Abstract
Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.
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Abbreviations
- Nxnl1 :
-
nucleoredoxin-like 1
- RdCVF:
-
rod-derived cone viability factor
- RP:
-
retinitis pigmentosa
- TRX:
-
thioredoxins
- FGF2:
-
fibroblast growth factor 2
- MAPs:
-
microtubule-associated proteins
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Acknowledgements
We thank Prof Matt Lavail (University of California, San Francisco, CA, USA) for advice regarding ONL measurements and calculations. Jean Bennett and Tonia Rex (University of Philadelphia, PA, USA) for advice during this work. Amandine Langelé and Manuel Simonutti for technical assistance in ERG measurements. Isabelle Renault for technical assistance in the animal facility, Alain Trembleau (UPMC) for electron microscopy, Theo van Veen (University of Lund, Sweden) for the C3 H rd1 and wt mice. The post-mortem human brain tissues were obtained from NeuroCEB (Paris), thanks to Charles Duyckaerts (ICM). This work was supported by Inserm, the European commission (RETinal Training NETwork), ANR Maladies rares 2006 Grant and FFB USA.
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Cronin, T., Raffelsberger, W., Lee-Rivera, I. et al. The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress. Cell Death Differ 17, 1199–1210 (2010). https://doi.org/10.1038/cdd.2010.2
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