Genetics of dark skin in mice
Genetics of dark skin in mice
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DOI：
10.1101/gad.1023703
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发表时间：
2003-01-15
影响因子：
10.5
通讯作者：
Barsh, GS
中科院分区：
文献类型：
--
作者：
Fitch, KR;McGowan, KA;Barsh, GS
小鼠的化学诱变是表型驱动遗传学的一种强有力的方法，但仍然存在问题，即通过表型确定的新突变可以被定位和识别的效率，以及这种知识应用于特定的生物学问题。在对大约30,000只动物的显性表型进行全球筛选的过程中，一类新的色素沉着突变通过暗皮肤(DSK)被鉴定出来。我们确定了10个新的DSK和2个新的暗衣(DCC)突变的遗传图谱位置、纯合子表型和组织学，并鉴定了Agti(Met1Leu，Dcc4)、Sox18(Leu220ter，Dcc1)、角蛋白2E(Thr500Pro，Dsk2)和EGFR(Leu863Gln，Dsk5)的突变。除角蛋白2E和EGFR突变外，大多数DSK突变对皮肤的影响仅限于黑素细胞，其中角化过度和表皮增厚先于表皮黑素细胞增多3-6wk。Dsk2突变可能损害中间丝组装，导致基底层以上角质形成细胞的细胞溶解，继发性角化过度和黑素细胞增多。Dsk5突变导致体内酪氨酸激酶活性增加和稳态受体水平下降。DSK突变代表以前与色素沉着无关的基因或图谱位置，并描绘了一条发育途径，其中突变可以根据身体区域、微观位置和色素积累的时间进行分类。
Chemical mutagenesis in the mouse is a powerful approach for phenotype-driven genetics, but questions remain about the efficiency with which new mutations ascertained by their phenotype can be localized and identified, and that knowledge applied to a specific biological problem. During a global screen for dominant phenotypes in about 30,000 animals, a novel class of pigmentation mutants were identified by dark skin (Dsk). We determined the genetic map location, homozygous phenotype, and histology of 10 new Dsk and 2 new dark coat (Dcc) mutations, and identified mutations in Agouti (Met1Leu, Dcc4), Sox18 (Leu220ter, Dcc1), Keratin 2e (Thr500Pro, Dsk2), and Egfr (Leu863Gln, Dsk5). Cutaneous effects of most Dsk mutations are limited to melanocytes, except for the Keratin 2e and Egfr mutations, in which hyperkeratosis and epidermal thickening precede epidermal melanocytosis by 3-6 wk. The Dsk2 mutation is likely to impair intermediate filament assembly, leading to cytolysis of suprabasal keratinocytes and secondary hyperkeratosis and melanocytosis. The Dsk5 mutation causes increased tyrosine kinase activity and a decrease in steady-state receptor levels in vivo. The Dsk mutations represent genes or map locations not implicated previously in pigmentation, and delineate a developmental pathway in which mutations can be classified on the basis of body region, microscopic site, and timing of pigment accumulation.