Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration.
Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration.
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发表时间：
1996-11
影响因子：
4.4
通讯作者：
R. M. Joseph;T. Li
中科院分区：
文献类型：
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作者：
R. M. Joseph;T. Li
目的验证抗凋亡蛋白Bcl-2或Bcl-XL基因在感光细胞中的过表达可能预防或延缓感光细胞变性的假说。方法通过视紫红质基因启动子调控bcl-2或bcl-XL转基因在感光细胞中的表达，建立转基因小鼠模型。将Bcl-2或bcl-XL转基因小鼠分别与携带rd/rd突变的小鼠品系和携带显性视紫红质基因突变的另一小鼠品系杂交;这两种遗传缺陷都会导致感光细胞变性。通过组织学和视网膜电图测量，研究了表达bcl转基因之一并携带rd同源突变或视紫红质异质突变的小鼠的感光细胞死亡。Bcl-2和bcl-XL转基因小鼠也在两种不同的实验条件下测试了对光诱导的感光细胞损伤的可能抗性。结果Bcl-2和bcl-XL转基因小鼠的感光细胞中均有表达。在rd和视紫红质突变小鼠中，bcl-2或bcl-XL转基因的表达并不能阻止或可测量地延迟感光细胞变性。凋亡相关的核DNA片段，在原位标记与末端脱氧核苷酸转移酶进行评估，存在于13日龄的RD/RD小鼠视网膜有或无转基因表达。在暴露于2小时的高强度光12天后，bcl-2转基因小鼠在中央视网膜中保留了大约4排感光细胞，而同窝对照组中没有感光细胞，而bcl-XL转基因小鼠对光损伤的抵抗力没有增加。bcl-2而不是bcl-XL转基因的表达也与视紫红质含量的减少有关。结论：bcl-2或bcl-XL转基因的过表达并不能拯救感光细胞免于由这两种基因突变引起的凋亡。在bcl-2转基因小鼠中观察到的对光损伤的抗性可能来自视紫红质含量的减少，而不是Bcl-2的抗细胞死亡活性。不受Bcl-2调节的细胞死亡途径可能在光感受器变性中起作用。
PURPOSE To test the hypothesis that overexpression of genes coding for the anti-apoptotic proteins Bcl-2 or Bcl-XL in photoreceptor cells may prevent or delay photoreceptor degenerations. METHODS Transgenic mice were generated in which the bcl-2 or bcl-XL transgenes were expressed in photoreceptor cells under the transcriptional control of a rhodopsin gene promoter. Bcl-2 or bcl-XL transgenic mice were crossed separately to a mouse strain carrying the rd/rd mutation and to another mouse line carrying a dominant rhodopsin gene mutation; both genetic defects result in photoreceptor degeneration. Photoreceptor cell death in mice expressing one of the bcl transgenes and carrying either the rd mutation homozygously or the rhodopsin mutation heterozygously was examined by histologic and electroretinographic measurements. Bcl-2 and bcl-XL transgenic mice also were tested for possible resistance to light-induced photoreceptor damage under two different experimental conditions. RESULTS Bcl-2 or bcl-XL transgenes were expressed in photoreceptor cells of all lines of transgenic mice. In both the rd and the rhodopsin mutant mice, expression of either bcl-2 or bcl-XL transgenes did not prevent or measurably delay photoreceptor degeneration. Apoptosis-related nuclear DNA fragmentation, as assessed by in situ labeling with terminal deoxynucleotidyl transferase, was present in 13-day-old rd/rd mouse retinas with or without transgene expression. Twelve days after exposure to 2 hours of high-intensity light, bcl-2 transgenic mice retained approximately four rows of photoreceptor cells in the central retina as compared to none in littermate controls, whereas bcl-XL transgenic mice showed no increased resistance to light damage. Expression of the bcl-2 but not the bcl-XL transgene also was associated with a reduction in rhodopsin content. CONCLUSIONS Overexpression of bcl-2 or bcl-XL transgenes does not rescue photoreceptor cells from apoptosis caused by the two genetic mutations tested. Resistance to light damage seen in the bcl-2 transgenic mice is likely from a reduction in rhodopsin content rather than an anti-cell death activity of Bcl-2. Cell death pathways not regulated by Bcl-2 may be operative in photoreceptor degeneration.