title: Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1.
abstract: 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.
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Ludwig F
authors.initials: LF
authors.lastname: Zeilbeck
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Birgit B
authors.initials: BB
authors.lastname: Müller
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Leopold
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Berna
authors.initials: B
authors.lastname: Senturk
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany. Electronic address: andreas.ohlmann@ur.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlmann
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D010100:Oxygen / Q000009:adverse effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D005136:Eye Proteins; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D010100:Oxygen
keywords: Angiogenesis; IGF-1; Norrin; Oxygen-induced retinopathy; Retinopathy of prematurity; Wnt signaling; β-catenin