Melanocortin signaling: genetic insight from X-linked color mutations in non-model organisms

 描述(申请人提供)：小鼠毛色突变的位置克隆为识别和理解旁分泌信号通路提供了基础，旁分泌信号通路在生物学和疾病中发挥重要作用。这种被称为色素类型转换的现象--毛囊黑素细胞在产生红色/黄色Peomelanin和产生黑色/棕色真黑素之间切换--对于神经内分泌、肾上腺、外分泌和色素系统使用的途径特别有用，因为Melanocortin 1受体发挥了中心作用。化学诱变和反向遗传学方面的大规模努力正在逐渐饱和实验室小鼠作为基因发现工具的潜力，但基因组技术的进步已经将正向遗传学的覆盖范围扩展到传统模式生物之外。尽管这些途径在进化上是保守的，但作为表型读数的颜色变化的敏感性，加上观察和选择同伴和家养动物中的异常突变的机会，提供了额外的机会。目前的建议集中在非模式生物中的两个“经典”毛色突变，即家猫中的橙色和叙利亚仓鼠中的性连锁黄色(Sly)；这些突变特别有趣，因为它们是X连锁的，但模仿了常染色体黑素皮质素1受体(MC1R)的功能丧失突变。我们的初步研究已经确定了Orange的候选突变和机制，以及Sly的遗传图谱位置和位置克隆策略。有关黑素皮质素信号的遗传学和生物学的更多知识将来自：(1)在培养细胞和转基因动物中进行实验遗传学研究，以实验证实和探索橙色的分子病理生理学；以及(2)仓鼠Sly突变的分子鉴定和表征。

 DESCRIPTION (provided by applicant): Positional cloning of mouse coat color mutations has provided a foundation for identifying and understanding paracrine signaling pathways that play fundamental roles in biology and disease. The phenomenon known as pigment-type switching-whereby hair follicle melanocytes switch between the production of red/yellow pheomelanin vs. black/brown eumelanin-has been especially informative for pathways used by the neuroendocrine, adrenal, exocrine, and pigmentary systems because of the central role played by the Melanocortin 1 receptor. Large-scale efforts in chemical mutagenesis and reverse genetics are gradually saturating the potential of the laboratory mouse as a tool for gene discovery, but advances in genomic technology have extended the reach of forward genetics beyond traditional model organisms. Although the pathways are evolutionarily conserved, the sensitivity of color variation as a phenotypic readout coupled with the opportunity to observe and select for unusual mutations in companion and domestic animals provides additional opportunities. The current proposal focuses on two "classical" coat color mutations in non-model organisms, Orange in the domestic cat and Sex-linked yellow (Sly) in the Syrian hamster; these are especially interesting because they are X-linked, yet mimic a loss-of-function mutation in the autosomal Melanocortin 1 Receptor (Mc1r). Our preliminary studies have identified a candidate mutation and mechanism for Orange, and a genetic map position and positional cloning strategy for Sly. Additional knowledge about the genetics and biology of melanocortin signaling will come from: (1) Experimental genetic studies in cultured cells and in transgenic animals to experimentally confirm and explore the molecular pathophysiology of Orange; and (2) Molecular identification and characterization of the hamster Sly mutation.