News and Publications

Intercellular Communication and Intracellular Signaling

X. Gong, P. Rong, R. Ojakian

We focus mainly on 2 areas of research: cell-cell communication via gap junctions that consist of connexins and the MAP kinase signaling pathways in the lens of the eye.

CONNEXINS

The mutations of different connexin genes are linked to many different human diseases, including cataracts, hearing loss, and neurodegeneration. To understand the mechanism for the pathologic process associated with human cataractogenesis, we generated strains of mice that lack the genes for 2 connexins and identified 2 natural, spontaneous, dominant cataractous strains of mice that are a result of 2 different point mutations in a single connexin gene. Both point mutations occurred in the conserved residues shared by all the members of the connexin gene family (more than 16 members have been identified so far) across species. We think that comparing the characteristics of mice with point mutations with the characteristics of wild-type and of mutant mice that lack genes for connexins will lead us to an understanding of the different molecular bases for the pathologic process in the various mutants and to an elucidation of the fundamental mechanisms for the structural and functional relationship of gap junction channels that consist of connexin subunits.

MAP KINASE PATHWAYS

The MAP kinase pathways mediate 2 major extracellular cues that regulate intracellular responses: growth stimuli and environmental stresses. We found that 3 distinctive MAP kinase pathways are used in the differentiation of lens epithelial cells into fiber cells in the eye lens in mice. Constitutive activation of these pathways in transgenic mice led to different pathologic phenotypes in the lens cells. Cataracts with macrophthalmia developed in the transgenic mice that expressed a constitutively active mutant of the MAP kinase kinase 1, MEK1(E), in their eye lenses. We also found that the lens phenotype was due, at least in part, to an alteration in the glucose metabolism. Using DNA chip technology, we identified an additional 50 MAP kinase downstream genes that were upregulated or downregulated in the transgenic lens. We are verifying the downstream genes that contribute to this lens phenotype.

PUBLICATIONS
Gong, X., Wang, X., Han, J., Niesman, I., Huang, Q., Horwitz, J. Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens. Invest. Ophthalmol. Vis. Sci. 42:539, 2001.