The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress
The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress
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DOI：
10.1038/cdd.2010.2
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发表时间：
2010-07-01
影响因子：
12.4
通讯作者：
Leveillard, T.
中科院分区：
文献类型：
--
作者：
Cronin, T.;Raffelsberger, W.;Leveillard, T.
视杆细胞源性视锥细胞活力因子（RdCVF）是一种硫氧还蛋白样蛋白，具有治疗视杆细胞营养不良如视网膜色素变性（RP）的潜力。RdCVF治疗有效减少RP啮齿动物模型中的视锥细胞损失。在这项研究中，我们调查的生理作用，RdCVF在视网膜上分析的表型缺乏RdCVF基因，Nxnl 1的小鼠。虽然小鼠没有表现出明显的发育缺陷，但视网膜电图（ERG）记录了与年龄相关的视锥细胞和视杆细胞功能的降低以及视网膜暗适应的延迟。这种功能变化伴随着锥体密度减少17%和外核层厚度减少20%。视网膜的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传导的基因表达的早期变化，随后是具有增加的小胶质细胞活化、GFAP、FGF 2和脂质过氧化水平的全身性损伤反应。此外，缺乏Nxnl 1的小鼠的视锥细胞对氧化应激更敏感，在高氧条件下测量的视锥细胞闪烁ERG振幅降低了65%。我们在这里表明，RdCVF基因，除了治疗特性，在感光细胞的维护和抗视网膜氧化应激的重要作用。Cell Death and Differentiation（2010）17，1199-1210; doi：10.1038/cdd.2010.2; 2010年2月5日在线发表
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. Cell Death and Differentiation (2010) 17, 1199-1210; doi:10.1038/cdd.2010.2; published online 5 February 2010