Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma

Leopold, Stephanie; Zeilbeck, Ludwig F.; Weber, G.; Seitz, R; Bösl, Michael R.; Jägle, Herbert; Fuchshofer, Rudolf; Tamm, Ernst R.; Ohlmann, Andreas

doi:10.1038/s41598-017-14423-8

Cited by 15 publications

(7 citation statements)

References 69 publications

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“…ERGs were recorded according to a procedure described previously [38,39]. Additionally, responses to flickering stimuli (intensity 0.5 log cds/m2) with frequencies ranging from 4 to 25 Hz were recorded.…”

Section: Electroretinogram Recordingmentioning

confidence: 99%

Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors

et al. 2020

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Genome duplication leads to an emergence of gene paralogs that are essentially free to undergo the process of neofunctionalization, subfunctionalization or degeneration (gene loss). Onecut1 (Oc1) and Onecut2 (Oc2) transcription factors, encoded by paralogous genes in mammals, are expressed in precursors of horizontal cells (HCs), retinal ganglion cells and cone photoreceptors. Previous studies have shown that ablation of either Oc1 or Oc2 gene in the mouse retina results in a decreased number of HCs, while simultaneous deletion of Oc1 and Oc2 leads to a complete loss of HCs. Here we study the genetic redundancy between Oc1 and Oc2 paralogs and focus on how the dose of Onecut transcription factors influences abundance of individual retinal cell types and overall retina physiology. Our data show that reducing the number of functional Oc alleles in the developing retina leads to a gradual decrease in the number of HCs, progressive thinning of the outer plexiform layer and diminished electrophysiology responses. Taken together, these observations indicate that in the context of HC population, the alleles of Oc1/Oc2 paralogous genes are mutually interchangeable, function additively to support proper retinal function and their molecular evolution does not follow one of the typical routes after gene duplication.

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Section: Electroretinogram Recordingmentioning

confidence: 99%

Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors

et al. 2020

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“…Nevertheless, DBA/2J mice made significant contribution to advances in glaucoma research and served as a valuable tool for translational research in glaucoma 24 37. Recently, a study reported ameliorated optic nerve degeneration in transgenic mice overexpressing Norrin crossed with DBA/2J mice (DBA/2J/Pax6-Norrin mice), providing a possible therapeutic target for glaucoma 38. Norrin is a secreted signalling molecule activating the Wnt/β-catenin pathway and protects retinal neurons after NMDA injection,39 suggesting that an activator of Norrin and its downstream signalling might be useful to prevent glaucomatous damage in human patients.…”

Section: Animal Models Of Glaucomamentioning

confidence: 99%

Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning

et al. 2018

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Glaucoma is one of the leading causes of vision loss in the world. Currently, pharmacological intervention for glaucoma therapy is limited to eye drops that reduce intraocular pressure (IOP). Recent studies have shown that various factors as well as IOP are involved in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. To date, various animal models of glaucoma have been established, including glutamate/aspartate transporter knockout (KO) mice, excitatory amino acid carrier 1 KO mice, optineurin E50K knock-in mice, DBA/2J mice and experimentally induced models. These animal models are very useful for elucidating the pathogenesis of glaucoma and for identifying potential therapeutic targets. However, each model represents only some aspects of glaucoma, never the whole disease. This review will summarise the benefits and limitations of using disease models of glaucoma and recent basic research in retinal protection using existing drugs.

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“…In our current study, we found an enhanced expression of Lif after treatment of wild-type mice retinae with NMDA and Norrin. However, in a mouse model with a chronic degeneration of RGC and an additional overexpression of Norrin in the retina, we also observed a protective effect of Norrin but no induction of Lif [45]. It is most likely, that other factors could be required for the Norrin-mediated induction of Lif after acute excitotoxic retinal damage.…”

Section: Discussionmentioning

confidence: 56%

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Kassumeh

Leopold

Fuchshofer

et al. 2020

Cells

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Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.

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Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma

Cited by 15 publications

References 69 publications

Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors

Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors

Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

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