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A. S. Hackam, H. Yi, R. E. I. Nakamura, O. Mohamed, D. Dufort; Wnt Signaling is a Novel Pro-Survival Pathway That is Activated During Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):629.
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© ARVO (1962-2015); The Authors (2016-present)
The Wnt pathway is an essential signaling cascade that mediates retinal development and is a critical regulator of cell survival in many tissues. Our research and others’ suggest that Wnt signaling may be involved in retinal degenerations, but its precise role in disease remains to be determined. In this study, we tested the hypothesis that Wnt signaling is a pro-survival pathway that is activated during retinal degeneration.
Tcf-LacZ transgenic mice, which express a reporter for Wnt signaling, were bred with retinal degeneration rd1 mice and immunohistochemistry was used to localize beta-gal expression. Primary retinal cultures were prepared from post-natal mice (P8) and cell viability was measured by Wst-1 assays. Wnt signaling was measured using luciferase reporter assays.
Activated Wnt signaling was localized to the INL and GCL during rod photoreceptor degeneration in rd1/Tcf-LacZ mice. Colocalization of beta-gal with glutamine synthetase indicated activated Wnt signaling in Muller glia. Consistent with this localization, we showed that cultured Muller glia activated the Wnt pathway in response to Wnt ligands. To determine potential functions of activated Wnt pathway in degenerating retina, we treated primary retinal cultures with hydrogen peroxide to induce oxidative stress. Peroxide reduced culture viability by 45% (p<0.001). Notably, the Wnt signaling activator SB216763 completely rescued the retinal cultures (p<0.001 compared with vehicle control), increasing the viability up to the level of non-peroxide treated cultures. Also, dose-dependent rescue was shown with the Wnt3a ligand activator. Furthermore, incubating the retinal cultures with the Wnt inhibitor Dkk1 reversed the protective effect of CNTF, suggesting that Wnt and growth factor pathways synergize in protecting the retina.
Our data indicate that Wnt signaling is activated in degenerating retina and protects retinal cultures from oxidative stress. We propose that Wnt activation, alone or in combination with growth factors, may increase the threshold for apoptosis and halt or delay further photoreceptor degeneration.
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