PMID- 23009755
OWN - NLM
STAT- MEDLINE
DCOM- 20130531
LR  - 20121231
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 50
DP  - 2013 Feb
TI  - Constitutive overexpression of Norrin activates Wnt/beta-catenin and endothelin-2 
      signaling to protect photoreceptors from light damage.
PG  - 1-12
LID - S0969-9961(12)00322-1 [pii]
LID - 10.1016/j.nbd.2012.09.008 [doi]
AB  - Norrin is a retinal signaling molecule which is expressed in Muller glia and 
      binds to Frizzled-4 to activate canonical Wnt/beta-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/beta-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/beta-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/beta-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.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Braunger, Barbara M
AU  - Braunger BM
AD  - Institute of Human Anatomy and Embryology, University of Regensburg, 
      Universitatsstr. 31, D-93053 Regensburg, Germany. 
      Barbara.Braunger@vkl.uni-regensburg.de
FAU - Ohlmann, Andreas
AU  - Ohlmann A
FAU - Koch, Marcus
AU  - Koch M
FAU - Tanimoto, Naoyuki
AU  - Tanimoto N
FAU - Volz, Cornelia
AU  - Volz C
FAU - Yang, Ying
AU  - Yang Y
FAU - Bosl, Michael R
AU  - Bosl MR
FAU - Cvekl, Ales
AU  - Cvekl A
FAU - Jagle, Herbert
AU  - Jagle H
FAU - Seeliger, Mathias W
AU  - Seeliger MW
FAU - Tamm, Ernst R
AU  - Tamm ER
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120923
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Endothelin-2)
RN  - 0 (Eye Proteins)
RN  - 0 (Ndph protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Wnt Proteins)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Endothelin-2/*metabolism
MH  - Eye Proteins/*metabolism
MH  - Light/adverse effects
MH  - Mice
MH  - Mice, Transgenic
MH  - Nerve Tissue Proteins/*metabolism
MH  - Photoreceptor Cells/*metabolism/pathology/radiation effects
MH  - Real-Time Polymerase Chain Reaction
MH  - Retina/metabolism/pathology/radiation effects
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology/radiation effects
MH  - Wnt Proteins/*metabolism
MH  - beta Catenin/*metabolism
EDAT- 2012/09/27 06:00
MHDA- 2013/06/01 06:00
CRDT- 2012/09/27 06:00
PHST- 2012/05/07 00:00 [received]
PHST- 2012/09/12 00:00 [revised]
PHST- 2012/09/15 00:00 [accepted]
PHST- 2012/09/27 06:00 [entrez]
PHST- 2012/09/27 06:00 [pubmed]
PHST- 2013/06/01 06:00 [medline]
AID - S0969-9961(12)00322-1 [pii]
AID - 10.1016/j.nbd.2012.09.008 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2013 Feb;50:1-12. doi: 10.1016/j.nbd.2012.09.008. Epub 2012 Sep 
      23.