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.
|Cvekl, Ales; Zhang, Xin (2017) Signaling and Gene Regulatory Networks in Mammalian Lens Development. Trends Genet 33:677-702|
|Balasubramanian, Revathi; Zhang, Xin (2016) Mechanisms of FGF gradient formation during embryogenesis. Semin Cell Dev Biol 53:94-100|
|Tao, Chenqi; Zhang, Xin (2016) Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis. Cell Rep 17:1832-1844|
|Mathew, Grinu; Hannan, Abdul; Hertzler-Schaefer, Kristina et al. (2016) Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A 113:13156-13161|
|Cai, Zhigang; Grobe, Kay; Zhang, Xin (2014) Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis. Dev Dyn 243:1310-6|
|Hertzler-Schaefer, Kristina; Mathew, Grinu; Somani, Ally-Khan et al. (2014) Pten loss induces autocrine FGF signaling to promote skin tumorigenesis. Cell Rep 6:818-26|
|Tao, Chenqi; Zhang, Xin (2014) Development of astrocytes in the vertebrate eye. Dev Dyn 243:1501-10|
|Pan, Yi; Carbe, Christian; Kupich, Sabine et al. (2014) Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis. Matrix Biol 35:253-65|
|Li, Hongge; Tao, Chenqi; Cai, Zhigang et al. (2014) Frs2? and Shp2 signal independently of Gab to mediate FGF signaling in lens development. J Cell Sci 127:571-82|
|Cai, Zhigang; Tao, Chenqi; Li, Hongge et al. (2013) Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma. Development 140:2711-23|
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