Barsh G, Gunn T, He L, Schlossman S, Duke-Cohan J
Department of Pediatrics and Genetics, and the HHMI, Stanford University School of Medicine, California 94305, USA.
Pigment Cell Res. 2000;13 Suppl 8:48-53. doi: 10.1034/j.1600-0749.13.s8.10.x.
Mutations that affect the balance between the synthesis of eumelanin and pheomelanin provide a powerful set of tools with which to understand general aspects of cell signaling. Previous work from our laboratory has demonstrated that pheomelanin synthesis is triggered by the ability of Agouti protein to inhibit signaling through the Melanocortin 1 receptor (Mc1r). In a bioassay based on the Xenopus Mc1r, Agouti protein has two effects, competitive inhibition of receptor occupancy by alpha-MSH and down-regulation of receptor signaling, which are mediated separately by domains in the amino- and carboxy-terminal regions of Agouti protein, respectively. Recently, we have used the genetics of pigmentation as an in vivo system to screen for and analyze other mutations in the Agouti-melanocortin pathway. The pigmentary effects of Agouti are suppressed by the previously existing coat-color mutations mahogany (mg), mahoganoid (md), and Umbrous (U). Double mutant studies, with animals deficient for the Mc1r or those which carry Ay, indicate that mg and md are genetically upstream of the Mc1r, and can suppress the effects of Ay on both pigmentation and body weight. Positional cloning has recently identified the gene mutated in mahogany as a single transmembrane-spanning protein whose ectodomain is orthologous to human Attractin (Atrn).
影响真黑素和褐黑素合成平衡的突变提供了一组强大的工具，可用于理解细胞信号传导的一般方面。我们实验室之前的工作表明，褐黑素的合成是由刺鼠蛋白抑制黑素皮质素1受体（Mc1r）信号传导的能力触发的。在基于非洲爪蟾Mc1r的生物测定中，刺鼠蛋白有两种作用，分别由刺鼠蛋白氨基末端和羧基末端区域的结构域介导，即竞争性抑制α-MSH对受体的占据以及下调受体信号传导。最近，我们利用色素沉着遗传学作为体内系统，筛选和分析刺鼠-黑素皮质素途径中的其他突变。刺鼠的色素沉着效应被先前存在的毛色突变体红木色（mg）、类红木色（md）和暗色（U）所抑制。对缺乏Mc1r或携带Ay的动物进行的双突变研究表明，mg和md在遗传学上位于Mc1r的上游，并且可以抑制Ay对色素沉着和体重的影响。定位克隆最近已确定红木色突变体中发生突变的基因为一种单跨膜蛋白，其胞外结构域与人吸引素（Atrn）同源。
