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

Barbara M. Braunger, Andreas Ohlmann, Marcus Koch, Naoyuki Tanimoto, Cornelia Volz, Ying Yang, Michael R. Bösl, Ales Cvekl, Herbert Jägle, Mathias W. Seeliger, Ernst R. Tamm

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalNeurobiology of Disease
Volume50
Issue number1
DOIs
StatePublished - Feb 2013

Fingerprint

Endothelin-2
Catenins
Endothelin B Receptors
Light
Brain-Derived Neurotrophic Factor
Transgenic Mice
Retina
Intravitreal Injections
Glial Fibrillary Acidic Protein
Neuroglia
Epithelium
Wounds and Injuries

Keywords

  • Brain-derived neurotrophic factor
  • Endothelin receptor B
  • Glial fibrillary acidic protein
  • PI3K-Akt
  • Retinal degeneration

ASJC Scopus subject areas

  • Neurology

Cite this

Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage. / Braunger, Barbara M.; Ohlmann, Andreas; Koch, Marcus; Tanimoto, Naoyuki; Volz, Cornelia; Yang, Ying; Bösl, Michael R.; Cvekl, Ales; Jägle, Herbert; Seeliger, Mathias W.; Tamm, Ernst R.

In: Neurobiology of Disease, Vol. 50, No. 1, 02.2013, p. 1-12.

Research output: Contribution to journalArticle

Braunger, BM, Ohlmann, A, Koch, M, Tanimoto, N, Volz, C, Yang, Y, Bösl, MR, Cvekl, A, Jägle, H, Seeliger, MW & Tamm, ER 2013, 'Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage', Neurobiology of Disease, vol. 50, no. 1, pp. 1-12. https://doi.org/10.1016/j.nbd.2012.09.008
Braunger, Barbara M. ; Ohlmann, Andreas ; Koch, Marcus ; Tanimoto, Naoyuki ; Volz, Cornelia ; Yang, Ying ; Bösl, Michael R. ; Cvekl, Ales ; Jägle, Herbert ; Seeliger, Mathias W. ; Tamm, Ernst R. / Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage. In: Neurobiology of Disease. 2013 ; Vol. 50, No. 1. pp. 1-12.
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abstract = "Norrin is a retinal signaling molecule which is expressed in M{\"u}ller 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.",
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