Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments

Kecia L. Feathers, Arkady L. Lyubarsky, Naheed W. Khan, Karen Teofilo, Anand Swaroop, David S. Williams, Edward N Pugh Jr, Debra A. Thompson

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1126-1135
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Issue number3
StatePublished - Mar 2008
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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