COUP-TFII is an orphan nuclear receptor that belongs to the steroid receptor superfamily. Ablation of COUP-TFII in mice results in early embryonic lethality due to defects in angiogenesis and heart development. To further understand the biological functions of COUP-TFII in vascular and heart development, LacZ knock-in and floxed COUP-TFII mice were generated. X-Gal staining of the LacZ knock-in mice shows high COUP-TFII expression in the endothelium of the vein but not in the artery. Further, chimera analysis showed that COUP-TFII plays a cell autonomous function in the endothelial cells of the vein but not the artery. These studies show for the first time that COUP-TFII is an essential transcription factor for vein identify. The insertion of loxP site into the COUP-TFII locus reduced the expression of COUP-TFII, rendering the COUP-TFII flox/- mutants genetically hypomorphic. The hypomorphic mutants exhibit atrioventricular septal defects (AVSD) commonly observed in congenital heart disease patients. The atrium malformation displayed by the COUP-TFII null mutant coupled with AVSD elicited by the hypomorphic mutant together suggest that COUP-TFII plays a critical role in cardiogenesis. Whether the heart defects are intrinsic or secondary to the vascular defects is currently unknown. Proper heart development requires the coordinated interactions between the endocardium and myocardium. Whether the endothelial cells in the endocardium or the myocardial cells in the myocardium are the targets of COUP-TFII regulation is also unclear. To elucidate the role of COUP-TFII in the maintenance of vein identity and in heart development, two Specific Aims are proposed.
In Aim 1, we will employ gain-of-function and loss-of-function of COUP-TFII in the endothelial cells to examine the role of COUP-TFII in the maintenance of arteriovenous identity. In addition, we will use DMA chip microarray analysis to identify novel downstream targets and signaling pathways that are regulated by COUP-TFII in the arteriovenous decision.
In Aim 2, we will use the hypomorphic mutant and the endothelial and myocardial conditional COUP-TFII knockouts to investigate the role of COUP-TFII in heart development. This study will enable us to determine how endothelial COUP-TFII versus myocardial COUP-TFII affects cardiogenesis and how COUP-TFII modulates the interaction between the myocardium and endocardium. Our proposed studies should provide timely new insights into how COUP-TFII impacts cardiovascular development and facilitate the diagnosis and treatment of congenital heart disease. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Schramm, Charlene A
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Zhao, Fei; Franco, Heather L; Rodriguez, Karina F et al. (2017) Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357:717-720
Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9
Qin, Jun; Wu, San-Pin; Creighton, Chad J et al. (2013) COUP-TFII inhibits TGF-?-induced growth barrier to promote prostate tumorigenesis. Nature 493:236-40
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Chen, Xinpu; Qin, Jun; Cheng, Chiang-Min et al. (2012) COUP-TFII is a major regulator of cell cycle and Notch signaling pathways. Mol Endocrinol 26:1268-77
Mayer, Sandra; Roeser, Marc; Lachmann, Peter et al. (2012) Chicken ovalbumin upstream promoter transcription factor II regulates renin gene expression. J Biol Chem 287:24483-91
Tang, Ke; Rubenstein, John L R; Tsai, Sophia Y et al. (2012) COUP-TFII controls amygdala patterning by regulating neuropilin expression. Development 139:1630-9
Lin, Fu-Jung; You, Li-Ru; Yu, Cheng-Tai et al. (2012) Endocardial cushion morphogenesis and coronary vessel development require chicken ovalbumin upstream promoter-transcription factor II. Arterioscler Thromb Vasc Biol 32:e135-46
Yu, Cheng-Tai; Tang, Ke; Suh, Jae Mi et al. (2012) COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival. Development 139:2330-9

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