RhoGTPases in Early Eye Development

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DESCRIPTION (provided by applicant): The long-term goal of this application is an understanding of the mechanisms of early eye development. More specifically, we wish to understand how actin-modulating GTPases influence the coordinated morphogenesis of the lens and retinal epithelium. The Rho family GTPases that are the focus of this application act as molecular switches that regulate signaling within the cell. They function in many different capacities, but have a prominent role in the regulation of actin rearrangement and consequently, the regulation of cell shape, cell migration and the generation of cellular protrusions. They can also influence cell survival. We outline 4 aims to investigate their function in early eye morphogenesis: (1) To determine whether Cdc42 and Rac1 function in a cascade to regulate lens vesicle closure and separation, (2) To determine whether early deletion of Cdc42, Rac1 or RhoA gives a defect in lens pit invagination, (3) To determine whether the optic vesicle has a dominant role in lens pit invagination, and (4) To determine whether the FGF signaling pathway modulates activity of the Rac1, Cdc42 or RhoA pathways. This application has direct significance to human health because the Rho family GTPases are implicated in a variety of human disease including cancer. The involvement of the GTPases in the etiology of cancer is derived from their ability to regulate cell adhesion, cell migration and cell survival. The process of epithelial invagination that we will study is in many ways analogous to the process of invasion that accompanies the development of aggressive cancers. For this reasop, this project may have implications for cancer therapy.