Regulation of zebrafish melanocyte development by ligand-dependent BMP signaling.

Abstract

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand <i>GDF6</i> as a novel melanoma oncogene showed <i>GDF6</i>-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for <i>GDF6</i> orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand <i>gdf6a</i>, a zebrafish ortholog of human <i>GDF6</i>, during the development of melanocytes from the neural crest. We establish that the loss of <i>gdf6a</i> or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on <i>mitfa</i>, an ortholog of <i>MITF</i>, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.