Establishment of Epithelial Planar Cell Polarity

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DESCRIPTION (provided by applicant): Epithelial cells require correct polarity for their function. Their polarity and patterning is established during organogenesis. Epithelial cells are often polarized in two axes, in the apical-basolateral axis and in the plane of the epithelium, called planar cell polarization or PCP. Typical PCP examples include features of mammalian skin or internal organs, e.g. the inner ear epithelium with its sensory cilia, and insect cuticular structures in invertebrates. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination and the coordination of polarized cell shape changes in general. PCP is coordinated by long range signals, resulting in the activation of the Frizzled (Fz) receptor- and its associated signaling cascade (Fz/PCP signaling). The Fz/PCP pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization, including directed cell migration during mammalian gastrulation. Strikingly, Fz/PCP signaling is distinct from the canonical Wnt/Fz-B-Catenin pathway. The regulation of signaling specificity between these two pathways activated by the same receptors is only poorly understood, but critical for development and disease. Moreover, the link between Fz/PCP signaling and the resulting cellular responses, including cytoskeletal reorganization and specific transcriptional events are not yet understood. The scope of this application is to investigate the specific roles of newly identified genes required for PCP determination and cell shape change coordination. Their function in Fz/PCP signaling and/or in cellular polarization events will be investigated genetically and biochemically. A combination of in vivo studies in Drosophila, cell culture analyses and biochemical experiments will be utilized to achieve these goals. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities (including deafness in the case of the inner ear epithelium) and cancer (several components of the pathway are proto-oncogenes or tumor suppressors). Thus the information acquired in this application will both advance our understanding of cellular polarization and patterning, and will be of medical relevance, particularly for the study of carcinogenesis.