PURPOSE. TO define rod and cone function further in terms of visual cycle mechanism, the retinal phenotype resulting from Rpe65 (retinoid isomerase I) deficiency in Nrl -/- mice having a single class of photoreceptors resembling wild-type cones was characterized and outcomes of retinoid supplementation evaluated. METHODS. Rpe65 -/- /Nrl -/- mice were generated by breeding Rpe65 -/- and Nrl -/- strains. Retinal histology, protein expression, retinoid content, and electroretinographic (ERG) responses were evaluated before and after treatment with 1 l-cis retinal by intraperitoneal injection. RESULTS Retinas of young Rpe65 -/- /Nrl -/- mice exhibited normal lamination, but lacked intact photoreceptor outer segments at all ages examined. Rpe65, Nrl, and rhodopsin were not detected, and S-opsin and M/L-opsin levels were reduced. Retinyl esters were the only retinoids present. In contrast, Nrl -/- mice exhibited decreased levels of retinaldehydes and retinyl esters, and elevated levels of retinols. ERG responses were elicited from Rpe65 -/- /Nrl -/- mice only at the two highest intensities over a 4-log-unit range. Significant retinal thinning and outer nuclear layer loss occurred in Rpe65 -/- Nrl -/- mice with aging. Administration of exogenous 11-cis retinal did not rescue retinal morphology or markedly improve ERG responses. CONCLUSIONS. The findings provide clarification of reported cone loss of function in Rpe65 -/- /Nrl -/- mice, now showing that chromophore absence results in destabilized cone outer segments and rapid retinal degeneration. The data support the view that rod-dominant retinas do not have a cone-specific mechanism for 11-cis retinal synthesis and have potential significance for therapeutic strategies for rescue of cone-rich retinal regions affected by disease in the aging human population.
ASJC Scopus subject areas
- Sensory Systems
- Cellular and Molecular Neuroscience