TY - JOUR
T1 - Constitutive overexpression of Norrin activates Wnt/β-catenin and endothelin-2 signaling to protect photoreceptors from light damage
AU - Braunger, Barbara M.
AU - Ohlmann, Andreas
AU - Koch, Marcus
AU - Tanimoto, Naoyuki
AU - Volz, Cornelia
AU - Yang, Ying
AU - Bösl, Michael R.
AU - Cvekl, Ales
AU - Jägle, Herbert
AU - Seeliger, Mathias W.
AU - Tamm, Ernst R.
N1 - Funding Information:
The authors thank the excellent technical assistance from Katharina Fizia, Silvia Babl, Angelika Pach, Margit Schimmel and Elke Stauber. We also would like to thank Joachim Griesenbeck and Alexander Probst (University of Regensburg) for extremely valuable advice. This work has been supported by Deutsche Forschungsgemeinschaft Grant FOR 1075 (TP7) and by an RPB unrestricted grant to the Department of Ophthalmology and Visual Sciences of the AECOM.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Brain-derived neurotrophic factor
KW - Endothelin receptor B
KW - Glial fibrillary acidic protein
KW - PI3K-Akt
KW - Retinal degeneration
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U2 - 10.1016/j.nbd.2012.09.008
DO - 10.1016/j.nbd.2012.09.008
M3 - Article
C2 - 23009755
AN - SCOPUS:84867652327
SN - 0969-9961
VL - 50
SP - 1
EP - 12
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -