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H. Yi, R. Nakamura, O. Mohamed, D. Dufort, A. S. Hackam; Characterization of Wnt Signaling During Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3005.
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© ARVO (1962-2015); The Authors (2016-present)
The Wnt signaling pathway is an essential intercellular communication pathway that regulates neuronal development and disease. We recently demonstrated altered expression of Wnt pathway genes during photoreceptor death in the retinal degeneration 1 (rd1) mouse model, suggesting an involvement for Wnt signaling in the disease process. In this study, we investigated the role of Wnt signaling in retinal degeneration.
The Wnt signaling reporter mouse line Tcf-LacZ was bred with rd1 mice and beta-galactosidase expression was used to localize Wnt signaling during photoreceptor death. Wnt signaling was measured using luciferase reporter assays and beta-catenin localization.
The canonical Wnt signaling pathway was activated in Muller glia and the ganglion cell layer during rod photoreceptor degeneration in rd1/Tcf-LacZ mice. Wnt signaling wasconfirmed in cultured primary Muller glia. The Wnt ligands Wnt5a, Wnt5b, Wnt10a and Wnt13 were expressed in the degenerating retina and are candidate Wnt signaling activators in vivo. We also demonstrated that the Wnt regulator Dkk3 was secreted from Muller glia and that it potentiated Wnt signaling. To determine potential roles of activated Wnt signaling we induced oxidative stress-mediated photoreceptor death in primary mixed retinal cultures in the presence of Wnt signaling activators. Photoreceptors were significantly protected from dying by activating the Wnt pathway using a Wnt ligand or a GSKbeta inhibitor, as measured by TUNEL and XTT assays.
This study is the first demonstration that Wnt signaling is activated in the degenerating retina and that it protects retinal cultures from oxidative stress. These data suggestthat Wnt signaling is a component of the glial protective response during photoreceptor injury. Therefore, inducing 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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