Role of RdCVF and RdCVF2 in Light-induced Damage

Abstract

Purpose: : Thioredoxins play a crucial role in the redox signalling of photoreceptors since these cells have an accelerated metabolism and are submitted to constant oxidative stress generated by light. In this line, light-induced damage is an attractive model for retinal dystrophies that are mediated by excessive photo-transduction signalling. Rod-derived Cone Viability Factors (RdCVF and RdCVF2) are a novel type of growth factors identified through their ability to promote survival of cone photoreceptors. They are encoded by the nucleoredoxin-like genes Nxnl1 and Nxnl2 which belong to the family of thioredoxins. We generated Nxnl1-/- and Nxnl2-/- mice by homologous recombination, and studied the retinal phenotype induced by photo-oxidative stress.

Methods: : Nxnl1-/- and Nxnl2-/- mice, along with their wild-type (WT) controls, on a BALB/c background, were exposed for 1 hour to white light ranging from 1700 to 5000 lux. Outer Nuclear layer (ONL) thickness was measured 10 days after the challenge, as an indication of photoreceptor loss, consequence of the severity of light damage. TUNEL assay was used to measure levels of apoptosis in retinal specimens 24 hrs after light exposure.

Results: : After illumination at 1700 and 2500 lux, Nxnl1-/- and Nxnl2-/- mice ONLs are thinner than WT controls. By contrast , after illumination at 5000 lux, Nxnl1-/- ONL is thicker than the WT control, while Nxnl2-/- is as affected by light as the WT control. These data suggest that there are differences in the signalling mechanisms of both genes. TUNEL assays performed 24 hrs after light-induced damage correlate well with these observations.

Conclusions: : Our data suggests that Nxnl1 and Nxnl2 are involved in the defence of photoreceptors against oxidative stress. However their roles in photoreceptor cell survival are not completely redundant, such that the two factors may participate in different signalling pathways in response to oxidative stress.

Keywords: retina: distal (photoreceptors, horizontal cells, bipolar cells) • oxidation/oxidative or free radical damage • growth factors/growth factor receptors