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Inner retinal photoreception independent of the visual retinoid cycle.

ABSTRACT: Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65(-/-); rdta and lrat(-/-); rd/rd mutant mice. Unexpectedly, both rpe65(-/-); rdta and lrat(-/-); rd/rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd/rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65(-/-); rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65(-/-) and lrat(-/-) ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.

SUBMITTER: Tu DC

PROVIDER: S-EPMC1502474 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Inner retinal photoreception independent of the visual retinoid cycle.

Tu Daniel C DC Owens Leah A LA Anderson Lauren L Golczak Marcin M Doyle Susan E SE McCall Maureen M Menaker Michael M Palczewski Krzysztof K Van Gelder Russell N RN

Proceedings of the National Academy of Sciences of the United States of America 20060620 27

Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65(-/-); rdta and lrat(-/-); rd/rd ...[more]

PMID: 16788071

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Project description:In order to maintain visual sensitivity at all light levels, the vertebrate eye possesses a mechanism to regenerate the visual pigment chromophore 11-cis retinal in the dark enzymatically, unlike in all other taxa, which rely on photoisomerization. This mechanism is termed the visual cycle and is localized to the retinal pigment epithelium (RPE), a support layer of the neural retina. Speculation has long revolved around whether more primitive chordates, such as tunicates and cephalochordates, anticipated this feature. The two key enzymes of the visual cycle are RPE65, the visual cycle all-trans retinyl ester isomerohydrolase, and lecithin:retinol acyltransferase (LRAT), which generates RPE65's substrate. We hypothesized that the origin of the vertebrate visual cycle is directly connected to an ancestral carotenoid oxygenase acquiring a new retinyl ester isomerohydrolase function. Our phylogenetic analyses of the RPE65/BCMO and N1pC/P60 (LRAT) superfamilies show that neither RPE65 nor LRAT orthologs occur in tunicates (Ciona) or cephalochordates (Branchiostoma), but occur in Petromyzon marinus (Sea Lamprey), a jawless vertebrate. The closest homologs to RPE65 in Ciona and Branchiostoma lacked predicted functionally diverged residues found in all authentic RPE65s, but lamprey RPE65 contained all of them. We cloned RPE65 and LRATb cDNAs from lamprey RPE and demonstrated appropriate enzymatic activities. We show that Ciona ß-carotene monooxygenase a (BCMOa) (previously annotated as an RPE65) has carotenoid oxygenase cleavage activity but not RPE65 activity. We verified the presence of RPE65 in lamprey RPE by immunofluorescence microscopy, immunoblot and mass spectrometry. On the basis of these data we conclude that the crucial transition from the typical carotenoid double bond cleavage functionality (BCMO) to the isomerohydrolase functionality (RPE65), coupled with the origin of LRAT, occurred subsequent to divergence of the more primitive chordates (tunicates, etc.) in the last common ancestor of the jawless and jawed vertebrates.

Project description:PurposeTo determine whether disorganization of retinal inner layers (DRIL) on optical coherence tomography (OCT) is associated with ischemia on ultra-widefield fluorescein angiography (UWFFA) and with visual outcomes in eyes with acute, treatment-naïve central retinal vein occlusion (CRVO).DesignRetrospective, single-institution, longitudinal cohort study.ParticipantsTwenty-five consecutive patients with treatment-naïve CRVO and ≥ 1 year follow-up.MethodsTwo independent masked graders evaluated the extent of DRIL, ellipsoid zone disruption, external limiting membrane disruption, and other OCT parameters at the baseline, 6- month, 12-month, and final visits. Baseline UWFFA images were assessed for ischemic index values and foveal avascular zone (FAZ) enlargement.Main outcome measuresAssociations of DRIL with UWFFA findings and clinical outcomes including corrected visual acuity (VA).ResultsThe median time to final follow-up was 24 months (range 12.1 - 43.9 months). Median DRIL extent at baseline was 765 µm (range 0 - 1000 µm). Eighteen of 25 eyes (72%) had some degree of DRIL at baseline, and 20 of 25 eyes (80%) had cystoid macular edema (CME). Neither the presence nor extent of DRIL at baseline was associated with presenting VA. In a cross-sectional analysis of each visit, extent of DRIL correlated with worse VA at both the 6-month (ρ = 0.656; p = 0.001) and final (ρ = 0.509; p = 0.016) visits. At final follow-up, DRIL extent was the OCT parameter most strongly correlated with baseline ischemic index (ρ = 0.418; p = 0.047) and baseline enlarged FAZ (p = 0.057) on UWFFA. On multivariate regression analysis, DRIL extent at final follow-up was the only OCT parameter associated with worse VA (p = 0.013) and remained significant when accounting for CME as a potential confounder.ConclusionsExtent of DRIL was not associated with presenting VA in treatment-naïve eyes with acute CRVO. Following six months of follow-up however, DRIL extent correlated with worse VA and was predictive of worse VA throughout more than 2 years of follow-up. Ischemic features on UWFFA at baseline are predictive of the extent of DRIL development at final follow-up.

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Inner retinal photoreception independent of the visual retinoid cycle.

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Inner retinal photoreception independent of the visual retinoid cycle.

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