DOCK/ELMO复合体诱导细胞顶端-基底极性发生起始的分子机制

细胞极性是生物中广泛存在的一个特征，对细胞迁移、组织器官形成等众多生物学过程起着关键性作用。细胞极性建立与维持依赖于一系列极性蛋白之间的正反馈和拮抗作用。然而对极性建立的起始事件，尤其是微管触发的极性建立机制，目前还缺乏深入研究。我们前期研究表明具有RhoGEF活性的DOCK/ELMO复合体位于极性建立信号通路的上游，且与微管存在互作，是一个潜在的偶联微管和极性建立的关键分子。然而对具体的分子机制，缺乏系统的研究。海洋模式生物海鞘基因组结构简单，细胞体积大，是研究极性建立的理想模型。本项目以海鞘脊索为模型，研究DOCK/ELMO与微管的空间分布关系，DOCK/ELMO对微管的响应机制，以及该复合体RhoGEF活性调控机制和底物选择的分子机制等。通过以上研究，我们将阐明微管调控DOCK/ELMO的分子机理，揭示微管在细胞极性建立初始的作用机理，完善我们对细胞极性建立的调控网络的认识和理解。

Cell polarity is defined by the establishment of distinct functional domains in the plasma membrane and cytoplasm, and is necessary for diverse biological processes such as cell differentiation, migration, asymmetric division and morphogenesis. The establishment and maintenance of cell polarity are extensively studied, and the positive feedback loops and antagonism between diametric signaling modules are known being essential during these processes. However, the molecular nature of the initiation of cell polarity is largely not characterized, especially the mechanism of how microtubules trigger the cell polarity establishment is not well understood. Our previous work has shown that the unconventional RhoGEF DOCK/ELMO complex regulates the polarity establishment via controlling the localization of Par3. DOCK/ELMO has been known binding to microtubules, which implies that DOCK/ELMO complex might bridge the gap between microtubules and cell polarity establishment. The molecular mechanism is not clear yet. Marine model organism, ascidian, Ciona intestinalis is an ideal model to investigate the regulation of DOCK/ELMO complex in the notochord cell polarity establishment, owing to the big size of notochord cell and the simple genome. Our studies are designed to reveal how DOCK/ELMO complex links the microtubule and cell polarity by the following aspects: the spatiotemporal and functional relations between microtubules and DOCK/ELMO complex; the regulation mechanism of RhoGEF activity and the substrate selection. Our research project aims to reveal the molecular mechanism of that how microtubules trigger the polarity establishment via DOCK/ELMO complex. Our proposed research will shed new lights on the understanding of the initiation of cell polarity establishment and provide a comprehensive framework of cell polarity establishment.