Photoreceptor cells in the vitiligo mouse die by apoptosis. TRPM-2/clusterin expression is increased in the neural retina and in the retinal pigment epithelium.
Photoreceptor cells in the vitiligo mouse die by apoptosis. TRPM-2/clusterin expression is increased in the neural retina and in the retinal pigment epithelium.
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发表时间：
1995-10
影响因子：
4.4
通讯作者：
S. B. Smith;N. Bora;D. McCOOL;G. Kutty;P. Wong;R. K. Kutty;B. Wiggert
中科院分区：
文献类型：
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作者：
S. B. Smith;N. Bora;D. McCOOL;G. Kutty;P. Wong;R. K. Kutty;B. Wiggert
目的 确定白癜风小鼠感光细胞死亡的机制，白癜风小鼠是一种视网膜变性模型，其中遗传缺陷不是视网膜特异性的，而是由编码基本螺旋-环-螺旋 DNA 转录因子的小眼 (mi) 基因的单点突变引起。方法 在第 1、2、4、6、8、16、32、40 和 52 周的动物中，使用 TUNEL 检测在固定的视网膜组织中检测凋亡细胞。电子显微镜分析用于确认细胞凋亡的形态学特征，Southern印迹分析用于检测核小体间DNA断裂。此外，还检查了与细胞凋亡相关的基因TRPM-2/簇蛋白的表达。结果 在超过正常视网膜程序性细胞死亡时间的年龄时，白癜风视网膜比对照组具有显着更多的 TUNEL 阳性感光细胞和更多带有浓缩染色质的感光细胞。 DNA 核小体间断裂梯甚至在 15 周时就出现在白癜风视网膜中，这一时间远远超过了对照中的发育细胞凋亡。白癜风神经视网膜中的 TRPM-2/簇蛋白 mRNA 水平最初与对照相似，但到 12 周时比对照高两倍。令人惊讶的是，突变体视网膜色素上皮中 TRPM-2/簇蛋白 mRNA 水平升高；尽管视网膜色素上皮细胞没有表现出凋亡的形态学证据，但一周时的表达量是正常值的两倍，并且在数月内保持升高状态。结论形态学和生化数据表明白癜风小鼠的感光细胞因凋亡而死亡。视网膜 TRPM-2/簇蛋白 mRNA 水平的增加可能是对这些事件的直接反应。然而，该基因在视网膜色素上皮中表达的增加可能反映了其在组织退化和膜重塑中的作用。提出了 mi 基因缺陷可能导致白癜风视网膜病变的机制。
PURPOSE To determine the mechanism of photoreceptor cell death in the vitiligo mouse, a model of retinal degeneration in which the genetic defect is not retina specific but is instead caused by single point mutation in the microphthalmia (mi) gene that codes for a basic helix-loop-helix DNA transcription factor. METHODS Detection of apoptotic cells was performed in fixed retinal tissue using the TUNEL assay in animals 1, 2, 4, 6, 8, 16, 32, 40, and 52 weeks. Electron microscopic analysis was used to confirm the morphologic hallmarks of apoptosis, and Southern blot analysis was used to detect internucleosomal DNA fragmentation. Additionally, the expression of a gene associated with apoptosis, TRPM-2/clusterin, was examined. RESULTS At ages beyond the time of normal retinal programmed cell death, vitiligo retinas had significantly more TUNEL-positive photoreceptor cells and more photoreceptor cells with condensed chromatin than controls. DNA internucleosomal fragmentation ladders were present in vitiligo retinas even as late as 15 weeks, a time well beyond developmental apoptosis in controls. TRPM-2/clusterin mRNA levels in vitiligo neural retinas were similar to controls initially but were two times greater than controls by 12 weeks. Surprisingly, TRPM-2/clusterin mRNA levels were elevated in the retinal pigment epithelium in the mutant; the expression at one week was two times greater than normals and remained elevated for many months, even though retinal pigment epithelial cells showed no morphologic evidence of apoptosis. CONCLUSIONS The morphologic and biochemical data suggest that photoreceptor cells die by apoptosis in vitiligo mice. The increased retinal TRPM-2/clusterin mRNA levels may be a direct response to these events. The increased expression of this gene in the retinal pigment epithelium, however, may reflect its role in tissue regression and membrane remodeling. Mechanisms by which the mi gene defect might result in the vitiligo retinopathy are proposed.