Acute Radiolabeling of Retinoids in Eye Tissues of Normal and<i>Rpe65</i>-Deficient Mice

Qtaishat, Nasser M.; Redmond, T. Michael; Pepperberg, David R.

doi:10.1167/iovs.02-0679

Cited by 31 publications

(41 citation statements)

References 45 publications

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“…Because we now recognized unusual coactivator functions of Six3 upon rhodopsin transcription, we next investigated whether Six3 cooperates with previously characterized coactivators of rhodopsin promoter, such as NRL (24) and CRX1 (25). We found that Six3 is as effective as NRL or CRX1 in inducing transcription from the rhod-promoter reporter (Fig.…”

Section: Resultsmentioning

confidence: 87%

Repression of Six3 by a corepressor regulates rhodopsin expression

Manavathi¹,

Peng²,

Rayala³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Here, we provide gain-of-function, loss-of function, and molecular evidence supporting genetic interactions between metastasis associated protein 1 (MTA1) and Six3 and between Six3 and rhodopsin. We discovered that MTA1 physically interacts with the Six3 chromatin in a histone deacetylase-dependent manner, leading to transcriptional suppression of the Six3 gene. MTA1 is also a Six3-interacting corepressor that contributes to a self-negative regulation of Six3 transcription by Six3. In contrast, deletion of the MTA1 alleles in murine embryonic fibroblasts or its knockdown in rat retinal ganglion cells stimulates Six3 expression. MTA1 inactivation in the MTA1-null mice results in an elevated Six3 level and proliferation of the retina cells with no obvious abnormities in eye formation. However, unexpectedly, we discovered an enhanced recruitment of Six3 to the rhodopsin chromatin in retina from the MTA1-null mice; Six3's homeodomain interacts with specific DNA elements in the rhodopsin promoter to stimulate its transcription, resulting in increased rhodopsin expression. Further, in holoprosencephaly patients, Six3 protein with a naturally occurring deletion mutation in the helix 3 of the homeodomain does not bind to rhodopsin DNA or stimulate rhodopsin transcription, implying a potential defective rhodopsin pathway in the affected holoprosencephaly patients. Further Six3 cooperates with Crx or NRL in stimulating transcription from the rhodopsin-luc. These findings reveal a previously unrecognized role for the MTA1 as an upstream modifier of Six3 and indicate that Six3 is a direct stimulator of rhodopsin expression, thus revealing a putative role for the MTA1/ Six3/rhodopsin pathway in vertebrate eye.MTA1 ͉ transcription repressor ͉ histone deacetylase

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Section: Resultsmentioning

confidence: 87%

Repression of Six3 by a corepressor regulates rhodopsin expression

Manavathi¹,

Peng²,

Rayala³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Elsewhere, we speculated that plasma lipoproteins taken up by RPE are stripped of nutrients required by photoreceptors (e.g., xanthophylls, cholesterol, vitamin E) and repackaged for secretion in BrM as large, EC-rich apoB-lipoproteins ( 24 ). Lipoprotein secretion by RPE cells could dispose of excess UC and forestall toxicity in concert with recycling of EC and retinoids ( 187 ) back to plasma. Within the RPE, apically-directed recycling of docosahexaenoate to the retina ( 124 ) may thus be accompanied by an independent, basally-directed recycling by guest, on April 29, 2019 www.jlr.org Downloaded from…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

Curcio

Johnson

Huang

et al. 2010

Journal of Lipid Research

166

145

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“…A second possibility is that RPE65 is also involved in the mobilization of stored retinyl esters (43). The accumulation of retinyl esters is clearly dependent on LRAT activity (Figure 2), and these esters accumulate in Rpe65−/− mice.…”

Section: Accumulation Of All-trans-retinyl Esters In the Rpementioning

confidence: 99%

“…RPE65 was also proposed to be a retinyl esterbinding protein (27,44,45), hinting of its possible role in this process. Most insightful was the observation made by Pepperberg et al that, in normal RPE, there is a substantial exchange of all-trans-retinol with the blood circulation, whereas in Rpe65−/−mice, despite the presence of abnormally high molar levels of RPE retinyl esters, the outward movement is inhibited (43).…”

Section: Accumulation Of All-trans-retinyl Esters In the Rpementioning

confidence: 99%

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

Maeda

Imanishi

et al. 2006

Biochemistry

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Regeneration of the visual chromophore, 11-cis-retinal, is a critical step in restoring photoreceptors to their dark-adapted conditions. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and the retinal pigment epithelium (RPE). Disabling mutations in nearly all of the retinoid cycle genes are linked to human conditions that cause congenital or progressive defects in vision. Several mouse models with disrupted genes related to this cycle contain abnormal fatty acid retinyl ester levels in the RPE. To investigate the mechanisms of retinyl ester accumulation, we generated single or double knockout mice lacking retinoid cycle genes. Alltrans-retinyl esters accumulated in mice lacking RPE65, but they are reduced in double knockout mice also lacking opsin, suggesting a connection between visual pigment regeneration and the retinoid cycle. Only Rdh5-deficient mice accumulate cis-retinyl esters, regardless of the simultaneous disruption of RPE65, opsin, and prRDH. 13-cis-Retinoids are produced at higher levels when the flow of retinoid through the cycle was increased, and these esters are stored in specific structures called retinosomes. Most importantly, retinylamine, a specific and effective inhibitor of the 11-cisretinol formation, also inhibits the production of 13-cis-retinyl esters. The data presented here support the idea that 13-cis-retinyl esters are formed through an aberrant enzymatic isomerization process.Vitamin A transformations in the eye are essential for vision. Absorption of light by the vitamin A-derived chromophore of visual pigments, 11-cis-retinal, leads to its photoisomerization to all-trans-retinal and the initiation of the signal transduction cascade (1-4). Through a chain of reactions, all-trans-retinal is recycled enzymatically back to 11-cis-retinal (5-8). These retinoid cycle reactions (Figure 1) take place in the outer segments of photoreceptor cells and in the adjacent retinal pigment epithelium (RPE). 1 Characterization of the knockout mice lacking genes involved in the retinoid cycle provides important insight into the flow of retinoids in the eye.11-cis-Retinol dehydrogenase (RDH), also known as RDH5, catalyzes the final oxidation reaction of 11-cis-retinol in the RPE (9, 10). Although RDH5 is responsible for the majority of 11-cis-RDH activity, RDH11 and other RDHs also have a measurable role in regenerating the visual pigment by complementing RDH5 in RPE cells (11). Disruption of the gene encoding RDH5 causes fundus albipunctatus in humans (12,13). Fundus albipunctatus is an autosomal recessive form of congenital stationary night blindness characterized by the appearance of numerous small white dots located in the RPE, a delayed course of dark adaptation, and † This research was supported by NIH Grant EY09339. Lipid droplet-like organelles known as retinosomes were characterized as specific sites of alltrans-retinyl ester accumulation in the RPE (19,20). All-trans-retinyl esters accumulate in the RPE of wild-type mice as the...

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Acute Radiolabeling of Retinoids in Eye Tissues of Normal andRpe65-Deficient Mice

Cited by 31 publications

References 45 publications

Repression of Six3 by a corepressor regulates rhodopsin expression

Repression of Six3 by a corepressor regulates rhodopsin expression

Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

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