The murine eye is composed of tissues that are derived from different cell lineages including ectoderm, neuroepithelium, neural crest, and mesoderm. Inductive interactions between these different tissues are, for the most part, thought to be mediated through growth factcr signaling. Fibroblast growth factor (FGF) family members expressed in the lens in transgenic mice can induce a switch in developmental fate for cells in the lens or cornea through stimulation of specific FGF receptors (FGFRs). Although FGFR stimulation can clearly influence cell fate, each cell type responds in a distinctive way implying that the intracellular targets are different in each cell type. At the moment we know little about the signaling cascades and target genes that are activated downstream of the FGFRs in ocular tissues. This application aims to identify some of the important targets by inappropriate activation or inhibition of signal transduction proteins and transcription factors in the lens and the cornea.
The specific aims of this grant application are: 1) to characterize transgenic mice with lens-specific expression of secreted versions of FGFR3(FR3) and FGFR1(FR1), and to use the FR3 mice to purify the endogenous factor that stimulates fiber cell maturation; 2) to express constitutively activated receptors (FGFR3, Trk and neu) in the lens epithelial cells in order to correlate signal transduction pathways with fiber cell induction and, also, to target expression of FGFR2b to the lens, and FGFR2c to the corneal epithelial cells; 3) to manipulate intracellular signal transduction programs in the lens and the cornea; and 4) to alter the comeal differentiation program by expression of lens-specific transcription factors. The proposed studies should provide insights into the signal transduction cascades that mediate lens and corneal cell fate specification and differentiation and, also, should improve our understanding of differential cellular responses to receptor activation.
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