title: Endocardial cushion morphogenesis and coronary vessel development require chicken ovalbumin upstream promoter-transcription factor II.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Fu-Jung
authors.initials: FJ
authors.lastname: Lin
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: You
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Yu
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Hsu
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D003331:Coronary Vessels / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D054089:Endocardial Cushions / Q000196:embryology / Q000378:metabolism; D004699:Endocardium / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D010496:Pericardium / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D000071250:Snail Family Transcription Factors; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D051837:COUP Transcription Factor II; D015820:Cadherins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099152:Cadherin 5; C497587:Nr2f2 protein, mouse; C000604429:Snai1 protein, mouse