Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast‐like alteration of melanocytes: a cAMP‐independent pathway

Tokimasa Hida,Shosuke Ito,Lluis Montoliu,M Lynn Lamoreux,Bin Yu,Kazumasa Wakamatsu,Dorothy C Bennett,Andrew J Donkin,Kowichi Jimbow,Elena V Sviderskaya,Glenn L Millhauser,Gregory S Barsh

doi:10.1111/j.1755-148x.2009.00582.x

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)

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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Discussion

Conclusion