- Associate Professor of Ophthalmic Sciences (in Ophthalmology & Pathology & Cell Biology)
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.
- BS, Physics, Beijing University (China)
- PhD, Biology, Johns Hopkins University
Education & Training
Edward S. Harkness Eye Institute635 West 165th Street
New York, NY 10032
- Lab Phone:
Honors & Awards
2014 Jules and Doris Stein Research to Prevent Blindness Professorship
2011 David D. Weaver Investigator
2005 Basil O'Connor Scholar
Project Dates: 1-Jan-06 to 31-Mar-20
Project Dates: 1-Apr-08 to 31-Dec-17
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. Accepted
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.
Pan Y, Carbe C, Kupich S, Pickhinke U, Ohlig S, Frye M, Seelige R, Pallerla SR, Moon AM, Lawrence R, Esko JD, Zhang X, Grobe K. 2013. Heparan Sulfate Expression in the Neural Crest is Essential for Mouse Cardiogenesis. Matrix Biology. 2013 Nov 4;. [Epub ahead of print]
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.
Qu X, Pan Y, Carbe C, Powers A, Grobe K, Zhang X. 2012. Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development. 139, 2730-2739.
Carbe C, Hertzler-Schaefer K, Zhang X. 2012. The functional role of the Meis/Prep-binding elements in Pax6 locus during pancreas and eye development. Developmental Biology. 363(1):320-9.
Cai Z, Simons DL, Fu XY, Feng GS, Wu SM, Zhang X. 2011. Loss of Shp2-mediated MAPK signaling in Müller glial cells results in retinal degeneration. Molecular and Cellular Biology. 31:2973-2983.
Qu X, Hertzler K, Pan Y, Grobe K, Robinson ML, Zhang X. 2011. Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development. Developmental Biology. 355:12–20.
*Qu X, Carbe C, Tao C, Powers A, Lawrence R, van Kuppevelt TH, Cardoso WV, Grobe K, Esko JD, Zhang X. 2011. Lacrimal gland development and Fgf10-Fgfr2b signaling is controlled by 2-O and 6-O sulfated heparan sulfate. Journal of Biological Chemistry. 286(16):14435-14444. *Rated at the top 2% of published articles in biology and medicine by the Faculty of 1000 (F1000).
Carbe C and Zhang X. 2011. Lens induction requires attenuation of ERK signaling by Nf1. Human Molecular Genetics. 20(7):1315–1323.