The goal of this project is to understand how aberrant lens expression of two activators of gene transcription by signal transduction pathways, gamma interferon(IFN) and FGF-3, perturb normal eye development in transgenic mice. Constitutive expression of IFN gamma in the lens of transgenic mice provides a useful model to study cytokine signaling during embryonic eye development. In collaborative studies with Dr. Charles Egwuagu (Laboratory of Immunology, NEI) we developed transgenic mice and rats with constitutive expression of IFN gamma, which became useful animal models for the study of experimental autoimmune uveitis and anterior uveitis. This ongoing collaboration allowed us to study how constitutive expression of IFN gamma and its induction and activation of IFN gamma-inducible transcriptional factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression. Furthermore, these studies led us to discover the expression of members of the IRF family of transcription factors in the lens. These findings have important implications for understanding signal transduction pathways in the lens.In collaboration with Drs. Paul Overbeek (Baylor College of Medicine) and Dr. Michael Robinson (Ohio State University) we developed transgenic mice with ectopic expression of FGF-3 in their lenses, which showed premature differentiation of their lens epithelia. We found that ectopic expression of secreted FGF-3 in the lens induces ectopic expression of the cyclin dependent kinase inhibitor p57/Kip2 gene, specifically expressed at the equatorial region of the wild type lens, followed by withdrawal from the cell cycle and differentiation of the entire lens epithelium. Taken together, the results obtained with both transgenes indicate that perturbation of gene transcription by ectopic activation of protein kinases involved in signal transduction pathways and the aberrant activation of transcription factors results in altered eye differentiation. - signal transduction, transgenic mice, eye gene expression, eye differentiation
