Regulation of lens development requires the coordinated activities of a number of growth factor signaling pathways, cell-cell and cell-matrix adhesion complexes, and cell cycle regulators. An important question is how all these different pathways are spatially and temporally coordinated so as to ensure proper lens formation. PDZ (PSD95/DLG/ZO-1) proteins are proteins that have the potential capacity to link all of these molecular pathways. Through their capacity to act as scaffolds, they assemble large protein complexes that, depending on the constituent molecules assembled, signal towards different cellular fates. In Drosophila, the tumor suppressor genes Discs Large (dig) and Scribble (scrib), which encode two PDZ proteins, are essential for establishing and maintaining normal epithelial cell structure, polarity and proliferation. Our recent transgenic mouse studies using of the E6 oncoprotein from human papillomavirus as a dominant inhibitor of PDZ proteins, suggests a heretofore unrecognized role for PDZ proteins such as Dlg-1 and Scrib in many stages of lens development. We also have shown that a hypomorphic allele of Dlg-1 gives rise to cataractous abnormalities in the mouse lens during embryogenesis. In this application, we propose to use a combination of genetic and molecular analyses on mouse mutants in Dlg-1, Scrib, and other interacting genes to (1) determine the requirements for Dlg-1 and/or Scrib in lens development, (2) determine if, and the mechanisms through which, Dlg-1 and/or Scrib regulate lens development by modulating cell adhesion protein complexes, and (3) define the pathway through which Dlg-1 and/or Scrib regulate the cell cycle. Loss of cell cycle control, cell architecture and polarity are observed in many cataractous conditions ranging from congenital cataracts to age-related cataracts in adults to secondary cataracts, that occur following cataract surgery. Factors that regulate these fundamental properties of lens cells during embryogenesis have the potential to be relevant to maintaining normal lens structure and transparency throughout the life of the animal. Additionally, defects in PDZ and polarity genes recently have been found to be associated with retinal degenerations in experimental animals and humans. Thus, the knowledge we gain from our novel studies to understand the role of Dlg-1 and Scrib in mouse lens development potentially will have significant impact on our understanding not only of lens development but also cataract, and other ocular diseases. ? ? ?
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