Department of Genetics, Institut de la Vision, INSERM, UPMC Univ Paris 06, UMR-S 968, CNRS 7210, Paris, France.
Cell Death Differ. 2010 Jul;17(7):1199-210. doi: 10.1038/cdd.2010.2. Epub 2010 Feb 5.
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.
Rod-derived cone viability factor (RdCVF) 是一种硫氧还蛋白样蛋白，对色素性视网膜炎（RP）等 rods-cone 变性疾病具有治疗潜力。RdCVF 治疗可有效减少 RP 啮齿动物模型中的 rods 损失。在这项研究中，我们通过分析缺乏 RdCVF 基因 Nxnl1 的小鼠表型来研究 RdCVF 在视网膜中的生理作用。尽管这些小鼠没有表现出明显的发育缺陷，但通过视网膜电图（ERG）记录到 cones 和 rods 功能的年龄相关下降以及视网膜暗适应延迟。这种功能变化伴随着 cones 密度降低 17%和外核层厚度降低 20%。视网膜转录组揭示了参与程序性细胞死亡、应激反应和氧化还原信号的基因表达的早期变化，随后是普遍的损伤反应，伴随着小胶质细胞激活、GFAP、FGF2 和脂质过氧化水平增加。此外，缺乏 Nxnl1 的小鼠的 cones 对氧化应激更敏感，在高氧条件下测量的 cone 闪烁 ERG 幅度降低了 65%。我们在这里表明，除了治疗特性外，RdCVF 基因在光感受器维持和抵抗视网膜氧化应激方面具有重要作用。
