Loss of bipolar cells resulting from the expression of bcl-2 directed by the IRBP promoter.

We have recently noted marked reductions in the electroretinographic (ERG) b-wave in HIBA transgenic mice expressing bcl-2 under control of the human IRBP promoter. These electrophysiological results are unexpected as this promoter has been shown to specifically target transgene expression to the rod and cone photoreceptors. Here, we have carried out a series of studies to better understand this result. ERGs were recorded from three lines of HIBA transgenic mice. Mice with higher levels of transgene expression developed progressive photoreceptor degeneration, and an associated reduction in the ERG a-wave. These higher-expressing lines also exhibited a severe reduction in the ERG b-wave that affected both rod- and cone-mediated responses. These mice were mated to L7 transgenic mice, which express beta-galactosidase in bipolar cells. In double transgenic mice, the ERG b-wave reduction was associated with a decrease in the number of bipolar cells in the inner retina. These results indicate that bcl-2, targeted to photoreceptors, can induce bipolar cell degeneration, and indicate that the potential benefit for bcl-2 in treating hereditary retinal disease appears limited.