Signaling Mechanisms Controlling Planar Cell Polarity

描述（由申请人提供）：上皮细胞与顶基轴正交的极性，被称为平面细胞极性（PCP），对多种发育事件至关重要，包括不对称细胞分裂的方向和平面极化细胞阵列的产生，例如耳蜗毛细胞顶表面kin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PCP的规范，以果蝇为我们的模型系统。我们已经发现，细胞极化是由细胞顶侧膜内七道跨膜蛋白Frizzled和其他蛋白质的不对称积累介导的，我们已经确定了一种机制，介导邻近细胞对立膜上Frizzled之间的竞争。这种卷曲的竞争有助于放大初始的不对称信号，并通过确保相邻细胞的局部对齐来提供保真机制，从而加强整个细胞场的均匀极性。我们还确定了一组蛋白质，它们通过偏倚卷曲竞争的方向和相对于组织轴的PCP定向来提供全局定向信号。虽然这些机制的整体组织现在是显而易见的，但主要问题仍然是关于介导卷曲竞争的分子机制，以及关于全局定向线索的组织和转导。我们建议通过结合遗传学、分子生物学和细胞生物学的方法来研究这些机制。我们将解决关于卷曲竞争机制的两个具体问题，我们将研究先前确定但尚未表征的全球定向信号系统组件，我们将表征我们实验室在新信号组件屏幕中确定的几个新组件。

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.