Essential role of synoviolin in embryogenesis
Essential role of synoviolin in embryogenesis
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DOI：
10.1074/jbc.m410863200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Nakajima, T
中科院分区：
文献类型：
--
作者：
Yagishita, N;Ohneda, K;Nakajima, T
我们最近报道了Synoviolin通过内质网（ER）相关降解（ERAD）系统在蛋白质质量控制中的重要性，以及通过其抗凋亡作用参与关节病的发病机制。为了进一步了解滑膜素在体内的作用，我们在本研究中通过基因靶向破坏产生滑膜素缺陷（syno（-/-）0）小鼠。引人注目的是，所有缺乏Syno的胎儿在胚胎第13.5天左右死于子宫内，尽管Hrd 1 p，一种Synoviolin的酵母直向同源物，对生存来说不是必需的。组织学上，syno（-/-）胎肝细胞减少和异常凋亡。此外，定型红细胞生成在syno（-/-）胚胎中以非细胞自主方式受到影响，导致子宫内死亡。来自syno（-/-）小鼠的培养胚胎成纤维细胞比来自syno（+/+）小鼠的培养胚胎成纤维细胞更容易受到内质网应激诱导的凋亡，但这种易感性可通过过度表达滑膜蛋白来挽救。我们的研究结果强调了Synoviolin在胚胎发生中不可或缺的作用。
We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno(-/-)0 mice by gene-targeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno(-/-) fetal liver. Moreover, definitive erythropoiesis was affected in noncell autonomous manner in syno(-/-) embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno(-/-) mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno(+/+) mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.