Endocardial cushion morphogenesis and coronary vessel development require chicken ovalbumin upstream promoter-transcription factor II.
Endocardial cushion morphogenesis and coronary vessel development require chicken ovalbumin upstream promoter-transcription factor II.
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DOI：
10.1161/atvbaha.112.300255
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Tsai SY
中科院分区：
文献类型：
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作者：
Lin FJ;You LR;Yu CT;Hsu WH;Tsai MJ;Tsai SY
间隔缺损和冠状血管异常是常见的先天性心脏病，但其个体发育和潜在的遗传机制还没有很好的理解。在这里，我们研究了鸡卵清蛋白上游启动子转录因子II（COUP-TFII，NR 2F 2）在心脏器官发生中的作用。我们分析了COUP-TFII缺陷的胚胎，并观察到一系列心脏缺陷，包括房室间隔缺损、薄壁心肌和异常冠状动脉形态发生。我们通过表达分析表明，COUP-TFII在心内膜和心外膜中表达，但不在心室的心肌中表达。使用内皮特异性COUP-TFII突变体和分子方法，我们发现COUP-TFII缺乏导致内膜垫发育不全。这是由于房室垫间充质细胞的生长和存活减少以及潜在内膜中的上皮-间充质转化（EMT）缺陷。此外，内皮细胞EMT缺陷伴随着Snai 1（EMT的主要调节因子之一）的下调和血管内皮钙粘蛋白的上调。此外，我们表明，虽然COUP-TFII不发挥主要作用，心外膜细胞囊肿的形成，它是至关重要的心外膜的形成。COUP-TFII消融损害心外膜EMT和冠状动脉丛形成。我们的研究结果表明，COUP-TFII在心内膜和心外膜中起着细胞自主作用，用于心内膜和心外膜EMT，这是心脏发育过程中正确的瓣膜和冠状血管形成所必需的。
Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis. We analyzed embryos deficient in COUP-TFII and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific COUP-TFII mutants and molecular approaches, we show that COUP-TFII deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of Snai1, one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation. Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.