F-Actin Remodeling at Newly Forming Cell-Cell Junctions

描述(由申请人提供)： 上皮细胞板驱动形态发生，在成人组织中，完整的上皮细胞在组织间提供活跃的屏障。这些功能需要上皮细胞被极化，而这种极化取决于细胞与细胞和细胞与基质的粘附性。细胞-细胞黏附的丧失会导致几种人类疾病，包括退行性皮肤起泡疾病、囊性肾脏疾病和癌症。事实上，细胞黏附的减弱与恶性细胞的侵袭性直接相关；而癌症的侵袭性是通过挽救细胞与细胞的黏附来对抗的。鉴于细胞与细胞之间的黏附对上皮细胞的正常和病理生理的必要性，了解细胞与细胞的连接是如何组装和维持的具有生物学和临床意义。这项拟议工作的目的是研究肌动蛋白在果蝇胚胎初级上皮细胞-细胞连接组装/稳定中所起的作用。具体地说，Nullo是一种细胞-细胞连接蛋白，可以协调膜插入和连接处的肌动蛋白重塑，将使用高时间和空间分辨率的共聚焦显微镜(三维和四维)来研究Nullo的功能。这项工作的目标是1)在这个模型系统中描述细胞-细胞连接的组装/维持与肌动蛋白动力学的关系，以及2)展示一种细胞机制，通过在连接处插入膜来协调连接处肌动蛋白的重塑。

DESCRIPTION (provided by applicant): Epithelial cell sheets drive morphogenesis, and in adult tissues intact epithelia provide active barriers between tissue compartments. These functions require cells of the epithelia to be polarized and this polarity depends on the adhesion of cells-to-cells and cells-to-substrate. Loss of cell-cell adhesion precipitates several human disorders including, degenerative skin blistering diseases, cystic kidney diseases and cancer. In fact, diminished cell adhesion directly correlates with invasiveness of malignant cells; and invasiveness of carcinomas is countered by rescuing cell-cell adhesion. Given the necessity of cell-cell adhesion to the normal and pathological physiology of epithelia, knowing how cell-cell junctions are assembled and maintained is biologically and clinically significant. The Aims of this proposed work address the role played by actin in assembly/stability of cell-cell junctions in the primary epithelium of the Drosophila embryo. Specifically, the function of Nullo, a cell-cell junction protein that may coordinate membrane insertion with actin remodeling at junctions, will be studied using high-temporal and -spatial resolution confocal microscopy (3-dimensional and 4-dimensional). The goals of the work are 1) to characterize assembly/maintenance of cell-cell junctions with respect to actin dynamics in this model system, and 2) to demonstrate a cellular mechanism whereby membrane insertion at junctions orchestrates actin remodeling at junctions.