IOVS Antimicrobial Agents and Chemotherapy
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(Investigative Ophthalmology and Visual Science. 2007;48:5733-5741.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0097
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Characterization of Wnt Signaling during Photoreceptor Degeneration

Hyun Yi,1 Rei E. I. Nakamura,1,2 Othman Mohamed,3 Daniel Dufort,3 and Abigail S. Hackam1,2,4

1From the Bascom Palmer Eye Institute, 2Neuroscience Graduate Program, and 4Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida; and the 3Department of Obstetrics and Gynecology, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada.

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 β-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 H2O2-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.






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Copyright © 2007 by the Association for Research in Vision and Ophthalmology