Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 1126-1135 |
| Number of pages | 10 |
| Journal | Investigative Ophthalmology and Visual Science |
| Volume | 49 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience
Cite this
Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. / Feathers, Kecia L.; Lyubarsky, Arkady L.; Khan, Naheed W.; Teofilo, Karen; Swaroop, Anand; Williams, David S.; Pugh Jr, Edward N; Thompson, Debra A.
In: Investigative Ophthalmology and Visual Science, Vol. 49, No. 3, 03.2008, p. 1126-1135.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments
AU - Feathers, Kecia L.
AU - Lyubarsky, Arkady L.
AU - Khan, Naheed W.
AU - Teofilo, Karen
AU - Swaroop, Anand
AU - Williams, David S.
AU - Pugh Jr, Edward N
AU - Thompson, Debra A.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
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U2 - 10.1167/iovs.07-1234
DO - 10.1167/iovs.07-1234
M3 - Article
VL - 49
SP - 1126
EP - 1135
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 3
ER -