Melanocyte differentiation and epidermal pigmentation is regulated by polarity proteins

ABSTRACT Pigmentation serves various purposes such as protection, camouflage, or attraction. In the skin epidermis, melanocytes react to certain environmental signals with melanin production and release, thereby ensuring photo-protection. For this, melanocytes acquire a highly polarized and dendritic architecture that facilitates interactions with surrounding keratinocytes and melanin transfer. How the morphology and function of these neural crest-derived cells is regulated remains poorly understood. Here, using mouse genetics and primary cell cultures, we show that conserved proteins of the mammalian Par3-aPKC polarity complex are required for epidermal pigmentation. Melanocyte-specific deletion of Par3 in mice caused skin hypopigmentation, reduced expression of components of the melanin synthesis pathway, and altered dendritic morphology. Mechanistically, Par3 was necessary downstream of α-melanocyte stimulating hormone (α-MSH) to elicit melanin production. Strikingly, pharmacologic activation of MITF using a salt-inducible kinase inhibitor was sufficient to restore melanocyte differentiation and skin pigmentation in the absence of Par3. This data reveals a central role of polarity proteins in transmitting external pigment-inducing signals through the α-MSH/Mc1R/MITF ‘tanning pathway’, exposing unexpected links between polarity signaling and melanogenesis with new insights for pigment cell biology.