Genetics of Dark Skin in Mice

描述(申请人提供)：色素变异是研究与人类疾病相关的基本生物过程的已建立的和生产性的模型遗传系统。这项工作的大部分是基于以前存在的小鼠皮毛颜色突变，其中几个与不同形式的人类白化病同源。然而，小鼠的毛色突变只是色素变异的一部分，因为控制毛发颜色的过程和基因至少部分不同于控制肤色的过程和基因。 在初步研究中，我们开发了一种新的基于小鼠肤色的哺乳动物遗传学模型系统。从接受全球显性表型筛选的大约30,000只动物中，我们重点研究了一类由暗皮肤识别的新型色素沉着突变体(DSK)。我们确定了10个新的DSK突变的遗传图谱位置、纯合子表型和组织学决定因素，并确定了GNAQ(Dsk1)、Keratin2e(Dsk2)、EGFR(Dsk5)和Gna11(Dsk7)的错义改变。DSK突变代表了以前在色素系统中没有涉及的基因或遗传图谱位置，并描绘了一个多步骤的发育途径，其中可以根据身体区域、微观位置和色素积累的时间对遗传损伤进行分类。 我们建议通过开发追踪发育中的色素细胞不同亚群的基因表达谱的方法，通过确定剩余dsk突变的分子识别和作用机制，并通过扩展dsk筛选包括额外的显性和隐性突变，来进一步研究小鼠黑皮肤的分子和细胞基础。

DESCRIPTION (provided by applicant): Pigmentary variation is an established and productive model genetic system for investigating basic biological processes relevant to human disease. Most of this work has been based on previously existing mouse coat color mutations, several of which are homologous to different forms of human albinism. However, mouse coat color mutations sample only a portion of pigmentary variation, because the processes and genes that control hair color are at least partially distinct from those that control skin color. In preliminary studies, we have developed a new model system for mammalian genetics based on mouse skin color. From about 30,000 animals subjected to a global screen for dominant phenotypes, we have focused on a novel class of pigmentation mutants identified by dark skin (Dsk). We determined the genetic map location, homozygous phenotype, and histological determinants of 10 new Dsk mutations, and identified missense alterations in Gnaq (Dsk1), Keratin2e (Dsk2), Egfr (Dsk5), and Gna11 (Dsk7). The Dsk mutations represent genes or genetic map locations not previously implicated in the pigmentary system, and delineate a multi-step developmental pathway in which genetic lesions can be classified based on the body region, microscopic site, and timing of pigment accumulation. We propose to further investigate the molecular and cellular basis for dark skin in mice by developing methods to trace the lineage and measure profiles of gene expression for different subsets of developing pigment cells, by determining the molecular identification and mechanism of action for the remaining Dsk mutations, and by expanding the Dsk screen to include additional dominant and recessive mutations.