CLONING OF THE MOUSE AGOUTI GENE PREDICTS A SECRETED PROTEIN UBIQUITOUSLY EXPRESSED IN MICE CARRYING THE LETHAL-YELLOW MUTATION
CLONING OF THE MOUSE AGOUTI GENE PREDICTS A SECRETED PROTEIN UBIQUITOUSLY EXPRESSED IN MICE CARRYING THE LETHAL-YELLOW MUTATION
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DOI：
10.1101/gad.7.3.454
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发表时间：
1993-03-01
影响因子：
10.5
通讯作者：
BARSH, GS
中科院分区：
文献类型：
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作者：
MILLER, MW;DUHL, DMJ;BARSH, GS
老鼠的agglutinase基因控制着黄色和黑色色素在毛发发育过程中的沉积。几个显性等位基因，包括致死黄色（A（y）），导致专门生产的黄色色素，并具有多效性的影响，包括肥胖和增加肿瘤易感性。在种间回交中，我们建立了agglutinase基因的遗传极限，发现A（y）和致死的非agglutinase（a（x））等位基因在Is1GsO染色体重排的断点处没有与先前鉴定的探针分离。使用Is1GsO探针，我们分离了agglutinase基因，发现它有可能编码在毛囊和表皮中表达的分泌蛋白，并且表达水平与黄色素的合成相关。在A（y）突变中，存在染色体重排，其导致产生在身体的几乎每个组织中表达的嵌合RNA。该嵌合RNA的5'部分含有高度表达的新5'序列，但3'部分保留了非突变等位基因的蛋白质编码潜力。我们推测，A（y）的显性多效性效应是由一种信号通路的异位激活引起的，这种信号通路类似于正常毛发生长期间使用的信号通路。
The mouse agouti gene controls the deposition of yellow and black pigment in developing hairs. Several dominant alleles, including lethal yellow (A(y)), result in the exclusive production of yellow pigment and have pleiotropic effects that include obesity and increased tumor susceptibility. In an interspecific backcross, we established genetic limits for the agouti gene and found that the A(y) and the lethal non-agouti (a(x)) allele were not separated from a previously identified probe at the breakpoint of the Is1GsO chromosomal rearrangement. Using the Is1GsO probe, we isolated the agouti gene, and find that it has the potential to code for a secreted protein expressed in hair follicles and the epidermis, and that the level of expression correlates with the synthesis of yellow pigment. In the A(y) mutation, there is a chromosomal rearrangement that results in the production of a chimeric RNA expressed in nearly every tissue of the body. The 5' portion of this chimeric RNA contains highly expressed novel 5' sequences, but the 3' portion retains the protein-coding potential of the nonmutant allele. We speculate that dominant pleiotropic effects of A(y) are caused by ectopic activation of a signaling pathway similar to that used during normal hair growth.