Abstract

Melanocortin-1 receptor (MC1R) and its ligands, α-melanocyte stimulating hormone (αMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (Ay/a and Mc1re/ Mc1re) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by αMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrnmg-3J/mg-3J or Mgrn1md-nc/md-nc) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP–MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.

Highlights

  • The diverse patterns of mammalian coat color are determined by the quantity and distribution of just two types of organic pigment: eumelanin and pheomelanin (Barsh, 2006; Ito, 2003)

  • Melanoblast-like morphology and reduced proliferation of melanocytes grown with agouti signal protein (ASIP) Melan-a cells (a ⁄ a) grown with 12-O-tetradecanoyl phorbol-13-acetate (TPA) normally show a dendritic, well-differentiated appearance with abundant eumelanosomes (Figure 1) (Bennett et al, 1987)

  • Melanoblasts are the predominant growing population in primary neonatal epidermal cultures in our melanocyte medium in the first 7–10 days, after which they differentiate into melanocytes (Sviderskaya et al, 1995)

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Summary

Introduction

The diverse patterns of mammalian coat color are determined by the quantity and distribution of just two types of organic pigment: eumelanin (black to brown) and pheomelanin (yellow to red) (Barsh, 2006; Ito, 2003) Both are produced by melanocytes in the hair bulbs and basal epidermis. Microphthalmia-related transcription factor is a master regulator for eumelanogenesis, melanocyte differentiation, proliferation, and survival It promotes transcription of melanocyte-specific gene products including melanosomal enzymes tyrosinase, TYRP1 and DCT and the matrix protein SILV ⁄ PMEL (Levy et al, 2006). The resulting dopaquinone can be a precursor for either eumelanin synthesis, promoted by TYRP1 and DCT, or pheomelanin in the presence of high cysteine concentrations and ⁄ or low tyrosinase activity (Ito, 2003; Land et al, 2003)

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