Cell polarity and embryonic heart development

心脏是所有脊椎动物的第一个功能器官，由三个不同的细胞群组成：第一心域、第二心域(SHF)和心脏神经脊。心脏发育受一系列相互作用的转录因子的调节，包括NKX2.5、Gata4、Tbx5和MEF2C。值得注意的是，NKX2.5是NK同源框基因家族的成员，是脊椎动物胚胎中最早的心肌细胞特异性标记之一。冠状动脉主要来源于几种前体来源，包括心外膜器官(PEO)和心外膜，其来源包括静脉窦内皮细胞和心内膜。最初，来自PEO的细胞向心肌迁移并形成心外膜。心外膜细胞亚群经历上皮到间充质转化(EMT)，迁移到心肌，形成血管平滑肌细胞和成纤维细胞，而心外膜下内皮祖细胞形成冠状动脉内皮细胞。Wilms Tumour-1(Wt1)是一种对心外膜内膜上皮细胞转化和冠状动脉血管生成起关键作用的转录因子。*细胞极性是指细胞在形状、方向或结构上的空间不对称性，包括顶端-基底、前后和平面的极性。Rac1是RAC小GTP酶家族中的一员，它调节包括细胞极性在内的许多细胞过程。我们最近证实，SHF特异性缺失的rac1基因会导致祖细胞组织异常，心肌细胞伸长受损，流出道和心间隔畸形。本研究的目的是研究rac1在小鼠心脏器官发生和冠状动脉血管形成中的心肌细胞和心外膜的特殊作用。*假设：rac1对心肌和冠状动脉的发育都是至关重要的。靶向阻断这些谱系中的rac1表达将导致不同的心脏和冠状动脉畸形。*目标1将研究rac1在心肌细胞极性和心脏发育中的作用。目的2研究rac1在心外膜极性、EMT和冠脉血管生成中的作用。心脏形态发生和冠状动脉形成将使用转基因小鼠模型进行研究。分子和细胞技术将被用来阐明潜在的机制。拟议的研究将为在胚胎心脏发育过程中，rac1在细胞极性、EMT和心脏/冠状动脉形态发生中的作用提供新的见解。**

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.**