Braunger, Barbara M. and Ohlmann, Andreas and Koch, Marcus and Tanimoto, Naoyuki and Volz, Cornelia and Yang, Ying and Boesl, Michael R. and Cvekl, Ales and Jaegle, Herbert and Seeliger, Mathias W. and Tamm, Ernst R. (2013) Constitutive overexpression of Norrin activates Wnt/beta-catenin and endothelin-2 signaling to protect photoreceptors from light damage. NEUROBIOLOGY OF DISEASE, 50. pp. 1-12. ISSN 0969-9961,
Full text not available from this repository. (Request a copy)Abstract
Norrin is a retinal signaling molecule which is expressed in Muller glia and binds to Frizzled-4 to activate canonical Wnt/beta-catenin signaling. Norrin is part of an essential signaling system that controls the formation of retinal capillaries during development To evaluate neuroprotective properties of Norrin independently from its function during retinal angiogenesis, we generated transgenic mice (Rpe65-Norrin) that constitutively express Norrin in the retinal pigmented epithelium. Substantial amounts of Norrin were secreted into the outer retina, which triggered retinal Wnt/beta-catenin signaling in conjunction with an increase in the expression of endothelin-2 (EDN2), endothelin receptor B (EDNRB), and glial fibrillary acidic protein (GFAP). Photoreceptors of Norrin-overexpressing mice were significantly less vulnerable to light-induced damage compared to their wild-type littermates. Following light damage, we observed less apoptotic death of photoreceptors and a better retinal function than in controls. The protective effects were abolished if either Wnt/beta-catenin or EDN2 signaling was blocked by intravitreal injection of Dickkopf-1 or BQ788, respectively. Light-damaged retinae from transgenic mice contained higher amounts of brain-derived neurotrophic factor (BDNF) and pAkt than those of wild-type littermates. We conclude that constitutive overexpression of Norrin protects photoreceptors from light damage, an effect that is mediated by Wnt/beta-catenin and EDN2 signaling and involves neurotrophic activities of BDNF. The findings suggest that Norrin and its associated signaling pathways have strong potentials to attenuate photoreceptor death following injury. (C) 2012 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MULLER CELLS; RETINITIS-PIGMENTOSA; VASCULAR DEVELOPMENT; GROWTH-FACTORS; INNER RETINA; TRKB; NEUROTROPHINS; FRIZZLED-4; RECEPTOR; GENE; Endothelin receptor B; Glial fibrillary acidic protein; Brain-derived neurotrophic factor; PI3K-Akt; Retinal degeneration |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Abteilung für Pädiatrische Ophthalmologie, Strabismologie und Ophthalmogenetik Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Humananatomie und Embryologie > Prof. Dr. Ernst Tamm |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Apr 2020 09:37 |
| Last Modified: | 28 Apr 2020 09:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17253 |
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