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Andreas Ohlmann, Fabian Boesl, Konstantin Drexler, Ernst R Tamm; Endogenous WNT/β-catenin signaling in Müller cells protects retinal ganglion cells against excitotoxic damage. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2553.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the protective effects of endogenous Wnt/β-catenin signaling in Müller cells on acutely damaged retinal ganglion cells (RGC).Excitotoxic damage of RGC is attenuated by treatment with Norrin, which enhances retinal Wnt/β-catenin signaling. In consequence synthesis of neuroprotective molecules such as leukemia inhibitory factor (LIF), endothelin-2 and fibroblast growth factor is induced, which likely mediate the protective effects on damaged RGC. Since in cultured Müller cells Norrin leads to a Wnt/β-catenin-mediated enhanced expression of neuroprotective molecules, we hypothesized that the specific activation of Wnt/β-catenin signaling in Müller cells is sufficient to induce neuroprotective effects on RGC in vivo.
Conditional β-catenin deficiency in Müller cells was induced in Slc1a3CreERT/Ctnnbfl/fl mice by intraperitoneal injections of tamoxifen. To induce excitotoxic RGC damage 3µl N-Methyl-D-aspartate (10mM) were injected into the vitreous cavity. For quantification of neuronal damage the numbers of optic nerve axons and TUNEL positive cells in retinal ganglion cell and inner nuclear layers were quantified. In addition, western blot analyses for retinal β-catenin and real-time RT-PCR for LIF mRNA in retinal RNA were performed.
Tamoxifen treatment significantly reduced β-catenin levels by approximately 40% in retinae from Slc1a3CreERT/Ctnnbfl/fl mice compared to Cre negative controls. Two weeks after NMDA injection the number of optic nerve axons was reduced by 20% (13,677±926) in mice with β-catenin deficiency in Müller cells compared to control littermates (17,029±778; p<0.01). Further on, in retinae of Slc1a3CreERT/Ctnnbfl/fl mice a substantial increase of TUNEL positive cells in the RGC layer by 40% (560±46 per 1,000 µm retinal length; p < 0.05) was detected compared controls (398±47 per 1,000 µm retinal length). Intriguingly, no difference between both genotypes was seen when comparing the number of apoptotic amacrine cells in the inner nuclear layer. In addition, in mice with Müller cell β-catenin deficiency the induction of LIF mRNA after NMDA treatment was substantially smaller (16.9±6.7-fold) compared to NMDA treated controls (37.5±11.6-fold; p<0.05).
Endogenous Wnt/β-catenin signaling in Müller cells mediates protective effects on acutely damaged RGC, most likely via an enhanced expression of protective factors including LIF.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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