Signaling Mechanisms Controlling Planar Cell Polarity

描述（由申请人提供）：上皮细胞极性与顶-基底轴正交，称为平面细胞极性（PCP），对于各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，例如由耳蜗毛细胞顶面上动纤毛和静纤毛的不对称显示产生的极化阵列。在过去的六年中，我们一直在研究PCP的规格，使用果蝇作为我们的模式系统。我们已经发现，细胞极化介导的七次跨膜蛋白卷曲，和其他蛋白质，在细胞的顶侧膜内的不对称积累，我们已经确定了一种机制，介导卷曲之间的竞争对相邻细胞的相对膜。这种卷曲竞争有助于放大最初的不对称线索，并通过确保相邻细胞的局部对齐来提供保真度机制，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，提供了一个全球性的方向信号，通过偏置的卷曲竞争的方向和定向PCP相对于组织轴。虽然这些机制的整体组织现在是显而易见的，主要问题仍然是关于介导卷曲竞争的分子机制，以及关于全球方向线索的组织和转导。我们建议通过遗传学、分子生物学和细胞生物学方法相结合来研究这些机制。我们将解决有关卷曲竞争机制的两个具体问题，我们将研究一个先前确定但尚未表征的全球定向信号系统的组成部分，我们将表征我们实验室在筛选新信号组分时确定的几个新组分。

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.