期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 32, 期 11, 页码 E135-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.300255
关键词
atrioventricular septal defect; cardiac morphogenesis; chicken ovalbumin upstream promoter-transcription factor II; epicardium; epithelial-mesenchymal transformation
资金
- National Science Council of Taiwan [NSC98-2320-B-010-010-MY3]
- Ministry of Education, Aim for the Top University Plan
- National Heart, Lung, and Blood Institute [R01 HL076448]
- National Institute of Child Health and Human Development [R01 HD17379]
- National Institute of Diabetes and Digestive and Kidney Disease [R01 DK45641, P01 DK059820, U19 DK062434]
- core facilities of Diabetes and Endocrinology Research Center [DK079638]
Objective-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. Methods and Results-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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2012;32:e135-e146.)
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