Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 48, Issue 11, Pages 4907-4918Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.07-0428
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- NEI NIH HHS [EY13132, R01 EY006855-22, P30 EY001583, R01 EY013132-08, R01 EY006855, EY06855, R01 EY013132] Funding Source: Medline
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PURPOSE. The T4R RHO mutant dog retina shows retinal degeneration with exposures to light comparable to those used in clinical eye examinations of patients. To define the molecular mechanisms of the degeneration, AP-1 DNA-binding activity, composition, posttranslational modification of the protein complex, and modulation of ERK/MAPK signaling pathways were examined in light-exposed mutant retinas. METHODS. Dark-adapted retinas were exposed to short-duration light flashes from a retinal camera used clinically for retinal photography and were collected at different time points after exposure. Electrophoretic mobility shift assay ( EMSA), super-shift EMSA, Western blot analysis, and immunocytochemistry were used to examine AP-1 signaling. RESULTS. Exposure to light of mutant retinas significantly increased AP-1 DNA-binding activity by 1 hour after exposure, and levels remained elevated for 6 hours. Shielded mutant retinas had similar AP-1 levels to shielded or exposed wildtype retinas. The parallel phosphorylation of c-Fos and activation of ERK1/2 was detected only in exposed mutant retinas. Exposure to light changed the composition of the AP-1 protein complex in the mutant retina from c-Jun/Fra-1/c-Fos to JunB/c-Fos. Immunohistochemistry showed that the components of activated AP-1 ( JunB, and phosphorylated c-Fos, and phosphorylated ERK1/2 isoforms) were localized in Muller cells. CONCLUSIONS. The inner nuclear layer/Muller cell localization of the key proteins induced by light exposure raises the question of the direct involvement of AP-1 in mediating photoreceptor cell death in this model of autosomal dominant retinitis pigmentosa.
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