Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage

Neurobiology of Disease

Ales Cvekl¹  Ying Yang¹  Cornelia Volz²  Herbert Jägle²  Mathias W. Seeliger³  Naoyuki Tanimoto³  Barbara M. Braunger⁴  Andreas Ohlmann⁴  Marcus Koch⁴  Ernst R. Tamm⁴  Michael R. Bösl⁵ 

[1] Albert Einstein-College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA;Department of Ophthalmology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany;Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, University of Tübingen, Schleichstr. 4/3, D-72076 Tübingen, Germany;Institute of Human Anatomy and Embryology, University of Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany;Max Planck Institute of Neurobiology, Am Klopferspitz 18A, 82152 Martinsried, Germany;

关键词: Endothelin receptor B;    Glial fibrillary acidic protein;    Brain-derived neurotrophic factor;    PI3K-Akt;    Retinal degeneration;   

DOI  :  

来源: DOAJ

【 摘 要 】

Norrin is a retinal signaling molecule which is expressed in Müller glia and binds to Frizzled-4 to activate canonical Wnt/β-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/β-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/β-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/β-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.

【 授权许可】

Unknown