THE EMBRYONIC LETHALITY OF HOMOZYGOUS LETHAL YELLOW MICE (A(Y)/A(Y)) IS ASSOCIATED WITH THE DISRUPTION OF A NOVEL RNA-BINDING PROTEIN
THE EMBRYONIC LETHALITY OF HOMOZYGOUS LETHAL YELLOW MICE (A(Y)/A(Y)) IS ASSOCIATED WITH THE DISRUPTION OF A NOVEL RNA-BINDING PROTEIN
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DOI：
10.1101/gad.7.7a.1203
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发表时间：
1993-07-01
影响因子：
10.5
通讯作者：
WOYCHIK, RP
中科院分区：
文献类型：
--
作者：
MICHAUD, EJ;BULTMAN, SJ;WOYCHIK, RP
致死黄 (A(y)) 是小鼠刺豚鼠 (a) 基因座的突变，与全黄皮毛颜色、肥胖、糖尿病、杂合子肿瘤以及纯合子植入前胚胎致死性相关。此前，我们克隆并表征了野生型刺豚鼠基因，并证明它在新生儿皮肤中表达 0.8 kb mRNA。相比之下，A(y) 表达一个 1.1-kb 的转录物，该转录物在所有检查的组织中异位过度表达。 A(y) mRNA 的整个编码区与野生型 a 转录本相同，但 a 基因的 5'-非翻译序列已被新序列取代。在这里，我们证明 A(y) mRNA 中的新 5' 序列对应于另一个基因的 5'-非翻译序列，该基因通常与小鼠 2 号染色体中的 a 紧密相连。该另一个基因 (Raly) 有可能编码一种新的 RNA 结合蛋白，该蛋白通常在植入前胚胎、整个发育过程以及所有检查的成体组织中表达。重要的是，A(y) 突变破坏了 Raly 基因的结构和表达。数据表明，A(y) 突变源于 DNA 结构改变，影响了agouti 和 Raly 的表达。我们认为与A(y)相关的显性多效性可能是由于Raly启动子控制下野生型a基因产物的异位过度表达造成的，而隐性胚胎致死性可能是早期胚胎中Raly基因表达缺失的结果。
Lethal yellow (A(y)) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, A(y) expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The A(y) mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the A(y) mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the A(y) mutation disrupts the structure and expression of the Raly gene. The data suggest that the A(y) mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with A(y) may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.