Regulation of Epithelial Polarity

Epithelial cells constitute the most widespread and evolutionarily ancient mode of animal tissue organization. The functions of epithelia rely on their highly polarized architecture, in which specific proteins are restricted to apical, junctional, and basolateral surfaces. We are working to understand the mechanisms that give rise to and maintain this polarized distribution of membrane proteins, which epitomize subcellular specialization.

One line of investigation seeks to understand the cellular mechanism by which established polarity regulators control this polarized protein distribution. These regulators include three evolutionarily conserved groups of scaffolding proteins: the Par (-3/Par-6/aPKC) and Crumbs (/Stardust) complexes, which are found at the adherens junctions and apical surface respectively, and the Scribble (Discs-large/Lethal Giant Larvae) group of neoplastic TSGs that act at the basolateral surface. While increasingly well-characterized genetically and biochemically, their basic cellular polarizing activities remain mysterious. We also believe that novel insights can continue to come from unbiased genetic screens, and have designed several to isolate new regulators of epithelial polarity. For instance, studies of epithelial Dynein function have stressed the role of an additional class of gene products —polarized mRNAs— into the polarity paradigm, while the isolation of canonical endocytic regulators reveals the importance of not only polarized protein delivery but also removal in membrane polarization. Using these and other genes as entry points, we are studying the cellular and molecular mechanisms underlying their various polarizing activities in order to expand existing paradigms of epithelial polarity and obtain an integrated picture of how the cell achieves the proper apicobasal distribution of proteins.