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Melanoma is a rare sporadic pediatric cancer caused byde novogenetic accidents. To analyze the involvement ofFBXO32of unknown biological significance, we set up original developmental invivo,ex vivo, andin vitromodels to unmask the biological role ofFBXO32in cephalic and trunk neural crest lineages. We show thatFBXO32silencing impairs melanocyte proliferation, differentiation, and vascularization. In rescue experiments, co-electroporation with the human wild-type gene compensates for the silencing of the endogenous gene and restores normal melanocyte phenotypes. By contrast, co-electroporation with the human variant,FBXO32G139S, alters melanocyte differentiation, pigment synthesis, triggers migration to the dermis, and favors angiotropism. Transcriptomic analysis reveals targets associated with melanocyte transformation, cytoskeleton remodeling, and focal adhesion. We show thatFBXO32orchestrates unexpected interactions withASIPfor melanogenesis andBAP1for the post-translational ubiquitination system. We proposeFBXO32as a tumor suppressor gene capable of preventing the onset of pediatric melanoma.

The neural crest, a unique cell population originating from the primitive neural field, has a multi-systemic and structural contribution to vertebrate development. At the cephalic level, the neural crest generates most of the skeletal tissues encasing the developing forebrain and provides the prosencephalon with functional vasculature and meninges. Over the last decade, we have demonstrated that the cephalic neural crest (CNC) exerts an autonomous and prominent control on forebrain and sense organs development. The present paper reviews the primary mechanisms by which CNC can orchestrate vertebrate encephalization. Demonstrating the role of the CNC as an exogenous source of patterning for the forebrain provides a novel conceptual framework with profound implications for understanding neurodevelopment. From a biomedical standpoint, these data suggest that the spectrum of neurocristopathies is broader than expected and that some neurological disorders may stem from CNC dysfunctions.