Characterization of Wnt signaling during photoreceptor degeneration.

PURPOSE The Wnt pathway is an essential signaling cascade that regulates multiple processes in developing and adult tissues, including differentiation, cellular survival, and stem cell proliferation. The authors recently demonstrated altered expression of Wnt pathway genes during photoreceptor death in rd1 mice, suggesting an involvement for Wnt signaling in the disease process. In this study, the authors investigated the role of Wnt signaling in retinal degeneration. METHODS The Wnt signaling reporter mouse line Tcf-LacZ was crossed with retinal degeneration rd1 mice, and beta-galactosidase expression was used to localize Wnt signaling during photoreceptor death. To analyze the role of Wnt signaling activation, primary mixed retinal cultures were prepared, and XTT and TUNEL assays were used to quantify cell death. Luciferase reporter assays were used to measure Wnt signaling. RESULTS The canonical Wnt signaling pathway was activated in Müller glia and the ganglion cell layer during rod photoreceptor degeneration in rd1/Tcf-LacZ mice. Wnt signaling was confirmed in cultured primary Müller glia. Furthermore, Wnt signaling activators protected photoreceptors in primary retinal cultures from H(2)O(2)-induced oxidative stress. The Wnt ligands Wnt5a, Wnt5b, Wnt10a, and Wnt13 were expressed in the degenerating retina and are candidate Wnt signaling activators in vivo. CONCLUSIONS 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 suggest that 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.