Congenital diaphragmatic hernia (CDH), a life-threatening birth defect, is a major cause of pediatric mortality and mobility. The pathological anomalies are characterized by the inappropriate protrusion of the abdominal contents, possibly including the stomach, liver, intestines and spleen, through an improperly formed diaphragm into the thoracic cavity which impairs lung growth and development. In addition to the secondary defect resulting from protrusion of abdominal contents, lung development itself may be also effected and contribute to CDH phenotypes in these patients. Although the disease was described more than 350 years ago, the etiology of CDH is poorly understood. Using a conditional null mutant in which COUP-TFII is deleted in the mesentery, we showed that tissue specific null mutants of COUP-TFII exhibit Bochdalek CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm and lung during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the post-hepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Recently a critical region within 15q26.1-26.2 has been mapped by array CGH and Fish analysis to be deleted in CDH patients. COUP-TFII is one of the four known genes resided within this critical region. Together with results of our COUP-TFII conditional mutants, the genetic analysis implicates COUP-TFII as most likely candidate gene for the most common type of Bochdalek CDH. To delineate how COUP-TFII regulates diaphragm and lung development and how perturbation of proper diaphragm formation might result in CDH, three specific aims are proposed: 1). Analysis of the defects exhibited by the conditional null mice during diaphragm development; 2). Analyze the role of COUP-TFII in lung development and its relationship to CDH; 3). Screen and characterize COUP-TFII mutations in CDH patients. With the proposed study, we hope to provide important insights on morphogenesis of the diaphragm and lung and how malformation of these organs leads to such devastating congenital defects. And eventually, by screening CDH patients for the mutations in COUP-TFII, it will certainly improve the translational prospect in setting up a diagnostic kit and devise an intervention for some CDH patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD017379-23
Application #
7383205
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Winer, Karen
Project Start
1983-02-01
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
23
Fiscal Year
2008
Total Cost
$392,289
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wu, San-Pin; Kao, Chung-Yang; Wang, Leiming et al. (2015) Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat Commun 6:8245
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
Lin, Fu-Jung; Qin, Jun; Tang, Ke et al. (2011) Coup d'Etat: an orphan takes control. Endocr Rev 32:404-21
Xie, Xin; Qin, Jun; Lin, Sue-Hwa et al. (2011) Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation. Proc Natl Acad Sci U S A 108:14843-8
Qin, Jun; Chen, Xinpu; Xie, Xin et al. (2010) COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci U S A 107:3687-92
Lin, Fu-Jung; Chen, Xinpu; Qin, Jun et al. (2010) Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J Clin Invest 120:1694-707
Tang, Ke; Xie, Xin; Park, Joo-In et al. (2010) COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 137:725-34
Lee, Dong-Kee; Kurihara, Isao; Jeong, Jae-Wook et al. (2010) Suppression of ERalpha activity by COUP-TFII is essential for successful implantation and decidualization. Mol Endocrinol 24:930-40

Showing the most recent 10 out of 54 publications