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CUL-4A Is Critical for Early Embryonic Development

机译：CUL-4A对于早期胚胎发育至关重要

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Ubiquitin-mediated degradation targets cell cycle regulators for proteolysis. Much of the ubiquitin pathway's substrate specificity is conferred by E3 ubiquitin ligases, and cullins are core components of some E3s. CUL-4A encodes one of six mammalian cullins and is amplified and/or overexpressed in breast cancer, which suggests a role in regulating cell cycle progression. To examine CUL-4A's physiologic function, we generated a CUL-4A deletion mutation in mice. No viable CUL-4A?/? pups and no homozygous mutant embryos as early as 7.5 days postcoitum (dpc) were recovered. However, CUL-4A?/? blastocysts are viable, hatch, form an inner cell mass and trophectoderm, and implant (roughly 4.5 dpc), indicating that CUL-4A?/? embryos die between 4.5 and 7.5 dpc. Despite 87% similarity between the Cul-4A and Cul-4B cullins, the CUL-4A?/? lethal phenotype indicates that CUL-4A has one or more distinct function(s). Surprisingly, 44% fewer heterozygous pups were recovered than expected by Mendelian genetics, indicating that many heterozygous embryos also die during gestation due to haploinsufficiency. Taken together, our findings indicate that appropriate CUL-4A expression is critical for early embryonic development.
机译：泛素介导的降解作用靶向细胞周期调节剂进行蛋白水解。 E3泛素连接酶赋予了泛素途径许多底物特异性，而cullins是某些E3的核心成分。 CUL-4A 编码六种哺乳动物花粉蛋白之一，在乳腺癌中被扩增和/或过表达，提示其在调节细胞周期进程中的作用。为了检查 CUL-4A 的生理功能，我们在小鼠中产生了 CUL-4A 缺失突变。早在交配后（dpc）7.5天，没有发现存活的 CUL-4A ？/？幼仔，也没有纯合突变体胚胎。但是， CUL-4A ？/？胚泡是可行的，孵化，形成内部细胞团和滋养外胚层并植入（约4.5 dpc），表明 CUL -4A ？/？胚胎死于4.5至7.5 dpc之间。尽管Cul-4A和Cul-4B cullins之间有87％的相似性，但 CUL-4A ？/？致死表型表明 CUL-4A 具有一个或多个不同的功能。出人意料的是，杂合幼崽的回收率比孟德尔遗传学所预期的少44％，这表明许多杂合子胚也由于单倍体机能不全而在妊娠期间死亡。综上所述，我们的发现表明适当的 CUL-4A 表达对于早期胚胎发育至关重要。

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