Systemic but not RPE specific deletion of REV-ERBα impairs visual function in mice

Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. In dry AMD, retinal pigment epithelium (RPE) dysfunction and atrophy can lead to photoreceptor cell death and in turn vision loss. We have previously shown that the nuclear receptor REV-ERBα has a protective effect against both age-related and oxidative stress-induced damage in the retinal pigment epithelium (RPE) in mouse models. Here we investigated if systemic and RPE-specific knockout of REV-ERBα affect retinal visual function with electroretinography (ERG) in aged mice.

Methods : Systemic Rev-erbα deficient (Rev-erbα^-/-) and RPE-specific Rev-erbα knockout (BEST1-cre:Rev-erbα^fl/fl) were validated for their knockout efficiency and specificity by RT-qPCR, Western blot and immunohistochemistry. Retinal function was assessed with scotopic ERG in 12-month-old Rev-erbα^-/-, BEST1-cre:Rev-erbα^fl/fl mice and their respective WT and fl/fl controls (n = 4-9 mice per group) after dark adaptation overnight. The saturating amplitude and sensitivity of rod and cone photoresponse a- and b-waves were analyzed.

Results : Knockout of REV-ERBα in Rev-erbα^-/- retinas was confirmed at protein levels in retinal lysate. RPE-specific knock-down of REV-ERBα in BEST1-Cre: Rev-erbα^fl/fl mice was confirmed with up to 80% efficiency. Rev-erbα^-/- mice showed significantly decreased visual response in ERG, with a marked decrease in a-wave, b-wave, and oscillatory potential amplitudes, compared with WT. However, no significant difference was observed in a-wave, b-wave or oscillatory response in BEST1-cre: Rev-erbα^fl/fl mice compared to fl/fl control mice.

Conclusions : These data suggest that REV-ERBα in retinal neurons but not RPE directly affects retinal visual function. This indicates REV-ERBα may have a neuronal intrinsic role in maintaining visual function in retinal neurons, including photoreceptors, bipolar and retinal ganglion cells.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.