Tbx20 is essential for cardiogenesis, and may be a human disease gene. We have identified two direct targets for repression and activation by Tbx20 in developing heart: tbx2 and Nmyc1. Interplay between these three transcription factors explains proliferative defects and aberrant chamber gene expression in tbx20 null mice. Nmyc1 and Tbx2 are essential for cardiac proliferation and specification. Consensus t-box elements within Nmyc1 and tbx2 promoters were identified, and tested in vitro, but their requirement in vivo has not been established. Nmyc1 is activated by Tbx20 and repressed by Tbx2. In regions where Tbx20, Tbx2, or other highly related Tbx proteins are coexpressed they may cooperate to regulate Nmyc1. Although tbx2 is repressed by Tbx20 in chamber myocardium, both proteins are coexpressed in outflow tract and atrioventricular canal, suggesting context dependent regulation by cofactor interaction. Tbx20 is highly expressed in endocardium and myocardium throughout development, and in adult heart, at high levels in the region of the developing valves and conduction system. From the foregoing, our hypotheses are: (1) Identified t-box consensus sites within Nmyc1 and tbx2 promoters are required for cardiac expression in vivo, and regulation of these promoters by Tbx20 is dependent on interaction with other cofactors, including other Tbx proteins; (2) Tbx20 is required within distinct tissues at distinct times for multiple aspects of heart development, including a critical role in valve formation, conduction system formation and function, and adult heart function. To test these hypotheses, we will generate transgenic mice to verify in vivo requirements for conserved t-box elements within Nmyc1 and tbx2 promoters. We will also investigate interactions between Tbx20 and candidate cofactors, including other Tbx proteins, in regulating tbx2 and Nmyc1 by in vitro transfections and biochemical studies. To define tissue specific requirement for Tbx20 in myocardium or endothelium at distinct stages in heart development and adult heart, we will utilize myocardial and endothelial specific Cre mouse lines, and inducible myocardial and endothelial-specific Cre lines to ablate tbx20. Histological and functional analyses will be performed on resulting mutants. Tbx20, Tbx2 and Nmyc1 play essential roles in heart development, and Tbx2 and Nmyc1 play critical roles in tumor cells, suggesting that results of our studies will be of significance for congenital heart disease, and potentially cancer. ? ? ?
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