REGULATION OF OCULAR LENS DEVELOPMENT BY GROWTH FACTORS

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The lens is a model tissue for studying which factors control mammalian development. The PI and others have begun to identify intracellular and extracellular factors that regulate the noraml morphogenesis of this epithelial tissue. The goals of this current grant application are to continue our efforts to define the moleccular pathways by which lens development is regulated. Through a combination of transgenic and gene targeting metholologies, the retinoblastoma susceptibility gene product, Rb, has been shown to be critical in regulating the process of terminal differentiation in the mouse lens. Inactivation of Rb led to aberrant cell proliferation and concomitant induction of apoptosis in the compartment of the lens where normally cells withdraw from the cell cycle and undergo a specific program of differentiation. In this differentiation program,organelles including nuclei and mitochondria are lost, while celluar integrity is maintained. A number of facts have led to the hypothesis that loss of nuclei in lens cells may occur through a mechanism related to that seen in programmed cell death. in this grant proposal the PI describes experiments to address the validity of this hypothesis. The Rb protein is though to regulate cellular processes at least in part through its modulation of the transcription factor, E2F. Evidence points to the potential role of N-myc, an E2F responsive gene, in mediating Rb's regulation of lens development. The PI will perform experiments to address the importance of N-myc. Lastly, the PI and others have used transgenesis to explore the role of the fibroblast growth factors, FGF-1 and FGF-2, inlens development. These extracellular factors are though to mediate the spatially restricted induction of terminall differentiationin the lens. Global disruption of the FGF signaling pathways in the lens to gross defects in lens development, demonstrating the importance of these growth factors. Additional experiments suggest that FGF-2 is a 'survival factor' when overexpressed in the lens. The PI will test the hypothesis that FGF-2 determines the fate of lens fiber cells by a combination of transgenic and targeted knockout strategies designed to interfere with FGF-2 function of eliminate its source of expression in the eye.