , 1998Reid et al 1996;Opdecamp et al 1998;Dupin et al 2000). In addition, exogenous overexpression of EDN3 driven by keratin 5 in transgenic mouse embryos induced proliferation of melanocyte precursors and led to hyperpigmentation on most areas of their skin (Garcia et al 2008).…”

Activation of Myelin Genes during Transdifferentiation from Melanoma to Glial Cell Phenotype

“…Melanoma and nevus cells can exhibit such phenotypic changes in vivo (53,54). The inducible transdifferentiation of the F10.9 cells may recapitulate molecular switches that operate when neural crest-derived progenitors develop into either melanocytic or glial lineages (55,56) and may help identify them. We investigated here mechanisms involved in the transcriptional activation of promoters from two myelin genes, Po and MBP.…”