Investigative Ophthalmology & Visual Science, Vol 37, 2434-2446, Copyright © 1996 by Association for Research in Vision and Ophthalmology

ARTICLES AND REPORTS

Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration

RM Joseph and T Li
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston 02114, USA.

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.

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