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. 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.
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. 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.
Authors: Gennadiy Moiseyev; Ying Chen; Yusuke Takahashi; Bill X Wu; Jian-Xing Ma Journal: Proc Natl Acad Sci U S A Date: 2005-08-22 Impact factor: 11.205
Authors: Andreas Wenzel; Johannes von Lintig; Vitus Oberhauser; Naoyuki Tanimoto; Christian Grimm; Mathias W Seeliger Journal: Invest Ophthalmol Vis Sci Date: 2007-02 Impact factor: 4.799
Authors: Dusanka Deretic; Andrew H Williams; Nancy Ransom; Valerie Morel; Paul A Hargrave; Anatol Arendt Journal: Proc Natl Acad Sci U S A Date: 2005-02-22 Impact factor: 11.205
Authors: Samuel G Jacobson; Tomas S Aleman; Artur V Cideciyan; Elise Heon; Marcin Golczak; William A Beltran; Alexander Sumaroka; Sharon B Schwartz; Alejandro J Roman; Elizabeth A M Windsor; James M Wilson; Gustavo D Aguirre; Edwin M Stone; Krzysztof Palczewski Journal: Proc Natl Acad Sci U S A Date: 2007-09-11 Impact factor: 11.205
Authors: J Pang; S E Boye; B Lei; S L Boye; D Everhart; R Ryals; Y Umino; B Rohrer; J Alexander; J Li; X Dai; Q Li; B Chang; R Barlow; W W Hauswirth Journal: Gene Ther Date: 2010-03-18 Impact factor: 5.250
Authors: Kollu N Rao; Linjing Li; Wei Zhang; Richard S Brush; Raju V S Rajala; Hemant Khanna Journal: Hum Mol Genet Date: 2016-01-24 Impact factor: 6.150
Authors: Artur V Cideciyan; Tomas S Aleman; Sanford L Boye; Sharon B Schwartz; Shalesh Kaushal; Alejandro J Roman; Ji-Jing Pang; Alexander Sumaroka; Elizabeth A M Windsor; James M Wilson; Terence R Flotte; Gerald A Fishman; Elise Heon; Edwin M Stone; Barry J Byrne; Samuel G Jacobson; William W Hauswirth Journal: Proc Natl Acad Sci U S A Date: 2008-09-22 Impact factor: 11.205
Authors: Fan Yang; Hongwei Ma; Joshua Belcher; Michael R Butler; T Michael Redmond; Sanford L Boye; William W Hauswirth; Xi-Qin Ding Journal: FASEB J Date: 2016-09-13 Impact factor: 5.191
Authors: M Dominik Fischer; Gesine Huber; Susanne C Beck; Naoyuki Tanimoto; Regine Muehlfriedel; Edda Fahl; Christian Grimm; Andreas Wenzel; Charlotte E Remé; Serge A van de Pavert; Jan Wijnholds; Marek Pacal; Rod Bremner; Mathias W Seeliger Journal: PLoS One Date: 2009-10-19 Impact factor: 3.240