Regulation of lens cell behaviour by RTK antagonists, Sef and Sprouty.

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Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mechanisms involved in cataract formation. Following cataract surgery, for example, many patients develop aftercataract which results from residual lens cells. These residual cells, unlike those tightly regulated in the normal lens, divide and differentiate to form a secondary cataract. The main aim of this study is to understand what molecules regulate the proliferation and differentiation of lens cells. Growth factors are key regulators of cell behaviour and our studies provide evidence that FGF growth factors play pivotal roles in the lens by influencing cell proliferation and differentiation. We have recently identified inhibitors of FGF in the lens, called Sprouty and Sef; molecules shown in other systems to effectively block FGF intracellular signalling pathways. To understand how Sef and Sprouty regulate lens cell proliferation and fibre differentiation, we plan to examine what regulates their expression, and more importantly their role in FGF-induced cell signalling in normal lens biology. To do this, we will use a well established explant culture system to monitor the effectiveness of these endogenous inhibitors on growth factor-induced lens cell proliferation and differentiation, as well as use transgenic mice technology to determine the role they play in situ. By understanding the molecular and cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.