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.
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