Nrl-Knockout Mice Deficient in Rpe65 Fail to Synthesize 11-cis Retinal and Cone Outer Segments

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...

Full description

Saved in:
Bibliographic Details
Published in:Investigative ophthalmology & visual science 2008-03, Vol.49 (3), p.1126-1135
Main Authors: Feathers, Kecia L, Lyubarsky, Arkady L, Khan, Naheed W, Teofilo, Karen, Swaroop, Anand, Williams, David S, Pugh, Edward N., Jr, Thompson, Debra A
Format: Article
Language:English
Subjects:
Animals
Basic-Leucine Zipper Transcription Factors - physiology
Biological and medical sciences
Blotting, Western
Carrier Proteins - physiology
Chromatography, High Pressure Liquid
cis-trans-Isomerases
Dark Adaptation
Electroretinography
Eye and associated structures. Visual pathways and centers. Vision
Eye Proteins - physiology
Female
Fluorescent Antibody Technique, Indirect
Fundamental and applied biological sciences. Psychology
Genotype
Injections, Intraperitoneal
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission
Ophthalmology
Retinal Cone Photoreceptor Cells - metabolism
Retinal Cone Photoreceptor Cells - physiopathology
Retinal Cone Photoreceptor Cells - ultrastructure
Retinal Degeneration - drug therapy
Retinal Degeneration - metabolism
Retinal Degeneration - physiopathology
Retinaldehyde - administration & dosage
Retinaldehyde - biosynthesis
Retinoids - metabolism
Rod Opsins - metabolism
Vertebrates: nervous system and sense organs
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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.
ISSN:0146-0404
1552-5783
1552-5783
DOI:10.1167/iovs.07-1234