- Department of Ophthalmology
- Department of Pathology & Cell Biology
- Associate Professor of Ophthalmic Sciences (in Ophthalmology & Pathology & Cell Biology)
As a part of the CNS, the retina shares many of the architectural, cellular and connective features with the rest of the brain. Because of its accessibility, the retina is an excellent model that allows detailed molecular analysis and direct therapeutic interventions. The main focus of our research is the mechanism of cell signaling during eye development. By combining biochemistry and mouse genetics, we are studying the molecular mechanism of FGF signaling in the patterning and differentiation of neural retina, examining its intracellular targets and the cross talks with other signaling pathways. In adult retina, FGF was one of the first neurotropic factors found to promote the survival of photoreceptors. We are investigating the neuroprotective mechanism of FGF signaling, aiming to develop it as therapeutic agent to prevent retinal degeneration. In addition, we are interested in cell surface proteoglycans, which are membrane proteins covalently linked with glycosaminoglycan chains. Since the function of these glycoproteins is largely unexplored in the retina, this presents an exciting opportunity for new discoveries. Our recent work has identified the critical role of retinal proteoglycans in astrocyte migration and angiogenesis. This sets the stage for us to further explore the function of proteoglycans in mediating the neural-glial-endothelial interactions in the eye.
The main focus of Dr. Zhang’s 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 the 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.& Dr. Zhang’s laboratory will employ the formidable mouse genetic tools to ultimately determine the signaling pathways governing eye development.
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.& Dr. Zhang’s laboratory has employed gene targeting techniques to specifically disrupt synthesis of heparan sulfate, a cell surface polysaccharide functionally important for multiple cellular signaling.& They have demonstrated that FGF signaling is disrupted in the heparan sulfates mutant embryos, resulting in a loss of lens induction and failure of lacrimal gland development in the eye. They will further understand how these heparan sulfate modifications regulate FGF/FGFR interaction at cell surface and modulate diffusion and stability of FGF in 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, Dr. Zhang’s laboratory will 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.
Molecular mechanism of FGF signaling. FGF activates downstream Ras and PI3K pathways in many biological systems. Dr. Zhang’s laboratory has 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. Dr. Zhang’s laboratory is 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, they will test potential Shp2 regulators and critical substrates.& Eventually, the goal is 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.& These studies will provide mechanistic insights into intercellular signaling in eye development and inform therapeutic research in the future.
Education & Training
Primary Lab Locations
Edward S. Harkness Eye Institute
635 West 165th Street
New York, NY 10032
- (212) 342-4446
- Lab Phone:
- (212) 305-6913
Honors & Awards
2014 Jules and Doris Stein Research to Prevent Blindness Professorship
2011 David D. Weaver Investigator
2005 Basil O'Connor Scholar
Collins TN, Mao Y, Li H, Bouaziz M, Hong A, Feng GS, Wang F, Quilliam LA, Chen L, Park T, Curran T, Zhang X. 2018. Crk proteins transduce FGF signaling to promote lens fiber cell elongation. Elife. e32586. doi: 10.7554/eLife.32586.
Garg A, Bansal B, Gotoh N, Feng G, Zhong J, Wang F, Kariminejad A, Brooks S and Zhang X. 2017. Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis. PLoS Genetics. 13(10):e1007047.
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, Hertzler-Schaefer K, Wang F, Feng G-S, Zhong J, Zhao J, Downward J, Zhang X. 2016. Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proceedings of the National Academy of Sciences. 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.