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F.J. Lovicu, P. Newitt, J. Boros, L.W. Reneker, J.W. McAvoy; Sef: A Negative Regulator of FGF Signalling in the Lens . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1985.
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Growth factors, including members of the FGF family, have been shown to play important roles in regulating lens epithelial cell proliferation and fiber differentiation, with recent evidence indicating that FGF signalling is essential for lens morphogenesis. Growth factor signalling, mediated via receptor tyrosine kinases (RTKs), is known to be tightly regulated by specific RTK signalling antagonists, including members of the Sef (similar expression to fgfs) and Sprouty (Spry) families, with Sef being more specific for FGF signalling. We have recently identified the presence of both Sef and Spry in the lens, with strongest expression in the lens epithelial cells. As FGFs play an important role in lens biology, we employed transgenic mouse strategies to identify the role these growth factor antagonists, in particular Sef, play in regulating lens cell behaviour.
A modified alpha–crystallin promoter was used to generate three lines of transgenic mice overexpressing Sef specifically in lenses of transgenic mice.
All transgenic lines of mice displayed microphthalmia, resulting from impaired lens and consequently eye development. With increased levels of Sef transgene expression at embryonic day 12.5, we observed the marked inhibition of primary lens fibre cell elongation and differentiation, consistent with a block in FGF signalling. This effect persisted in lenses of postnatal stages that continued to express high levels of Sef. We also noted apoptosis and a decrease in the number of lens epithelial cells; however, the rate of lens cell proliferation was relatively normal. Although fibre cell elongation was substantially inhibited, fibre–specific crystallins were still expressed in these lenses.
The normal expression patterns of Sef and Spry in the lens are consistent with a role for these molecules as negative regulators of growth factor signalling, potentially contributing to the establishment and maintenance of the lens epithelium. Any disruption to the normal expression of these genes may alter the responsiveness of lens cells to growth factors such as FGF, leading to aberrant cell proliferation and/or fibre cell differentiation. In conclusion, tight regulation of growth factors in the eye is essential for maintenance of the distinctive lens architecture, and it may be specific growth factor antagonists, such as Sef and Spry, that contribute to this regulation.
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