The Functional Role of Norrin
Norrin is the gene product of the NDP gene that is mutated in Norrie disease. Previous data indicate a role of Norrin during retinal vascular development and a neuroprotective effect on retinal neurons.
Norrin is a secreted signaling protein that can activate the canonical Wnt / β-catenin signaling pathway via a specific binding to frizzled-4 receptors. During development, the Wnt / β-catenin signaling pathway is essential for normal development of retinal vasculature. A lack of Norrin causes a complete lack of intraretinal capillaries and a delayed formation of the retinal superficial vascular plexus. In a previous work we could demonstrate that a transgenic overexpression of Norrin could rescue the vascular phenotype of Norrin-deficient mice. In addition, following an oxygen-induced retinopathy, the model of retinopathy of prematurity in mice, Norrin promotes enhanced vessel regrowth into vaso-obliterated retinal areas and formation of intraretinal capillaries, and hereby inhibits the formation of preretinal neovascularization.
Further on, Norrin not only has angiogenic properties but also neuroprotective effects on retinal neurons. During retinal development in Norrin-deficient mice a continuous loss of retinal ganglion cells was observed. In line, after an acute NMDA-induced excitotoxic damage of retinal ganglion cells we could demonstrate that Norrin, independent from its angiogenic function, mediates neuroprotective properties on retinal neurons. The protective function of Norrin involves an enhanced expression of leukemia inhibitory factor (Lif), endothelin (Edn)2 and neuroprotective factors in müller cells. Homologues observations were made in mice with a transgenic overexpression of Norrin in the retinal pigment epithelium after an induction of an acute damage of photoreceptors. In damaged photoreceptors transgenic Norrin expression most likely mediates its effect via Wnt / β-catenin and Edn2 signaling and involves neurotrophic activities of Bdnf.
The analysis of Norrin-mediated downstream mechanisms and cellular interactions between retinal endothelial cells or neurons with glial cells is currently in the focus of our research.
Principal Investigator: Andreas Ohlmann
Team: Stephanie Leopold, Birgit Müller, Ludwig Zeilbeck
Grant Support: Research Unit (Forschergruppe) FOR 1075 “Regulation and pathology of homeostatic systems for visual function”, TP7, and Pro Retina Foundation, Germany
Funding period: 1.8.2011 - 31.7.2014