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Andreas Ohlmann, Silke Eggerstorfer, Christian Eimer, Roswitha Seitz, Gregor Weber, Muna I Naash, Siegfried Priglinger, Ernst R Tamm; Norrin protects photoreceptors against inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4882.
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© ARVO (1962-2015); The Authors (2016-present)
Norrin is a secreted protein that activates the canonical Wnt/β-catenin signaling pathway via binding to frizzled-4 receptors. In previous studies we showed that Norrin mediates substantial neuroprotective effects on acutely and chronically damaged retinal neurons via canonical Wnt/β-catenin signaling. Here we analyzed if Norrin prevents photoreceptor degeneration in a mouse model of autosomal-dominant retinitis pigmentosa (RP).
Mice with a transgenic expression of Norrin in the retinal pigment epithelium under control of the Rpe65 promoter (Rpe65-Norrin, Braunger B, Neurobiol. Dis. 2013) were bred with VPP mice suffering from hereditary RP (VPP, Naash MI, Proc. Natl. Acad. Sci.1993). The retinal phenotype of Rpe65-Norrin, VPP, Rpe65-Norrin/VPP mice and wild-type littermates was analyzed and quantified by light microscopy and TUNEL labeling. Levels of β-catenin and pAKT, were analyzed by Western blotting. The expression of Gfap, Edn2, Lif and Fgf2 was studied by real-time RT-PCR. To block either Wnt/β-catenin or pAKT signaling, DKK-1 or Triciribine, respectively, were injected into the vitreous cavity.
A substantial loss of nuclei and a distinct number of TUNEL positive cells in the outer nuclear layer (ONL) were detected in VPP mice. Both effects were significantly reduced in Rpe65-Norrin/VPP mice. Expression levels of Gfap, Edn2, Lif and Fgf2 were decreased in double transgenic mice when compared to VPP mice. By western blot analysis, a significant increase of retinal β-catenin was detected in VPP and Rpe65-Norrin/VPP mice when compared to wild-type controls, but no difference between both transgenic groups was found. Following intravitreal injection of DKK-1, an inhibitor of Wnt/β-catenin signaling, no increase of TUNEL positive cells in the ONL was seen in double transgenic mice. In retinae of Rpe65-Norrin/VPP mice, enhanced pAKT signaling was observed by western blot analysis when compared to VPP littermates. After blocking the AKT pathway by intravitreal injection of Triciribine in double transgenic mice, a significant increase of TUNEL positive cells was detected.
Norrin protects photoreceptors against chronic degeneration, an effect that is most likely mediated via an enhanced pAKT signaling. Since the intravitreal injection of DKK-1 has no effect on photoreceptor apoptosis in double transgenic mice, the Norrin-mediated effect may involve other pathways than Wnt/β-catenin signaling.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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