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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY017061-08S1
Application #
8604790
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2006-01-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$55,880
Indirect Cost
$17,371
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Tao, Chenqi; Zhang, Xin (2014) Development of astrocytes in the vertebrate eye. Dev Dyn 243:1501-10
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; 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
Cai, Zhigang; Tao, Chenqi; Li, Hongge et al. (2013) Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma. Development 140:2711-23
Carbe, Christian; Garg, Ankur; Cai, Zhigang et al. (2013) An allelic series at the paired box gene 6 (Pax6) locus reveals the functional specificity of Pax genes. J Biol Chem 288:12130-41
Carbe, Christian; Hertzler-Schaefer, Kristina; Zhang, Xin (2012) The functional role of the Meis/Prep-binding elements in Pax6 locus during pancreas and eye development. Dev Biol 363:320-9
Carbe, Christian; Zhang, Xin (2011) Lens induction requires attenuation of ERK signaling by Nf1. Hum Mol Genet 20:1315-23
Cai, Zhigang; Simons, David L; Fu, Xin-Yuan et al. (2011) Loss of Shp2-mediated mitogen-activated protein kinase signaling in Muller glial cells results in retinal degeneration. Mol Cell Biol 31:2973-83
Qu, Xiuxia; Hertzler, Kristina; Pan, Yi et al. (2011) Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development. Dev Biol 355:12-20

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