APOPTOTIC PHOTORECEPTOR CELL-DEATH IN MOUSE MODELS OF RETINITIS-PIGMENTOSA
APOPTOTIC PHOTORECEPTOR CELL-DEATH IN MOUSE MODELS OF RETINITIS-PIGMENTOSA
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DOI：
10.1073/pnas.91.3.974
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发表时间：
1994-02-01
影响因子：
11.1
通讯作者：
ADLER, R
中科院分区：
文献类型：
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作者：
PORTERACAILLIAU, C;SUNG, CH;ADLER, R
视网膜色素变性（RP）是一组遗传性人类疾病，其中感光细胞变性导致视力丧失并最终导致失明。虽然在视紫红质，外周蛋白和cGMP磷酸二酯酶基因的突变已被确定在某些形式的RP，它仍然有待确定这些突变是否导致感光细胞死亡，通过坏死或凋亡机制。在本文中，我们报告了一个测试的假设，即感光细胞死亡发生的凋亡机制在三个小鼠模型的RP：视网膜变性缓慢（RDS）所造成的外周蛋白突变，视网膜变性（RD）所造成的缺陷cGMP磷酸二酯酶，和转基因小鼠携带的视紫红质Q344ter突变负责常染色体显性RP。两种互补的技术被用来检测凋亡特异性核小体间DNA片段：琼脂糖凝胶电泳和原位标记的凋亡细胞末端dUTP缺口末端标记。这两种方法都显示了在所有三种视网膜变性小鼠模型中光感受器的广泛凋亡。我们还表明，凋亡性死亡发生在正常发育过程中的视网膜，这表明不同的机制可以通过激活这些细胞的内在死亡程序导致感光细胞死亡。这些发现提出了通过干预凋亡机制本身来减缓视网膜变性的可能性。
Retinitis pigmentosa (RP) is a group of inherited human diseases in which photoreceptor degeneration leads to visual loss and eventually to blindness. Although mutations in the rhodopsin, peripherin, and cGMP phosphodiesterase genes have been identified in some forms of RP, it remains to be determined whether these mutations lead to photoreceptor cell death through necrotic or apoptotic mechanisms. In this paper, we report a test of the hypothesis that photoreceptor cell death occurs by an apoptotic mechanism in three mouse models of RP: retinal degeneration slow (rds) caused by a peripherin mutation, retinal degeneration (rd) caused by a defect in cGMP phosphodiesterase, and transgenic mice carrying a rhodopsin Q344ter mutation responsible for autosomal dominant RP. Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling. Both methods showed extensive apoptosis of photoreceptors in all three mouse models of retinal degeneration. We also show that apoptotic death occurs in the retina during normal development, suggesting that different mechanisms can cause photoreceptor death by activating an intrinsic death program in these cells. These findings raise the possibility that retinal degenerations may be slowed by interfering with the apoptotic mechanism itself.