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Exp Eye Res. 2016 Apr;145:317-326. doi: 10.1016/j.exer.2015.12.001. Epub 2015 Dec 17.

Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1.

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Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany. Electronic address:


Norrin is an angiogenic signaling molecule that activates canonical Wnt/β-catenin signaling, and is involved in capillary formation in retina and brain. Moreover, Norrin induces vascular repair following an oxygen-induced retinopathy (OIR), the model of retinopathy of prematurity in mice. Since insulin-like growth factor (IGF)-1 is a very potent angiogenic molecule, we investigated if IGF-1 is a downstream mediator of Norrin's angiogenic properties. In retinae of transgenic mice with an ocular overexpression of Norrin (βB1-Norrin), we found at postnatal day (P)11 a significant increase of IGF-1 mRNA compared to wild-type littermates. In addition, after treatment of cultured Müller cells or dermal microvascular endothelial cells with Norrin we observed an increase of IGF-1 and its mRNA, an effect that could be blocked with DKK-1, an inhibitor of Wnt/β-catenin signaling. When OIR was induced, the expression of IGF-1 was significantly suppressed in both transgenic βB1-Norrin mice and wild-type littermates when compared to wild-type animals that were housed in room air. Furthermore, at P13, one day after the mice had returned to normoxic conditions, IGF-1 levels were significantly higher in transgenic mice compared to wild-type littermates. Finally, after intravitreal injections of inhibitory α-IGF-1 antibodies at P12 or at P12 and P14, the Norrin-mediated vascular repair was significantly attenuated. We conclude that Norrin induces the expression of IGF-1 via an activation of the Wnt/β-catenin signaling pathway, an effect that significantly contributes to the protective effects of Norrin against an OIR.


Angiogenesis; IGF-1; Norrin; Oxygen-induced retinopathy; Retinopathy of prematurity; Wnt signaling; β-catenin

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