Planar cell polarity mechanisms and systems architecture

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Summary/Abstract Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium, orienting asymmetric cellular structures, cell divisions and cell migration and is well conserved from Drosophila to vertebrates. Most of our mechanistic understanding of PCP signaling has and will likely continue to derive from work using Drosophila as a model system. In flies, PCP signaling controls the orientation of hairs on the adult cuticle, chirality and orientation of ommatidia in the eye, orientation of cell divisions, and related processes in other tissues. While much of our focus is on mechanistic studies in flies, numerous medically important developmental defects and physiological processes in vertebrates are also under control of PCP signaling, motivating considerable interest in studying PCP both in Drosophila and in vertebrate model systems. In vertebrates, defects in the core PCP mechanism result in a range of developmental anomalies and diseases including open neural tube defects, conotruncal heart defects, deafness and situs inversus and heterotaxy, and has been (incorrectly) implicated in polycystic kidney diseases. PCP is also believed to underlie the directed migration of malignant cells during invasion and metastasis and during wound healing. PCP polarizes skin and hair and the ependyma. The PCP component Prickle, though perhaps not involving the PCP pathway, is mutated in an epilepsy-ataxia syndrome. Mutations in `global' PCP components have recently been associated with a human disorder of neuronal migration and proliferation. These phenotypes can be studied in vertebrate models of PCP gene mutants, and provide excellent opportunities to understand vertebrate PCP signaling and its morphogenetic manifestations. Cellular behaviors controlled by PCP in vertebrates vary, and the expanded numbers of paralogs for the PCP genes in mouse compared to flies suggests the possibility of functional diversification. Hence there is a strong need to understand how PCP signaling is adapted in these various contexts. This proposal aims to dissect the molecular and cell biological mechanisms of PCP signaling using Drosophila as a model system and to extend our understanding to selected vertebrate PCP signaling events. The proposed work will both enhance our knowledge of fundamental mechanisms as well as lay the groundwork for potential therapeutic interventions for PCP related pathologies.