Signaling Mechanisms of Lens Development

PROJECT SUMMARY Defective lens development is a major cause of congenital eye diseases, because the human lens is the culmination of elaborate cell proliferation, differentiation and morphogenesis, 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 originating from defective lens genesis. We have previously demonstrated that Abl tyrosine kinase modulates actin cytoskeleton remodeling to prevent persistent lens stalk, a hallmark of Peters anomaly. In this application, we will investigate the direct targets of Abl kinases. Using conditional mutant mice and cell culture models, we will identify protein tyrosine phosphatase Ptpn12 as a novel substrate of Abl signaling. Furthermore, we will test the hypothesis that Cas and Paxillin cooperate to induce Crk signaling in lens morphogenesis. Lastly, we will investigate the role of regulation of Abl interactor Abi in the lens. As a major signaling pathway, perturbation in Abl signaling can cause not only congenital disorders but also inflammation, neural degeneration and cancer. Therefore, the study of Abl signaling has far- reaching implications for both human health and vision research.