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 previously identified Frs2 as a key adaptor protein which recruits Shp2 protein tyrosine phosphatase to transmitting FGF signaling in lens morphogenesis. In this application, we will test the hypothesis that Crk and CrkL are also important mediators of FGF signaling in lens development. Using conditional mutant mice and cell culture models, we will identify the molecular mechanism of Crk and CrkL function during lens induction and differentiation. Furthermore, we will test the hypothesis that Crk/Crkl cooperate with Frs2/Shp2 to regulate 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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