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CE Reme, A Wenzel, F Hafezi, C Grimm; Light-Induced Photoreceptor Apoptosis: Protection by c-fos Gene Knock Out is Abolished by the 450-Leucin Variant in the Pigmentepithelial RPE65 Protein . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3721.
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Purpose: Previous studies using short term high-level light exposure have shown that a) rhodopsin is crucial for mediating light-induced photoreceptor apoptosis, b) lack of c-Fos completely protects against light damage, c) fast rhodopsin regeneration increases light damage susceptibility, d) rhodopsin regeneration kinetics depend on the amino acid composition of RPE65. Methionin at position 450 (450M/M) of RPE65 causes slow regeneration and reduces vulnerability against light damage, while leucine at this position (450L/L) accelerates regeneration and increases light damage susceptibility. c-fos knock out (ko) mice resistant to light damage were of the Rpe65 450M/M genotype. We tested whether the protective effect of c-fos ko could be overcome by the Rpe65 450L/L variant. Methods: Groups of c-fos ko mice with Rpe65 450M/M, 450L/L or 450L/M were exposed to 15'000lux of diffuse white light for 2 or 6h. Retinas were analyzed morphologically, the activity and composition of AP-1 was analyzed biochemically, the amenability of light induced AP-1 to glucocorticoid receptor mediated interference was tested by application of dexamethasone. Results: c-fos ko mice with Rpe65 450M/M were completely protected against light-induced apoptosis even after 6h of intense white light exposure. c-fos ko mice with Rpe65 450L/L or 450L/M, however, showed massive apoptotic photoreceptor death. AP-1 was activated in c-fos ko mice with Rpe65 450L/L, but not in c-fos ko mice with Rpe65 450M/M. While light-induced AP-1 in wildtype mice mainly consisted of c-Fos and Jun proteins, it consisted of mainly Fra-2, FosB and Jun proteins in c-fos ko mice with Rpe65L/L. Application of dexamethasone yielded almost full protection in the latter mice despite a different AP-1 composition. Conclusion: The Rpe65 450L/L variant can overcome the protective effect of c-fos ko. In contrast to c-fos ko mice with Rpe65 450M/M, AP-1 is activated during light damage in c-fos ko with Rpe65 450L/L. Apparently, the Rpe65 450L/L variant in contrast to 450M/M may allow the absorption of sufficient photons situation to induce apoptosis even in the c-fos knockout. Our data demonstrate that for light damage studies in mice it is essential to be aware of the Rpe65 genotype.
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