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P. J. Newitt, M. L. Robinson, J. W. McAvoy, F. J. Lovicu; Negative Regulation of FGF Signaling in the Lens by Sef. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2004.
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Sef (a transmembrane protein antagonistic for FGF signalling via FGF receptors 1 & 2) is primarily expressed in the lens epithelial cells (Boros et al., 2007, SCDB). Overexpression of full length Sef in the lens of transgenic mice hinders fiber cell elongation during lens morphogenesis. The main aims of this study were to better understand the mechanism(s) underlying this process, as well as to determine which ocular factors are important for the maintenance of Sef expression in the epithelium of the intact lens.
We characterised the progeny of transgenic lines of mice overexpressing Sef specifically in the lens, that were crossed to FGF receptor (FGFR1 & 2)-deficient lines. Moreover, we examined transgenic lines overexpressing hSef-b, a spliced isoform of Sef lacking a signal peptide sequence. Rat lens epithelial explants were also used in an attempt to identify the putative ocular factors that modulate Sef expression in vivo.
In contrast to full length Sef, overexpression of hSefb in lenses of transgenic mice did not impact on lens development. Furthermore, overexpression of full length Sef in lenses of transgenic mice deficient for FGFR1 & 2 was still able to hinder primary fiber cell elongation. These FGFR-deficient lenses were more sensitive to the effects of overexpressing Sef, displaying a more severe lens phenotype. In vitro studies also showed that aqueous but not vitreous humor was sufficient to maintain lens epithelial expression of Sef.
Our study demonstrated that membrane- associated Sef is required to influence FGF signalling in the lens. Moreover, this is the first report of Sef influencing FGFR activity, independent of FGFR1 and FGFR2. Our in vitro studies also indicate that aqueous-derived factors are required for the maintenance of Sef expression in the lens epithelium.
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