Xiaohua Gong

Associate Professor of Vision Science and Optometry

Molecular mechanisms for eye development and disease

Research in the lab has been directed to study molecular and cellular mechanisms that control vertebrate organgenesis and diseases, mainly, the eye development and ocular diseases, by a combination of both basic and clinical methods with multidiscipline techniques from the fields of molecular and cellular biology, genetics, biochemistry, and electrophysiology etc. We are particularly interested in theidentification and characterization of novel genetic factors that play essential roles in the development of the eye as well as in pathological process of diseases like retinal degeneration, vascular disorders, and cataracts, etc. Ultimately, we’d like to develop additional biological and/or chemical tools to diagnose, prevent and/or cure related human eye diseases.

Current Projects

Eye Development and Diseases: This research involves a forward genetic approach to identify and characterize the genes that play essential roles in eye development and diseases. An ENU-induced saturation mutagenesis mouse program in C57BL/6J strain has been screened for ocular phenotypes by clinical examinations using an indirect ophthalmoscope and a slit lamp. Defined genetic mutants were subjected to chromosomal mapping of their mutations using a genome wide mapping strategy. Their ocular phenotypes were further characterized morphologically and biochemically. So far, more than dozens eye mutations have been identified. These mutants develop clinical symptoms like yellow spots, white spots or hyperpigmentation in the retina, lens cataracts, corneal dystrophies, respectively. Further analyses verified distinctive cellular and molecular alterations in each mutation. For example, morphological data showed abnormal aggregations between retinal pigment epithelium and photoreceptor cells, a loss of outer segment of photoreceptor cells, selective death of photoreceptor cells, and a loss of cells in the inner nuclear layer in the eyes of two dominant and two recessive retinal mutations respectively. We are continuing to study the molecular and cellular mechanisms in these mutants that develop similar ocular disorders as in human.

The Lens Biology: This research involves the studies of cell-to-cell communication and intracellular signaling pathways in the lens. The development of vertebrate lens uses a sophisticated cell-cell communication network via gap junction channels, which are made up of at least three connexin isoforms, alpha8 (Cx50), alpha3 (Cx46) and alpha1 (Cx43). A gap junction channel is formed by the docking of two hemichannels called "connexons"from adjacent cells. Each connexon consists of 6 subunit proteins called "connexins."So far, at least 20 different connexin genes have been reported in this multi-gene family from humans and mice. The mutations of different connexin genes have been reported to be linked to many different human diseases, including cataracts, hearing loss, heart diseases, and neurodegeneration.

The MAP kinase pathways have been reported to mediate two major extracellular cues to regulate intracellular responses: growth stimuli and environmental stresses. We have found that three distinctive MAP kinase pathways are utilized in the differentiation process of lens epithelial cells into fiber cells in the mouse lens and have established a database of lens gene expression and proteins by using DNA chip technology and proteomic technique like multi-dimensional mass-spectrometry. So far, we have identified hundreds of proteins in human lens epithelium isolated from cataract patients and in the lens fibers from human and mice. We are trying to define specific posttranslational modifications of downstream targets that are regulated by different MAP kinase pathways in lens.

Selected Publications

2006

Xia CH, Liu H, Cheung D, Cheng C, Wang E, Du X, Chang B, Beutler B, Lo WK, Gong X. (2006) Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development. Development 133, 2033-40. (Cover paper)

Dunia I, Cibert C, Gong X, Xia CH, Recouvreur M, Levy E, Kumar N, Bloemendal H, and Benedetti EL. (2006) Structural and immunocytochemical alterations in eye lens fiber cells from Cx46 and Cx50 knock-out mice Euro. J of Cell Biology 85(8):729-52.

Xia CH, Cheng C, Cheung D, Huang Q, Dunia I, Benedetti LE, Horwitz J, Gong X. (2006) Absence of gap junction channels lead to cataractogenesis by reducing g-crystallin. Experimental Eye Research 83, 688-96.

Xia CH, Chang B, Cheung D, Liu H, Wang M, Huang Q, Horwitz J, Gong X. (2006) Arginine 54 and tyrosine 118 residues of aA-crystallin are crucial for its roles in lens formation and transparency. Investigative Ophthalmology & Visual Science (IOVS) 47, 3004-10.

Xia CH, Cheung D, DeRosa AM, Chang B, Lo WK, White TW, Gong X. (2006) Knockin a3 (Cx46) connexin prevents severe cataracts caused by an a8 (Cx50)-G22R mutation. J Cell Science 119. 2138-44.

Xia CH, Liu H, Wang M, Cheung D, Park A, Yang Y, Du X, Chang B, Beutler B, Gong X. (2006) Retinal Degenerative Diseases edited by Hollyfield JG, Anderson RE, and LaVail MM. New York. Chapter 16, Characterization of mouse mutants with abnormal RPE cells. p95-100.

2005

Liu H, Du X, Wang M, Huang Q, Ding L, McDonald HW, Yates, JR, Beutler B, Horwitz J, Gong X. (2005) Crystallin gammaB-I4F mutant protein binds to alpha-crystallin and affects lens transparency. Journal of Biological Chemistry 280, 25071-8

2004

Shentu X, Yao K, Xu W, Zheng S, Hu S, Gong X. (2004) Special fasciculiform cataract caused by a mutation in the gammaD-crystallin gene.  Molecular Vision. 10:233-9.

Sandilands A, Wang X, Hutcheson AM, James J, Prescott AR, Wegener A, Pekny M, Gong X, Quinlan RA. (2004) Bfsp2 mutation found in mouse 129 strains causes the loss of CP49 and induces vimentin-dependent changes in the lens fibre cell cytoskeleton. Experimental Eye Research 78: 109-23.

Du X, Tabeta K, Hoebe K, Liu H, Mann N, Mudd S, Crozat K, Sovath S, Gong X, Beutler B. (2004) Velvet, a    dominant Egfr mutation that causes wavy hair and defective eyelid development in mice. Genetics. 166:331-40.

Gao J, Sun X, Martinez-Wittinghan FJ, Gong X, White TW and Mathias RT. (2004) Connections between connexins, calcium, and cataracts in the lens. J. Gen. Physiol. 124:1-12, 2004. (Cover paper)

2003

Martinez-Wittinghan F.J., Sellitto C, Li L, Gong X, Brink PR, Mathias RT, White TW. (2003) Dominant cataracts result from incongruous mixing of wild-type lens connexins. J Cell Biology 161: 969-78. (Cover paper)

2002

Rong, P., Wang, X., Niesman, I., Wu,  Y., Levy, E., Dunia, I., Benedetti, L.E., Gong, X. (2002) A loss-of-function of a8 connexin (Cx50) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation.  Development 129: 167-174.

Petrich, BG., Gong, X., Lerner, DL., Wang, X., Brown, JH., Saffitz, JE., Wang, Y. (2002)  c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes.  Circulation Research  91:640-647.

Chang, B., Wang, X., Hawes, N.L., Davisson, M. T., Ojakian, R., Lo, W.K., Gong, X. (2002) A Gja8 (a8 connexin) point mutation causes an alteration of a3 connexin and semi-dominant cataracts in Lop10 mice.  Human Molecular Genetics 11:5 507-513.

2001

Gong, X., Wang, X., Han, J., Niesman, I., Huang, Q. and Horwitz, J. (2001) Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens. Investigative Ophthalmology & Visual Science (IOVS) 42:539-548.

Baldo, G.J., Gong, X., Martinez-Wittinghan, F.J., Kumar, N.M., Gilula, N.B. and Mathias, R.T. (2001) Gap junctional coupling in lenses from alpha8 connexin knockout mice. J Gen Physiol. 118:447-56.

Tian, J., Gong, X. and Xie, Z. (2001) Signal-transducing function of Na(+)-K(+)-ATPase is essential for ouabain's effect on [Ca(2+)](i) in rat cardiac myocytes.  Am J Physiol Heart Circ Physiol 281:H1899-907.

2000

Smith, R.S., Hawes, N.L., Chang, B., Roderick, T.H., Akeson, E.C., Heckenlively, J.R., Gong, X., Wang, X. and Davisson, M.T. (2000) Lop12, a mutation in mouse crygd causing lens opacity similar to human coppock cataract. Genomics 63:314-320. (Cover paper)

1999

Gong, X., Agopian, K., Kumar N.M. and Gilula, N.B. (1999) Genetic factors influence cataract formation in a3 connexin knockout mice. Developmental Genetics 24:27-32.

1998

Gong, X., Baldo, G.J., Kumar, N.M., Gilula, N.B. and Mathias, R.T. (1998) Gap junctional coupling in lenses lacking a3 connexin. PNAS 95:15303-15308.

1997

Gong, X., Kaushal, S., Ceccarelli, E., Bogdanova, N., Neville, C., Nguyen, T., Clark, H., Khatib, Z. A., Valentine, M., Look, A. T. and Rosenthal, N. (1997) Developmental regulation of Zbu1, a DNA-binding member of the SWI2/SNF2 family.  Developmental Biology 183:166-182.

Gong, X., Li, E., Klier, G.F., Huang, Q., Wu, Y., Lei, H., Kumar, N.M., Horwitz, J. and Gilula, N.B. (1997) Disruption of a3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell 91:833-843.

Links

The Gong Lab Website

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