July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Norrin protects photoreceptors against inherited retinal degeneration
Author Affiliations & Notes
  • Andreas Ohlmann
    Dept. of Ophthalmology, University of Munich, Munich, Germany
  • Silke Eggerstorfer
    Dept. of Anatomy, University of Regensburg, Germany
  • Christian Eimer
    Dept. of Anatomy, University of Regensburg, Germany
  • Roswitha Seitz
    Dept. of Anatomy, University of Regensburg, Germany
  • Gregor Weber
    Dept. of Ophthalmology, University of Munich, Munich, Germany
  • Muna I Naash
    Department of Biomedical Engineering, University of Houston, Texas, United States
  • Siegfried Priglinger
    Dept. of Ophthalmology, University of Munich, Munich, Germany
  • Ernst R Tamm
    Dept. of Anatomy, University of Regensburg, Germany
  • Footnotes
    Commercial Relationships   Andreas Ohlmann, None; Silke Eggerstorfer, None; Christian Eimer, None; Roswitha Seitz, None; Gregor Weber, None; Muna Naash, None; Siegfried Priglinger, None; Ernst Tamm, None
  • Footnotes
    Support  German Research Foundation (DFG), Pro Retina Foundation, National Eye Institute # R01-EY10609 for MIN
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4882. doi:
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    • Get Citation

      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)

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Abstract

Purpose : 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).

Methods : 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.

Results : 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.

Conclusions : 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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