The molecular mechanisms by which cells are induced to differentiate in vivo is not understood for most cell types, yet these processes are fundamental to virtually every aspect of human health. The lens has become an increasingly popular organ system to dissect these developmental processes at the molecular level. This is due, in part, to its simplicity and accessibility. The lens is one of the few organs that normally continue to grow throughout the vertebrate life-span. This growth is a consequence of a continuous, characteristic pattern of proliferation and differentiation. Lens epithelial cells are the proliferative component of the lens, and these epithelial cells are induced to differentiate into fiber cells by an, as yet, undetermined molecular signal. Fibroblast growth factors (FGFs) possess the ability to induce lens fiber cell differentiation both in lens epithelial explants and in transgenic mice. While there are several FGFs expressed in the eye throughout development, it is unknown if these play an essential role in lens fiber cell differentiation. FGFs are thought to exert most of their biological effects through FGF receptor tyrosine kinases (FGFRs). There are three FGFR genes expressed in the developing lens, and null mutations exist for all three of these. Homozygous null mutations in FGFR1 and FGFR2 lead to embryonic lethality prior to lens formation, and mice deficient in FGFR3 have apparently normal lenses. The goal of this project is to determine if FGFRs play an essential role in the process of lens fiber cell differentiation. To do this, a method to delete specific gene expression in the lens epithelium will be developed using the Cre/loxP system of P1 bacteriophage. These mice will be crossed to mice carrying conditional mutations in FGFR1 or FGFR2. These strategies should avoid the problems of embryonic viability encountered with the traditionally constructed null alleles. In addition to determining if any single FGFR is essential for fiber cell differentiation, we will also create mice deficient in multiple FGFRs to determine if the loss of a single FGFR can be compensated for by the expression of other FGFRs.
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