Cell polarity and embryonic heart development

心脏是所有脊椎动物中第一个发挥功能的器官，由三种不同的细胞群发育而成：第一心区、第二心区（SHF）和心脏神经嵴。心脏发育受一系列相互作用的转录因子调控，包括Nkx2.5、Gata 4、Tbx 5和Mef 2c。值得注意的是，NK同源框基因家族的成员Nkx2.5是脊椎动物胚胎中最早的心肌细胞特异性标志物之一。** 冠状动脉主要由几个祖细胞来源发育而成，包括心外膜器官（PEO）和心外膜，静脉窦和内膜的内皮细胞也有贡献。最初，来自PEO的细胞向心肌迁移并形成心外膜。心外膜细胞的一个亚群经历上皮-间充质转化（EMT），迁移到心肌并产生血管平滑肌细胞和成纤维细胞，而心外膜下内皮祖细胞产生冠状动脉内皮细胞。对心外膜EMT和冠状动脉血管生成至关重要的转录因子是Wilms肿瘤-1（Wt 1）。细胞极性是指细胞在形状、方向或结构上的空间不对称性，包括顶基极性、前后极性和平面极性。Rac 1是Rac small GT3家族的一员，调节包括细胞极性在内的许多细胞过程。我们最近发现，SHF特异性Rac 1缺失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Rac 1在小鼠心脏器官发生和冠状动脉血管发生中的心肌细胞和心外膜特异性作用。** 假设：Rac 1对心肌和冠状动脉发育至关重要。在这些谱系中的每一个中靶向破坏Rac 1表达将引起不同的心脏和冠状动脉畸形。目的1研究Rac 1在心肌细胞极性和心脏发育中的作用。目的2探讨Rac 1在心外膜极性、EMT和冠状动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基因修饰的小鼠模型进行研究。 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Rac 1在胚胎心脏发育过程中的细胞极性，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.**