Signaling Mechanisms Controlling Planar Cell Polarity

描述(申请人提供)：与顶端-基底轴垂直的上皮细胞极性，称为平面细胞极性(PCP)，对各种发育事件至关重要，包括细胞不对称分裂的定向和平面极化细胞阵列的产生，例如耳蜗毛细胞顶面动纤毛和立体纤毛的不对称显示所产生的极化阵列。在过去的六年里，我们一直在研究五氯苯酚的规格，以黑腹果蝇为模型系统。我们发现，细胞极化是由细胞顶端侧膜中七次跨膜蛋白Frizzled1和其他蛋白质的不对称积累所介导的，我们还确定了一种机制，即介导Frizzled七次跨膜蛋白在相邻细胞的相反膜上的竞争。这种Frizzled型竞争起到放大初始不对称信号的作用，并通过确保相邻细胞的局部排列来提供保真机制，从而加强整个细胞领域的统一极性。我们还鉴定了一组蛋白质，它们通过偏向Frizzleed竞争的方向和相对于组织轴定位PCP来提供全球方向信号。虽然这些机制的总体组织现在是显而易见的，但主要问题仍然是关于调节FrizzledTM竞争的分子机制，以及关于全球定向信号的组织和转导。我们建议通过结合遗传、分子和细胞生物学的方法来研究这些机制。我们将解决与FrizzledTM竞争机制有关的两个具体问题，我们将研究全球定向信号系统中以前已识别但尚未表征的组件，以及我们实验室在筛选新信号组件时确定的几个新组件的特征。

DESCRIPTION (provided by applicant): Epithelial cell polarity orthogonal to the apical-basal axis, referred to as Planar Cell Polarity (PCP), is critical for a variety of developmental events, including the orientation of asymmetric cell divisions and the generation of planar polarized cellular arrays, such as the polarized arrays resulting from the asymmetric display of kinocilia and stereocilia on the apical surfaces of cochlear hair cells. During the past six years, we have been studying the specification of PCP, using Drosophila melanogaster as our model system. We have found that cell polarization is mediated by the asymmetric accumulation of the seven-pass transmembrane protein Frizzled, and other proteins, within the apicolateral membrane of the cell, and we have identified a mechanism that mediates a competition between Frizzled on opposing membranes of neighboring cells. This Frizzled competition serves to amplify initial asymmetry cues, and to provide a fidelity mechanism by ensuring the local alignment of neighboring cells, thus reinforcing a uniform polarity throughout the field of cells. We have also identified a group of proteins that provide a global directional signal by biasing the direction of the Frizzled competition and orienting PCP with respect to the tissue axes. While the overall organization of these mechanisms is now apparent, major questions remain concerning the molecular mechanisms that mediate the Frizzled competition, and concerning the organization and transduction of the global directional cue. We propose to investigate these mechanisms through a combination of genetic, molecular and cell biological approaches. We will address two specific questions concerning the mechanism of the Frizzled competition, we will study a previously identified but not yet characterized component of the global directional signal system, and we will characterize several new components identified by our lab in screens for new signaling components.