THE ABSENCE OF C-FOS PREVENTS LIGHT-INDUCED APOPTOTIC CELL-DEATH OF PHOTORECEPTORS IN RETINAL DEGENERATION IN-VIVO

Apoptotic cell death in the retina was recently demonstrated in animal models of the hereditary human retinal dystrophy known as retinitis p igmentosa(1,2). Although recent evidence indicates that the proto-onco gene c-fos is a mediator of apoptosis(3-7), its precise role is unclea r. In fact, under some conditions, c-fos may even protect against apop totic cell death(8). In the retina, c-fos is physiologically expressed in a diurnal manner and is inducible by light(9,10). We previously ob served a light-elicited, dose-dependent apoptotic response in rat phot oreceptors(11). To determine whether c-fos is involved in the light-in duced apoptotic pathway we have used control mice and mice lacking c-f os. We found that following dark adaptation and two hours of light exp osure both groups of animals exhibited only a few apoptotic cells. How ever, at 12 and 24 additional hours after light exposure, apoptosis in creased dramatically in controls but was virtually absent in those mic e lacking c-fos. Therefore, c-fos is essential for light-induced apopt osis of photoreceptors. Notably, c-fos is continuously upregulated con comitant with apoptotic photoreceptor death in our system and in anima l models of retinitis pigmentosa (Agarwal, N. et al., Invest. Ophthalm ol. Vis. Sci. Suppl. 36, S638 and Rich, K.A, et al., Invest. Ophthalmo l. Vis. Sci. Suppl. 35, 1833). Inhibition of c-fos expression might th erefore represent a novel therapeutic strategy to retard the time cour se of retinal dystrophies and light-induced retinal degeneration.