The long-term goal of the proposal is to understand the fundamental mechanisms through which GATA factors control development of the heart. Recently we have produced mouse embryos from embryonic stem (ES) cells in which both Gata4 and Gata6 genes, which encode zinc finger transcription factors, were simultaneously disrupted. Examination of these embryos revealed that cardiac myocyte differentiation was completely blocked and the resulting embryos exhibited acardia. Although these data are provocative we do not know i) whether this requirement for either GATA4 or GATA6 during the onset of heart cell differentiation is conserved in humans, ii) whether redundant roles for GATA4 and GATA6 also exist for maintaining cardiac myocyte gene expression in terminally differentiated cardiac myocytes, or iii) if the dependency of cardiac myocyte differentiation on both GATA4 and GATA6 reflects only a cell autonomous role. These questions will be addressed in three specific aims:
Aim 1 : Do GATA4 and GATA6 have evolutionary conserved roles in controlling cardiac myocyte differentiation? The evolutionary conservation of the roles of GATA4 and GATA6 during development will be examined using human ESCs as a model of cardiomyocyte specification and differentiation.
Aim 2 : Do GATA4 and GATA6 have functionally redundant roles in controlling a transcription factor network that is essential for maintaining cardiac myocyte gene expression? This will be tested using a combination of gene array and chromatin immunoprecipitation analyses on primary cardiomyocytes in which GATA4, GATA6, or both GATA4 and GATA6 have been ablated.
Aim 3 : Do GATA 4 and GATA6 act in multiple tissues to ensure the completion of cardiogenesis? The role of GATA4 and GATA6 in the cardiac myocytes and endoderm will be evaluated using conditional knockout mice and human ES cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Medical College of Wisconsin
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Kolander, Kurt D; Holtz, Mary L; Cossette, Stephanie M et al. (2014) Epicardial GATA factors regulate early coronary vascular plexus formation. Dev Biol 386:204-15
Lakshmikanthan, Sribalaji; Zieba, Bartosz J; Ge, Zhi-Dong et al. (2014) Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. Arterioscler Thromb Vasc Biol 34:1486-94
Fisher, Joseph B; Kim, Min-Su; Blinka, Steven et al. (2012) Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes. PLoS One 7:e31569
Van Orman, Jordan R; Si-Tayeb, Karim; Duncan, Stephen A et al. (2012) Induction of cardiomyogenesis in human embryonic stem cells by human embryonic stem cell-derived definitive endoderm. Stem Cells Dev 21:987-94
Auchampach, John A; Maas, Jason E; Wan, Tina C et al. (2011) Are we putting too much stock in mice? J Mol Cell Cardiol 50:584-5
Si-Tayeb, Karim; Noto, Fallon K; Sepac, Ana et al. (2010) Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev Biol 10:81
Si-Tayeb, Karim; Noto, Fallon K; Nagaoka, Masato et al. (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51:297-305
Van Orman, Jordan R; Weihrauch, Dorothee; Warltier, David C et al. (2009) Myocardial interstitial fluid inhibits proliferation and cardiomyocyte differentiation in pluripotent embryonic stem cells. Am J Physiol Heart Circ Physiol 297:H1369-76