OVEREXPRESSION OF BCL-2 OR BCL-X(L) TRANSGENES AND PHOTORECEPTOR DEGENERATION

Purpose. To test the hypothesis that overexpression of genes coding fo r the anti-apoptotic proteins Bcl-2 or Bcl-X(L) in photoreceptor cells may prevent or delay photoreceptor degenerations. Methods. Transgenic mice were generated in which the bcl-2 or bcl-X(L) transgenes were ex pressed in photoreceptor cells under the transcriptional control of a rhodopsin gene promoter. Bcl-2 or bcl-X(L) transgenic mice were crosse d separately to a mouse strain carrying the rd/rd mutation and to anot her mouse line carrying a dominant rhodopsin gene mutation; both genet ic defects result in photoreceptor degeneration. Photoreceptor cell de ath in mice expressing one of the bcl transgenes and carrying either t he rd mutation homozygously or the rhodopsin mutation heterozygously w as examined by histologic and electroretinographic measurements. Bcl-2 and bcl-X(L) transgenic mice also were tested for possible resistance to light-induced photoreceptor damage under two different experimenta l conditions. Results. Bcl-2 or bcl-X(L) transgenes were expressed in photoreceptor cells of all lines of transgenic mice. In both the rd an d the rhodopsin mutant mice, expression of either bcl-2 or bcl-X(L) tr ansgenes did not prevent or measurably delay photoreceptor degeneratio n. Apoptosis-related nuclear DNA fragmentation, as assessed by in situ labeling with terminal deoxynucleotidyl transferase, was present in 1 3-day-old rd/rd mouse retinas with or without transgene expression. Tw elve days after exposure to 2 hours of high-intensity light, bcl-2 tra nsgenic mice retained approximately four rows of photoreceptor cells i n the central retina as compared to none in littermate controls, where as bcl-X(L) transgenic mice showed no increased resistance to light da mage. Expression of the bcl-2 but not the bcl-X(L) transgene also was associated with a reduction in rhodopsin content. Conclusions. Overexp ression of bcl-2 or bcl-X(L) transgenes does not rescue photoreceptor cells from apoptosis caused by the two genetic mutations tested. Resis tance to light damage seen in the bcl-2 transgenic mice is likely from a reduction in rhodopsin content rather than an anti-cell death activ ity of Bcl-2. Cell death pathways not regulated by Bcl-2 may be operat ive in photoreceptor degeneration.