COUP-TFI and II are members of the orphan subgroup of the steroid/thyroid hormone receptor superfamily. Although COUP-TFs are well characterized biochemically, the precise physiological roles of COUP-TFs are largely undefined. Mutational analysis and ectopic expression of COUP-TFs in flies and frogs suggest that COUP-TFs are important for survival during embryonic development. Although the expression patterns of COUP-TFI and COUP-TFII overlap in some regions, each factor possesses its own distinct expression profile and, hence a unique specific physiological role. The temporal and spatial expression pattern of COUP-TFII in the mesenchyme of many developing organs, including kidney, suggests that COUP-TFII is important for organogenesis via mesenchymal-epithelial interactions. To assess the molecular and physiological roles of COUP-TFII in development and organogenesis, we have generated COUP-TFII null mutant mice by homologous recombination. Mice deficient of COUP-TFII die before E10.0 with striking fetal vasculature defects. The aberrant vasculature formation in the COUP-TFII null mutants suggests COUP-TFII either directly regulates periendothelial cell differentiation or regulates endothelial cells through paracrine signals. In either event, it may be hypothesized that COUP-TFII is important for mesenchyme-epithelial interactions in formation of embryonic vasculature. Since the COUP-TFII deficient mutants die prior to kidney formation, it is necessary to generate a kidney-specific knock out in order to evaluate the role of COUP-TFII in nephrogenesis. To facilitate the identification of a kidney-specific COUP-TFII promoter, we need to study possible tissue-specific regulation of COUP-TFII. Finally, we have recently shown that COUP-TFII is regulated by sonic hedgehog (Shh), a key morphogen controlling pattern formation and mesenchymal-epithelial interactions. Thus, we will identify the factor(s) which mediates the sonic hedgehog response. We believe that this is a timely proposal, and that results obtained from the studies will define the role of COUP-TFII in mesenchymal-epithelial interactions during organogenesis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Endocrinology Study Section (END)
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Margolis, Ronald N
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Lee, Kevin Y; Jeong, Jae-Wook; Tsai, Sophia Y et al. (2007) Mouse models of implantation. Trends Endocrinol Metab 18:234-9
Lee, Kevin Y; Jeong, Jae-Wook; Wang, Jinrong et al. (2007) Bmp2 is critical for the murine uterine decidual response. Mol Cell Biol 27:5468-78
Lee, Kevin; Jeong, JaeWook; Kwak, Inseok et al. (2006) Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet 38:1204-9
Takamoto, Norio; Kurihara, Isao; Lee, Kevin et al. (2005) Haploinsufficiency of chicken ovalbumin upstream promoter transcription factor II in female reproduction. Mol Endocrinol 19:2299-308
You, Li-Ru; Takamoto, Norio; Yu, Cheng-Tai et al. (2005) Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc Natl Acad Sci U S A 102:16351-6
Takamoto, Norio; You, Li-Ru; Moses, Kelvin et al. (2005) COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development 132:2179-89
Zhou, Hai-Jun; Yan, Jun; Luo, Weiping et al. (2005) SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res 65:7976-83
Lee, Christopher T; Li, Luoping; Takamoto, Norio et al. (2004) The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Mol Cell Biol 24:10835-43
Yamaguchi, Hideki; Zhou, Cheng; Lin, Song-Chang et al. (2004) The nuclear orphan receptor COUP-TFI is important for differentiation of oligodendrocytes. Dev Biol 266:238-51
Ichikawa, H; Lin, S-C; Tsai, S Y et al. (2004) Effect of mCOUP-TF1 deficiency on the glossopharyngeal and vagal sensory ganglia. Brain Res 1014:247-50

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