Norrin: Molecular and functional properties of an angiogenic and neuroprotective growth factor Andreas Ohlmann 1 , Ernst R. Tamm * ,1 Institute of Human Anatomy and Embryology, University of Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany article info Article history: Available online 21 February 2012 Keywords: Angiogenesis Neuroprotection Wnt b-Catenin Retinopathy of prematurity Glaucoma Müller cells abstract Norrin is a secreted signaling molecule with structural and functional characteristics of an autocrine and/ or paracrine acting growth factor. In the eye, Norrin is constitutively expressed in Müller cells. Norrin specifically binds to Frizzled-4 receptors and activates the canonical Wnt/b-catenin signaling pathway that is profoundly enhanced when Tspan12 is present at the Norrin/Frizzled-4 receptor complex. In the absence of Norrin or Frizzled-4, intraretinal capillaries are not formed during developmental angio- genesis. As a result there is considerable evidence that Norrin and Frizzled-4 are part of an essential signaling system that controls the formation of the retinal vasculature during eye development. Intriguingly, Norrin promotes vessel regrowth and induces the formation of intraretinal capillaries following oxygen-induced retinopathy in mice, an animal model of retinopathy of prematurity. More- over, Norrin has pronounced neuroprotective properties on retinal ganglion cells (RGC) with the distinct potential to decrease the damaging effects of excitotoxic NMDA-induced RGC injury. The neuroprotective effects of Norrin similarly involve an activation of Wnt/b-catenin signaling and the subsequent induction of neuroprotective growth factor synthesis in Müller cells, such as that of fibroblast growth factor-2 (FGF2) or ciliary neurotrophic factor (CNTF). Overall, Norrin and the molecules involved in its signaling pathway appear to be promising targets to develop strategies that induce intraretinal vessel formation in patients suffering from ischemic retinopathies, or that increase RGC survival in glaucoma. Ó 2012 Elsevier Ltd. All rights reserved. Contents 1. Introduction ...................................................................................................................... 244 2. Molecular and structural characteristics of Norrin ..................................................................................... 244 2.1. Gene and protein structure .................................................................................................... 244 2.2. Expression and localization of Norrin ........................................................................................... 244 2.3. Signaling pathways of Norrin .................................................................................................. 244 2.4. Biochemical characteristics of Norrin ................................................ .......................................... 247 3. Functional properties of Norrin ....................................................... ............................................... 247 3.1. The angiogenic functions of Norrin .................................................. ........................................... 247 3.1.1. The role of Norrin in vascular pathology ............................................ ..................................... 250 3.2. The neuroprotective function of Norrin ......................................................................................... 251 3.3. The role of Norrin in the female reproductive system ......................................... ................................... 252 4. Different phenotypes of Norrin-, Frizzled-4-, Tspan12- and Lrp5-deficient mice ........................................................... 252 5. Histopathology and clinical signs of Norrie disease .................................................................................... 254 6. Mutations in NDP ............................................................. .................................................... 255 7. Future directions ............................................................. .................................................... 255 Acknowledgments .............................................................................................................. 255 References .............................................................. ...................................................... 256 * Corresponding author. Tel.: þ49 941 9432839; fax: þ49 941 9432840. E-mail address: ernst.tamm@vkl.uni-regensburg.de (E.R. Tamm). 1 Percentage of work contributed by each author in the production of the manuscript: Andreas Ohlmann: 50%; Ernst R. Tamm: 50%. Contents lists available at SciVerse ScienceDirect Progress in Retinal and Eye Research journal homepage: www.elsevier.com/locate/prer 1350-9462/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.preteyeres.2012.02.002 Progress in Retinal and Eye Research 31 (2012) 243e257