Members of the steroid/thyroid receptor superfamily have been shown to be important for the regulation of target genes essential for cellular differentiation and development. In our laboratory, we have concentrated on the elucidation of physiological functions of COUP-TFs. A null mutation of the COUP-TFI gene in mice has been generated in our laboratory through the support of this grant. These animals display many defects in the peripheral and central nervous system (PNS and CNS). In the PNS, we have determined that differentiation of ganglia IX is compromised resulting in the apoptosis of neural crest derived superior ganglia (1). In addition, we observed defects in axon arborization and guidance. In the CNS, COUP-TFI mutation results in the malformation of cortical layers and hippocampus, defects in axon myelination and failure of corpus callosum and hippocampal commissures to cross the midline. Furthermore, we also detected defects in bone morphogenesis and development of the inner ear (see preliminary results). In the next grant period, we would like to determine the underlying mechanisms for these defects and identify the COUP-TFI target genes responsible. Finally, we would like to determine which signals regulate the expression of the COUP-TFI gene in a spatio- and temporal-specific manner. To achieve these goals, we propose the following three specific aims: 1. Characterization of the COUP-TFI mutant mice for cortical layer and axonal myelination defects; 2. Identification of signals regulating the COUP-TFI gene expression in transgenic animals; 3. Isolation and characterization of COUP-TFI target genes for rescue COUP-TFI phenotypes. It is expected that the understanding derived from this project will be relevant to the biology of development and differentiation. The proposed studies will also be pertinent to the development of more precise theories for the biochemical mechanism of action of hormones and their receptors.
| 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 |
| Lee, Hui-Ju; Kao, Chung-Yang; Lin, Shih-Chieh et al. (2017) Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Sci Rep 7:3136 |
| Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer (2016) COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest 126:3929-3941 |
| Wu, San-Pin; Yu, Cheng-Tai; Tsai, Sophia Y et al. (2016) Choose your destiny: Make a cell fate decision with COUP-TFII. J Steroid Biochem Mol Biol 157:7-12 |
| 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 |
| Xu, Mafei; Qin, Jun; Tsai, Sophia Y et al. (2015) The role of the orphan nuclear receptor COUP-TFII in tumorigenesis. Acta Pharmacol Sin 36:32-6 |
| Qin, Jun; Lee, Hui-Ju; Wu, San-Pin et al. (2014) Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 124:5013-26 |
| Bosch, Daniëlle G M; Boonstra, F Nienke; Gonzaga-Jauregui, Claudia et al. (2014) NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet 94:303-9 |
| 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 |
| Xie, Xin; Tang, Ke; Yu, Cheng-Tai et al. (2013) Regulatory potential of COUP-TFs in development: stem/progenitor cells. Semin Cell Dev Biol 24:687-93 |
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