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 journalArticle

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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 languageEnglish (US)
Pages (from-to)1126-1135
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume49
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

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Retinal Photoreceptor Cell Outer Segment
Retinaldehyde
Retinal Cone Photoreceptor Cells
Knockout Mice
Retinoids
Opsins
Esters
Retinal Rod Photoreceptor Cells
Retinal Degeneration
Vertebrate Photoreceptor Cells
Rhodopsin
Intraperitoneal Injections
Vitamin A
Breeding
Retina
Histology
Phenotype

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Feathers, K. L., Lyubarsky, A. L., Khan, N. W., Teofilo, K., Swaroop, A., Williams, D. S., ... Thompson, D. A. (2008). Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. Investigative Ophthalmology and Visual Science, 49(3), 1126-1135. https://doi.org/10.1167/iovs.07-1234

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 journalArticle

Feathers, KL, Lyubarsky, AL, Khan, NW, Teofilo, K, Swaroop, A, Williams, DS, Pugh Jr, EN & Thompson, DA 2008, 'Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments', Investigative Ophthalmology and Visual Science, vol. 49, no. 3, pp. 1126-1135. https://doi.org/10.1167/iovs.07-1234
Feathers, Kecia L. ; Lyubarsky, Arkady L. ; Khan, Naheed W. ; Teofilo, Karen ; Swaroop, Anand ; Williams, David S. ; Pugh Jr, Edward N ; Thompson, Debra A. / Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. In: Investigative Ophthalmology and Visual Science. 2008 ; Vol. 49, No. 3. pp. 1126-1135.
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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

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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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