The lens has for some time served as a simple model in which to study the processes of cellular proliferation, migration and differentiation that constitute many aspects of development. Despite a large body of data describing lens development, the molecular mechanism by which this structure forms remains largely a matter of conjecture, in part because there have been few attempts to directly address questions of mechanism using in vivo systems. It is our long term aim to determine the role of fibroblast growth factor (FGF) and insulin-like growth factor type I (IUF- I) in lens development. Previous in vitro experiments have implicated these growth factors in lens development and we have chosen to develop in vivo systems that will allow us to determine if this is the case.
Our specific aims i nclude: (1 and 2) determining whether FGF is required for the differentiation of lens fiber cells and/or the proliferation of lens epithelial cells. (3 and 4) determining whether IGF-I is required for the differentiation of lens fiber cells and/or the proliferation of lens epithelial cells. (5) determining the earliest discernible time in lens development that each of these growth factors is required. (6) determining whether migration of lens epithelial cells is dependent on FGF and/or IGF- I. (7) determining whether FGF and IGF-I act in concert in a synergistic manner to stimulate lens development. Our general approach to these questions is to block growth factor signal transduction in transgenic mice using dominant negative forms of the FGF and IGF-I receptors. This approach has proven fruitful in the past for answering questions about growth factor requirements during development. A key element of the proposed experiments is our ability to direct expression of a transgene to different populations of lens cells. By using the appropriate transgene (or combination of transgenes), we will have the ability to direct expression of a dominant negative growth factor receptor to those lens cells that are either proliferating or differentiating. This experimental system is made possible by the natural expression region of alphaA-crystallin in rodents. The anterior expression boundary of alphaA- crystallin corresponds precisely to the boundary between proliferating and differentiating cells in the lens. Thus, the alphaA-crystallin promoter can be used to express transgenes in differentiating cells directly or indirectly to restrict transgene expression to proliferating cells. This experimental system will give us a unique opportunity to determine whether FGF and/or IGF-I are required for lens cell proliferation of differentiation. Abnormal modifications of the lens are a frequent cause of impaired vision. A complete knowledge of the way in which the lens forms will almost certainly have an impact on our understanding of the way in which its structure is disrupted.
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