Similarly, FGFs can induce lens differentiation in vivo: lens-specific expression of certain members of the FGF family induces premature differentiation of the epithelial cells ( Robinson et al., 1995b Lovicu and Overbeek, 1998 Robinson et al., 1998). Lower doses of FGFs induce the epithelial cells to proliferate and higher doses of FGFs induce the epithelial cells to differentiate into fiber cells ( McAvoy and Chamberlain, 1989). FGFR2IIIc binds to FGF1 and FGF4 but not FGF7 and FGF10 ( Ornitz et al., 1996).Īddition of FGFs to rodent lens epithelial explants induces cellular responses in a dose-dependant manner ( McAvoy and Chamberlain, 1989). For instance, FGFR2IIIb binds to FGF7 and FGF10 but not FGF5 and FGF6. These splice forms of each receptor differ in their ligand binding specificity ( Ornitz et al., 1996). With the exception of FGFR4, the C-terminal half of the third immunoglobulin loop of the receptors is encoded by alternatively spliced exons resulting in either the IIIb or the IIIc splice forms ( Szebenyi and Fallon, 1999). The extracellular portions of the receptors contain two or three immunoglobulin-like motifs (Ig loops) that are important for ligand binding. They are all structurally similar transmembrane receptor tyrosine kinases. To date, four high-affinity FGF receptors (FGFR1-FGFR4) have been identified. FGFs bind to and signal through low- and high-affinity FGF receptors (FGFRs) ( Szebenyi and Fallon, 1999). The FGF family has at least 23 different members and FGFs have been shown to be involved in various aspects of mammalian development ( Martin, 1998). Both in vitro and in vivo studies have implicated fibroblast growth factors (FGFs) in this process ( McAvoy and Chamberlain, 1989 Chow et al., 1995 Robinson et al., 1995a Robinson et al., 1995b Lovicu and Overbeek, 1998 Robinson et al., 1998 Stolen and Griep, 2000). It has been proposed that the differentiation signal that induces the epithelial cells to differentiate into fiber cells is a diffusible factor that is made and secreted into the vitreous humor by the neural retina ( McAvoy et al., 1999).
The newly formed lens acquires a distinct polarity that is maintained throughout life: the anterior cells are maintained as proliferating epithelial cells with cuboidal morphology, while the posterior cells are induced to differentiate as fiber cells with columnar morphology. Following induction, the head ectoderm thickens to form a lens placode, and subsequently the placode invaginates and pinches off to form the lens vesicle. In vertebrates, the lens is formed as a result of inductive interactions between the optic vesicle and head ectoderm. Based on these results we propose that the initiation of lens fiber cell differentiation in mice requires FGF receptor signaling and that one of the lens differentiation signals in the vitreous humor is a ligand for FR3, and is therefore likely to be an FGF or FGF-like factor. Though differentiation was delayed in FR3 mice, the lens epithelial cells still retained their intrinsic ability to respond to FGF stimulation.
Phosphorylation of Erk1 and Erk2 was reduced in the lenses of FR3 mice compared with nontransgenic mice. This delay is most apparent postnatally and correlates with appropriate changes in expression of marker genes including p57 KIP2, Maf and Prox1. Expression of FR3, but not FR1, leads to an expansion of proliferating epithelial cells from the anterior to the posterior side of the lens due to a delay in the initiation of fiber cell differentiation. To test this possibility, we have generated transgenic mice with ocular expression of secreted self- dimerizing versions of FGFR1 (FR1) and FGFR3 (FR3). Though FGFs have been shown to be sufficient for induction of lens differentiation both in vivo and in vitro, they have not been demonstrated to be necessary for endogenous initiation of fiber cell differentiation. The differentiation factors have been hypothesized to be members of the fibroblast growth factor (FGF) family. It has been proposed that the anterior-posterior polarity of the lens is imposed by factors present in the ocular media surrounding the lens (aqueous and vitreous humor). The vertebrate lens has a distinct polarity with cuboidal epithelial cells on the anterior side and differentiated fiber cells on the posterior side.
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