Comparative analysis of PCP signaling architecture

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): The Planar Cell Polarity (PCP) system polarizes cells in diverse epithelial sheets along an axis orthogonal to their apical-basal axis, and is necessary for numerous physiological functions. Studies in the fruit fly, Drosophila, have led to the concept of a modular system controlling PCP, in which functional modules each comprise a genetically and biochemically related unit. However, studies in different tissues and compartments have led to different models for how these modules are interconnected. We have recently identified unifying features, yet we also find unexpected differences in signaling architecture. This variation is likely also to be reflected in the adaptations of PCP signaling to the range of vertebrate functions it controls. Starkly different schemas for the connectivity between the two most understood modules, the Ft/Ds/Fj global module, the core module, and their downstream effector modules have been proposed based on studies in different epithelia, suggesting either a series (green and black pathways) or parallel (red and black) architecture. These analyses did not account for potential contributions of other global modules. Here, I propose to define the connectivity between modules across different compartments and determine whether signals from global modules converge on the core module or produce bypass signals to effector modules. Furthermore, isoforms of Prickle (Pk) are essential regulators of the link between the Ft/Ds/Fj and core modules. We have identified a unique function for these isoforms in modulating the polarity of microtubules that translate directional information between these modules. Yet, our data reveal that the current isoform model for Pk is incomplete. I propose to re-define the Pk isoforms and to search for Pk interacting proteins using state-of-the-art molecular methods.