): 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. Typical examples of planar polarization include features of vertebrate skin or internal organs like the inner ear epithelium with its sensory cilia in vertebrates, and insect cuticular structures in invertebrates. The establishment of the precise polarization patterns in Drosophila serves as a paradigm to study epithelial planar polarity determination and the coordination of polarized cell shape changes in general. It is thought that planar polarization is coordinated by long range signals. The Frizzled (Fz) receptor and its signaling cascade serve as an entry point to study the molecular aspects controlling these processes. The underlying Fz signaling pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization in vertebrates and invertebrates. Fz mediated planar polarity signaling is, however, distinct from the canonical Wnt Fz pathway and its components are largely unknown. Moreover, the link between Fz/planar polarity signaling and the resulting cellular responses including cytoskeletal reorganiza60n and specific transcriptional events are not understood. The scope of this application is to investigate the specific roles of newly identified genes required for planar polarity determination and cell shape change coordination. Their function in Fz signaling and/or directly in cellular polarization events will be investigated. A combination of in vivo studies in Drosophila and biochemical experiments will be utilized to achieve these goals. The process of planar polarization and Fz signaling have been linked to several medical abnormalities (including deafness in the case of the inner ear epithelium) and cancer (several components required for the process 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 also be of medical relevance, particularly for the study of carcinogenesis
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