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Kecia L. Feathers, Arkady L. Lyubarsky, Naheed W. Khan, Karen Teofilo, Anand Swaroop, David S. Williams, Edward N. Pugh, Jr, Debra A. Thompson; Nrl-Knockout Mice Deficient in Rpe65 Fail to Synthesize 11-cis Retinal and Cone Outer Segments. Invest. Ophthalmol. Vis. Sci. 2008;49(3):1126-1135. doi: 10.1167/iovs.07-1234.
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© ARVO (1962-2015); The Authors (2016-present)
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 11-cis retinal by intraperitoneal injection.
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.
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