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R. E. I. Nakamura, Y. Wang, M. L. Bajenaru, R. K. Lee, A. S. Hackam; Identification of Wnt Signaling Activity in Retinal Ganglion Cells in the Normal and Glaucomatous Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5192.
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© ARVO (1962-2015); The Authors (2016-present)
An important therapeutic strategy for treating glaucoma and other optic neuropathies is to prevent retinal ganglion cell (RGC) death while maintaining neuronal function. Discovering signaling pathways that confer RGC survival will identify novel treatments for halting glaucoma progression and visual field loss. The Wnt pathway is an essential signaling cascade that is well characterized in development and oncology. We recently demonstrated that Wnt signaling rescued photoreceptors in retinal co-cultures exposed to oxidative stress (Yi, IOVS; 2007). In this study, we investigated Wnt signaling activity in RGCs in normal and high IOP mice.
Wnt activity and Wnt gene expression was localized in the Wnt signaling reporter mouse line Tcf-LacZ and the rat RGC cell line RGC-5 using immunohistochemistry. Wnt signaling was measured using luciferase reporter assays and beta-catenin nuclear localization in RGC-5 cells. Microarray analyses were performed on DBA/2J and C57Bl/6 mice using Affymetrix arrays.
Wnt pathway activation was identified in RGC and INL layers in normal mouse retina. We also localized Wnt ligands (Dkk3) and receptors (Fzd3, Krm1/2, and LRP6) to RGCs. Wnt signaling was stimulated in RGC-5 cells by incubation with the Wnt activators Wnt3a and LiCl. To explore the role Wnt signaling plays in RGC survival in glaucoma, we analyzed gene expression in 12 month old DBA/2J mice. We found increased expression of Wnt pathway activators and decreased Wnt inhibitors, compared with age-matched controls, suggesting that the Wnt pathway is activated during RGC death.
These data identify candidate Wnt activator proteins that are expressed during RGC death and demonstrate that RGCs are Wnt responsive cells. This suggests Wnt signaling is upregulated in RGCs in glaucomatous retinas. Because Wnt signaling is neuroprotective elsewhere in the retina and the CNS, we hypothesize that Wnt signaling protects RGCs in glaucoma.
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