Research Faculty

Edward S. Harkness Eye Institute
635 West 165th Street
Room 902A
New York, NY 10032

Phone: 212-342-4446
Fax: 212-305-0417
Education and Training
BS: Physics, Beijing University (China)
PhD: Biology, Johns Hopkins University

Pathology and Cell Biology
Integrated Program in Cellular, Molecular and Biomedical Studies
Xin Zhang, Ph.D.
Jules & Doris Stein RPB Associate Professor of Ophthalmology, Pathology and Cell Biology
Research Summary

The main focus of our research is mechanism of cell signaling during eye development. The eye is a prominent system to study signal transduction, not only because of its biomedical significance, but also because of the rich resource of experimental tools available in eye research. Previous studies have also identified multiple signaling pathways including FGF signaling in mediating cellular interactions in the eye. However, the specific signaling components of these pathways and their precise in vivo functions in the eye remain poorly understood. With the advent of genome wide analysis and the rapidly expanding collection of mouse models, it has now become increasingly important to determine the in vivo function of every mouse gene by genetic approaches. We would therefore like to employ the formidable mouse genetic tools to ultimately determine the signaling pathways governing eye development.

Molecular mechanism of FGF signaling. FGF activates downstream Ras and PI3K pathways in many biological systems. We have shown that NF1, a frequently mutated tumor-suppressor gene in human that negative regulates Ras-MAPK signaling, is required for lens induction. Epidermal deletion of another tumor-suppressor gene Pten, however, leads to PI3K/mTOR-mediated activation of FGF signaling, which drives squamous cell carcinoma. These studies demonstrate the power of genetics in dissecting signaling pathways which are not only essential for embryonic development but also functionally important for congenital syndrome and cancer biology. We are also interested in Shp2 protein-tyrosine phosphatase, which is essential in activating Ras-MAPK signaling pathway in lens induction, lacrimal gland budding, retinal neurogenesis and neuroprotection. One of the most enduring questions in Receptor Tyrosine Kinase signaling is how a phosphatase like Shp2 can positively regulates tyrosine phosphorylation cascade. By combining biochemistry and mouse genetics, we would like to test potential Shp2 regulators and critical substrates. Eventually, we would like to determine how FGF signaling can elicit such diverse responses as branching morphogenesis of lacrimal gland and differentiation of the lens. The discovery 20 years ago that FGF could promote photoreceptor cell survival has positioned it at the forefront of retinal degeneration therapy. Our studies will provide mechanistic insights into intercellular signaling in eye development and inform therapeutic research in the future.

Developmental glycobiology. As an interdisciplinary area, this research is challenging because synthesis of carbohydrates, unlike that of DNA and protein, is non-template driven. Thus, the regular molecular biology tools can not be easily applied to understand the structural-functional correlations of these complex molecules. Nevertheless, these carbohydrate modifications play essential roles in development, metabolism and cancer. We have employed gene targeting techniques to specifically disrupt synthesis of heparan sulfates, cell surface polysaccharides functionally important for multiple cellular signaling. We have demonstrated that FGF signaling is disrupted in heparan sulfates mutant embryos, resulting in a loss of lens induction and failure of lacrimal gland development in the eye. We would like to further understand how these heparan sulfate modifications regulate FGF/FGFR interaction at cell surface and modulate diffusion and stability of FGF in the extracellular matrix. On the other hand, heparan sulfate is but one member of the glycosaminoglycan family of polysaccharides which are covalently attached to plasma member protein. Therefore, we would like to investigate functions of other glycosaminoglycans such as chondroitin sulfate and dermatan sulfate and the role of cell surface proteoglycan in signaling pathways. Since function of heparan sulfate is largely unexplored in many ocular tissues, this presents an exciting opportunity for new discoveries in eye development.
Selected Publications

Tao C, Zhang X. 2016. Neuronal-derived Proteoglycans Control Astrocyte Migration and Angiogenesis by Regulating Basement Membrane Assembly. Cell Reports. 17, 1832–1844.

Mathew G, Hannan A, Hertzler-Schaefer K, Wang F, Feng GS, Zhong J, Zhao JJ, Downward J, Zhang X. Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A. 113, 13156–13161.

Hertzler-Schaefer K, Mathew G, Somani A, Tholpady S, Kadakia MP, Chen Y, Spandau DF, Zhang X. 2014. Pten loss induces autocrine FGF signaling to promote skin tumorigenesis. Cell Reports. 6(5):818-26.

Li H, Tao C, Cai Z, Hertzler-Schaefer K, Collins TN, Wang F, Feng GS, Gotoh N, Zhang X. 2014. Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development. Journal of Cell Science. 127:571–582.

Cai Z, Tao C, Ladher R, Gotoh N, Feng G, Wang F, Zhang X. 2013. Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma. Development. 140:2711-2723.

Carbe C, Garg A, Cai Z, Li H, Powers A, Zhang X. 2013. An Allelic Series at the Pax6 Locus Reveals the Functional Specificity of Pax Genes. Journal of Biological Chemistry. 288:12130-12141.

Honors and Awards

2014 – present
Jules and Doris Stein Research to Prevent Blindness Professorship

2011 – 2013
David D. Weaver Investigator

2005 – 2007
Basil O'Connor Scholar

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