SIGNALING MECHANISMS CONTROLLING PLANAR CELL POLARITY

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DESCRIPTION: (Verbatim from the applicant's description): Whereas much work has addressed the determination of apical-basal polarity in epithelia, relatively little is known about the specification of polarity orthogonal to the apical-basal axis [referred to as planar cell polarity (PCP)]. Nevertheless, PCP is integral to the function of many tissue-systems ranging from the specialized hair cells of the mammalian ear to the dynamic cilia of the tracheal and reproductive tract epithelia. Planar polarity might contribute not only to the establishment of polarized epithelial structures, but also to the ability of cells to communicate in a directional fashion. It is likely that directional signaling mechanisms are of ubiquitous importance in development. The goal of this proposal is to elucidate, using a genetically tractable system, the mechanism(s) by which signals orient the cytoskeleton of epithelial cells along an axis orthogonal to their apical-basal axes. A powerful set of genetic, molecular and phenotypic tools makes Drosophila an extremely attractive system for investigating the controls governing PCP. We will use Drosophila as our primary model system. Dissection of the signaling pathway regulating PCP has revealed roles for Frizzled and Dishevelled, thereby implicating a Wnt as ligand. Knowledge of PCP signaling will therefore also contribute to our understanding of the diversity of Wnt/Frizzled signaling mechanisms and responses. PCP signaling requires the establishment of subcellular asymmetry in response to extracellular cues. Our previous results led us to test the model that, in vivo, subcellular asymmetry in response to the PCP signal results from an asymmetric relocalization of the Dishevelled protein. Dishevelled could then serve as a marker establishing intrinsic polarity and directing the resulting cytoskeletal reorganization. Indeed, we have demonstrated asymmetric segregation of Dishevelled that is consistent with this model. This proposal describes experiments aimed at characterizing the roles of Dishevelled and other proteins in generation of an asymmetric PCP response. Specifically, the aims of this proposal are to 1) determine how asymmetric segregation of Dsh contributes to cell polarization during the PCP response, 2) identify additional components of the signaling pathway that may be involved in transducing the PCP signal, and 3) characterize some of these newly identified components.