The goal of this project is to understand how aberrant lens expression of gamma interferon or FGF-3, activators of gene transcription by signal transduction pathways, perturbs normal eye development in transgenic mice. Constitutive expression of gammaIFN in the lens of transgenic mice provides a useful model to study cytokine signalling during embryonic eye development. The ectopic expression of gammaIFN and FGF-3 in the eye, allows us to understand how perturbation of gene transcription by ectopic activation of protein kinases involved in signal transduction and the aberrant activation of transcription factors results in altered eye differentiation. A collaboration between LMDB and the Laboratory of Immunology at the NEI resulted in the development of transgenic mice and rats with constitutive expression of gammaIFN in their eyes. This ongoing collaboration allowed us to study how constitutive expression of gammaIFN and its induction and activation of gammaIFN-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. Another collaboration, with Baylor College of Medicine, allowed us to develop transgenic mice with ectopic expression of FGF-3 in their lenses, with premature differentiation of lens central epithelia that resulted in lens expulsion from the eye. Taken together, the results obtained with both transgenes indicate that perturbation of lens gene transcription by ectopic activation of protein kinases involved in signal transduction and the aberrant activation of transcription factors results in altered eye differentiation. We found that ectopic expression of secreted FGF-3 in the lens induces KIP2 gene expression, a cyclin dependent kinase inhibitor, 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.
