Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia

Stowers Institute For Medical Research, Kansas City MO

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Abstract

? DESCRIPTION (provided by applicant): Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia Project Summary During development and homeostasis of multicellular animals, adherent layers of proliferating epithelial cells provide the spatial and structural contet essential for nearly all aspects of organ morphogenesis and physiology. In humans, defects in the control of epithelial cell proliferation can result in a wide range of pathologies, including te approximate 80% of cancers derived from epithelia (carcinomas). Nevertheless, despite the central importance of understanding epithelial proliferation in development and disease, precisely how mitotic division is spatially and temporally coordinated with the maintenance of epithelial architecture remains poorly understood. In this proposal, we take advantage of Drosophila imaginal discs as a genetic model to uncover fundamental molecular and cellular mechanisms that coordinate cell proliferation with epithelial apico-basal polarization in vivo. In Aim 1 we use genetic analysis and innovative live imaging methods to investigate how mitotic epithelial cells disassemble their complex interphase morphologies at prophase entry and subsequently round up at the apical epithelial surface. In Aim 2 we use genetic, biochemical, and proteomic approaches to interrogate interactions between the mitotic spindle poles and the junction-localized tumor suppressors Scribble and Discs Large during planar spindle alignment in vivo. Lastly, in Aim 3 we investigate the molecular and cellular features of epithelial-to-mesenchymal transitions (EMTs) that result from defective planar orientation of the mitotic spindle during epithelial cell division. At the conclusion of these studies, we will have greatly expanded our fundamental knowledge of epithelial cell division and planar spindle orientation developed a novel genetically-tractable model for abnormal EMT events that result from defective spindle orientation in vivo, and provided detailed mechanistic insight into the molecular genetic control of both of these processes.