Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε
Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε
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DOI：
10.1128/mcb.25.6.2191-2199.2005
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发表时间：
2005-03-01
影响因子：
5.3
通讯作者：
Kataoka, T
中科院分区：
文献类型：
--
作者：
Tadano, M;Edamatsu, H;Kataoka, T
磷脂酶C是一类新的肌醇特异性磷脂酶C，被鉴定为Ras和Rap小GTP酶的下游效应子。我们在这里报告的第一个遗传分析的生理功能与小鼠的磷脂酶C370是催化失活的基因靶向。靶向等位基因纯合子小鼠的心脏发生主动脉瓣和肺动脉瓣的先天性畸形，其引起中度至重度反流伴轻度狭窄并导致心室扩张。该畸形包括瓣叶明显增厚，这似乎是由半月瓣形成晚期瓣膜重塑缺陷引起的。这种表型与携带减弱的表皮生长因子受体或缺乏肝素结合表皮生长因子样生长因子的小鼠的表型有显著的相似性。Smad 1/5/8，这是在下游的骨形态发生蛋白的瓣膜细胞的增殖有牵连，显示异常激活在边缘的发育半月瓣组织在胚胎缺乏磷脂酶C β。这些结果表明，在控制半月瓣膜通过抑制骨形态发生蛋白信号传导的表皮生长因子受体的磷脂酶C17下游的关键作用。
Phospholipase Cepsilon is a novel class of phosphoinositide-specific phosphollipase C, identified as a downstream effector of Ras and Rap small GTPases. We report here the first genetic analysis of its physiological function with mice whose phospholipase Cepsilon is catalytically inactivated by gene targeting. The hearts of mice homozygous for the targeted allele develop congenital malformations of both the aortic and pulmonary valves, which cause a moderate to severe degree of regurgitation with mild stenosis and result in ventricular dilation. The malformation involves marked thickening of the valve leaflets, which seems to be caused by a defect in valve remodeling at the late stages of semilunar valvulogenesis. This phenotype has a remarkable resemblance to that of mice carrying an attenuated epidermal growth factor receptor or deficient in heparin-binding epidermal growth factor-like growth factor. Smad1/5/8, which is implicated in proliferation of the valve cells downstream of bone morphogenetic protein, shows aberrant activation at the margin of the developing semilunar valve tissues in embryos deficient in phosphollipase Cepsilon. These results suggest a crucial role of phosphollipase Cepsilon downstream of the epidermal growth factor receptor in controlling semillunar vaivulogenesis through inhibition of bone morphogenetic protein signaling.