Maintaining proper control over cell growth and differentiation is fundamentally important not only during embryonic development but also throughout the life of the animal when tissue homeostasis and self-renewal are required for long-term survival. Despite their importance, the molecular mechanisms through which these cellular processes are controlled in vivo are only poorly understood. The ocular lens has become an important model system for evaluating the roles of specific gene products in regulating growth and differentiation in vivo. In recent years, we and others, through the analysis of transgenic and mutant mice generated by gene targeting strategies, determined that the retinoblastoma susceptibility protein, i.e., is an essential regulator of cell cycle withdrawal during lens fiber cell differentiation. More recently, we also learned that the pRB-related proteins, p107 and/or p130, play a role with pRB in cell cycle control both in the undifferentiated epithelium and during fiber cell differentiation. Although it is thought that the E2F transcription factors are critical targets of pRB proteins during lens fiber differentiation, the specific roles, if any, for individual E2Fs in mediating normal growth and differentiation or the effects of Rb inactivation, remain to be determined. Factors other than the pRB family members contribute to the regulation of cell growth and differentiation in the lens. Our recent studies suggest a heretofore unrecognized role of the PDZ domain proteins, discs-large (DLG), a tumor suppressor in Drosophila, in regulating cell proliferation and structural integrity in the epithelium and newly differentiating fiber cells. In this renewal application, we propose four aims to further our understanding of the roles of these factors in regulating lens cell growth and differentiation in vivo.
The aims of the proposal are to: (1) determine if PDZ domain proteins are required for regulating cell cycle and epithelial cell structure in the lens epithelium; (2) determine the role of pRB and pRB-like proteins in cell cycle control in the undifferentiated and differentiating cells of the lens; (3) determine the role of pocket protein-E2F interactions in cell cycle control during fiber differentiation; (4) determine if pRB and/or pRB-like proteins play a role as a differentiation factor in lens differentiation. Together, the results of these studies will contribute to our understanding of how tumor suppressor proteins regulate cell proliferation and differentiation in vivo and how disrupting their function contributes to human disease such as cataracts.
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