Secreted FGFR3, but not FGFR1, inhibits lens fiber differentiation.
The vertebrate lens has a distinct polarity with cuboidal epithelial cells on the anterior side and differentiated fiber cells on the posterior side. 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 differentiation factors have been hypothesized to be members of the fibroblast growth factor (FGF) family. 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. To test this possibility, we have generated transgenic mice with ocular expression of secreted self-dimerizing versions of FGFR1 (FR1) and FGFR3 (FR3). 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. This delay is most apparent postnatally and correlates with appropriate changes in expression of marker genes including p57(KIP2), Maf and Prox1. Phosphorylation of Erk1 and Erk2 was reduced in the lenses of FR3 mice compared with nontransgenic mice. Though differentiation was delayed in FR3 mice, the lens epithelial cells still retained their intrinsic ability to respond to FGF stimulation. 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.
Govindarajan
V
V
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Overbeek
P A
PA
D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D003459:Crystallins / Q000096:biosynthesis; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins / Q000302:isolation & purification; D004627:Embryonic Induction; D004847:Epithelial Cells; D005346:Fibroblast Growth Factors; D018398:Homeodomain Proteins / Q000302:isolation & purification; D007908:Lens, Crystalline / Q000098:blood supply / Q000166:cytology* / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000302:isolation & purification; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification; D051257:Proto-Oncogene Proteins c-maf; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D019076:Transgenes; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein
C493965:Cdkn1c protein, mouse; D003459:Crystallins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C495608:Maf protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D017468:Receptors, Fibroblast Growth Factor; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases