Anophthalmia and extreme microphthalmia occur in 1 per 5000 live births, but nearly all of them have unknown genetic etiology. Defective lens development is a major cause of these congenital eye diseases, because the human lens is the culmination of elaborate cell proliferation, differentiation and movement, requiring precise regulation by signaling pathways. A molecular understanding of lens development could potentially lead to new ways of diagnosing and treating congenital eye diseases originated from defective lens genesis. We have identified Shp2, a protein tyrosine phosphatase, as a key factor in orchestrating lens morphogenesis by regulating FGF signaling. In this application, we will focus on the mechanism of Shp2 regulated FGF signaling in lens development. Using conditional mutant mice and cell culture models, we will identify the molecular interactions in mediating FGF signaling during lens induction and differentiation. Furthermore, we will test the hypothesis that Ras and/or PI3K signaling are necessary and sufficient for FGF signaling in lens development. As a major signaling pathway, perturbation in FGF signaling can cause not only congenital diseases, but also metabolic syndromes and cancer. Therefore, study of FGF signaling has far reaching implications for both human health and vision research.
The genetic bases of many ocular syndromes remain unresolved, due to our limit in understanding the mechanism of lens development. This study has the potential to identify the molecular mechanism of FGF signaling in orchestrating lens morphogenesis. Such an understanding will help to guide our efforts in treating ocular related birth defects.
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