Analysis of FGF receptor signalling involved in lens cell proliferation and differentiation

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Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family play pivotal roles in lens developmental biology by influencing lens cell proliferation and differentiation. An important finding from our laboratory is that FGF induces lens epithelial cell proliferation and differentiation at different concentrations. The FGFs elicit intracellular responses upon binding to and activating cell surface FGF receptors (FGFRs). The FGFRs are membrane bound tyrosine kinases which upon activation, activate specific signalling pathways leading to a specific cellular response. To understand how FGFs mediate and regulate different responses in lens cells, namely cell proliferation and fibre differentiation, we plan to examine the role of FGFRs in normal lens development using genetically altered FGFRs that will be expressed specifically in lenses of transgenic mice. While it is known that four different FGF receptor genes are expressed by the normal developing lens, it is unknown what role each of these play in the process of lens cell proliferation and differentiation. In addition, as we can reproduce a specific FGF-induced lens cellular response in vitro, we will use our lens explant culture system to dissect the signalling pathway(s) downstream from specific receptor activation and correlate this with a specific cellular response. By identifying the molecules and mechanisms that control the cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.