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J.W. McAvoy, Y. Chen, R.J. W. Stump, S. Ang, F.J. Lovicu; Overexpression of Sfrp2 Indicates Roles for Wnt/Frizzled Signaling in Lens Cell Differentiation and Maintenance . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1099.
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© ARVO (1962-2015); The Authors (2016-present)
Growth factors play key roles in lens development. Recently, members of the Wnt growth factor family, their Frizzled (Fz) receptors and various Wnt/Fz signaling regulators, have been shown to be expressed in the lens. Functional studies also point to an important role for the Wnt growth factor family in the differentiation of both lens epithelial and fiber cells. To further assess the role of Wnt/Fz signaling in lens development we ectopically expressed one of the members of the secreted frizzled–related protein (sfrp) family that reportedly act as Wnt/Fz signaling regulators. We selected Sfrp2 because it is expressed early in lens morphogenesis, in sites where Wnt/Fz signaling appears to be inhibited.
A modified alpha–crystallin promoter was used to generate several lines of transgenic mice that overexpressed Sfrp2 in the lens.
Two transgenic lines of mice, Sfrp2–m1 and Sfrp2–m2 displayed cataract resulting from abnormal lens development. In contrast with the wild type mouse lens, Sfrp2 is strongly expressed in the lens fibers of both transgenic lines from embryonic day 12.5 (E12.5) to postnatal day 21 (P21). In the Sfrp2–m2 transgenic mouse line, Sfrp2 is also weakly expressed in the epithelial cells at P21. Both transgenic lines had a severely disrupted lens cellular architecture at P21. In Sfrp2–m1 lenses, epithelial cells appeared to be arranged normally but had swollen/larger nuclei in comparison with wild type lenses. The epithelial cells in Sfrp2–m2 mice were vacuolated and had lost their apical baso–lateral polarity. Some epithelial cells had detached and appeared to be invading the fiber mass. In both transgenic mouse lines, in the lens cortex, where fiber cell maturation occurs, cells often appeared disorganised. Fiber cells were highly vacuolated and, in the innermost region, were often completely broken down. PAS staining showed that some transgenic mice lenses also had ruptured posterior capsules.
These results, utilizing a transgenic approach to impair Wnt/Fz signaling in the lens, are consistent with a role for Wnt/Fz signaling in epithelial cell maintenance and fiber differentiation. Currently it is not clear which Wnt/Fz signaling cascades are involved; however, further analyses should yield insights into the downstream signaling and cellular processes that are disrupted in the epithelium and differentiating fiber cells of these transgenic mice.
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