The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo
The absence of c-fos prevents light-induced apoptotic cell death of photoreceptors in retinal degeneration in vivo
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DOI：
10.1038/nm0397-346
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发表时间：
1997-03-01
期刊：
影响因子：
82.9
通讯作者：
Reme, CE
中科院分区：
文献类型：
--
作者：
Hafezi, F;Steinbach, JP;Reme, CE
最近在遗传性人类视网膜营养不良（称为视网膜色素变性）的动物模型中证实了视网膜中的细胞凋亡（1，2）。尽管最近的证据表明原癌基因c-fos是细胞凋亡的介导者（3-7），但其确切作用尚不清楚。事实上，在某些情况下，c-fos甚至可以防止细胞凋亡（8）。在视网膜中，c-fos在生理上以昼夜方式表达，并且可被光诱导（9，10）。我们先前在大鼠光感受器中观察到光诱导的剂量依赖性凋亡反应（11）。为了确定c-fos是否参与光诱导的细胞凋亡途径，我们使用了对照小鼠和缺乏c-fos的小鼠。我们发现，在暗适应和两个小时的光照下，两组动物都只表现出少量凋亡细胞。然而，在光照后12和24小时，对照组的细胞凋亡急剧增加，但在缺乏c-fos的小鼠中几乎不存在。因此，c-fos在光诱导的光感受器凋亡中是必需的。值得注意的是，在我们的系统和视网膜色素变性的动物模型中，c-fos持续上调伴随着凋亡性感光细胞死亡（Agarwal，N.例如，Invest.眼用酚维斯。Sci. Suppl.36，S638和Rich，K.A等人，Invest.眼用酚维斯。Sci. Suppl.35，1833）。因此，抑制c-fos表达可能代表一种新的治疗策略，以延缓视网膜营养不良和光诱导的视网膜变性的时间进程。
Apoptotic cell death in the retina was recently demonstrated in animal models of the hereditary human retinal dystrophy known as retinitis pigmentosa(1,2). Although recent evidence indicates that the proto-oncogene c-fos is a mediator of apoptosis(3-7), its precise role is unclear. In fact, under some conditions, c-fos may even protect against apoptotic cell death(8). In the retina, c-fos is physiologically expressed in a diurnal manner and is inducible by light(9,10). We previously observed a light-elicited, dose-dependent apoptotic response in rat photoreceptors(11). To determine whether c-fos is involved in the light-induced apoptotic pathway we have used control mice and mice lacking c-fos. We found that following dark adaptation and two hours of light exposure both groups of animals exhibited only a few apoptotic cells. However, at 12 and 24 additional hours after light exposure, apoptosis increased dramatically in controls but was virtually absent in those mice lacking c-fos. Therefore, c-fos is essential for light-induced apoptosis of photoreceptors. Notably, c-fos is continuously upregulated concomitant with apoptotic photoreceptor death in our system and in animal models of retinitis pigmentosa (Agarwal, N. et al., Invest. Ophthalmol. Vis. Sci. Suppl. 36, S638 and Rich, K.A, et al., Invest. Ophthalmol. Vis. Sci. Suppl. 35, 1833). Inhibition of c-fos expression might therefore represent a novel therapeutic strategy to retard the time course of retinal dystrophies and light-induced retinal degeneration.