Cell polarity and embryonic heart development

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The heart is the first organ to function in all vertebrates, and is developed from three distinct populations of cells: the first heart field, the second heart field (SHF) and the cardiac neural crest. Heart development is regulated by a cascade of interacting transcription factors, including Nkx2.5, Gata4, Tbx5 and Mef2c. Notably, Nkx2.5, a member of the NK homeobox gene family, is one of the earliest cardiomyocyte specific markers in vertebrate embryos. ******Coronary arteries are mainly developed from several progenitor sources including the proepicardial organ (PEO) and the epicardium with contributions from the endothelial cells of sinus venosus and the endocardium. Initially, cells from the PEO migrate toward the myocardium and form the epicardium. A subset of epicardial cells undergo epithelial-to-mesenchymal transition (EMT), migrate to the myocardium and give rise to vascular smooth muscle cells and fibroblasts while subepicardial endothelial progenitors give rise to coronary endothelial cells. A transcription factor critical to epicardial EMT and coronary vasculogenesis is Wilms tumour-1 (Wt1).******Cell polarity refers to spatial asymmetries in the shape, orientation or structure of cells, and includes apical-basal, front-rear and planar polarity. Rac1, a member of the Rac small GTPase family, regulates many cellular processes including cell polarity. We recently demonstrated that SHF specific deletion of Rac1 results in aberrant progenitor cellular organization, impairment of cardiomyocyte elongation, and malformation of outflow tract and the cardiac septum. The goal of the present proposal is to study cardiomyocyte and epicardial specific roles for Rac1 in heart organogenesis and coronary vasculogenesis in mice. ******Hypothesis: Rac1 is critical to both myocardial and coronary artery development. Targeted disruption of Rac1 expression in each of these lineages will give rise to distinct heart and coronary artery malformations.******Aim 1 will study the role of Rac1 in cardiomyocyte polarity and heart development. Aim 2 will investigate the role of Rac1 in epicardial polarity, EMT and coronary vasculogenesis. Heart morphogenesis and coronary artery formation will be studied using genetically modified mouse models. Molecular and cellular techniques will be employed to shed light on the underlying mechanisms. The proposed studies will provide new insight on the role of Rac1 in cell polarity, EMT and heart/coronary morphogenesis during embryonic heart development.**