New insights into retinoid metabolism and cycling within the retina

In the paper

“Data to support this come from Lrat-/- mouse studies (Fan et al., 2008; Zhang et al., 2008), where the lack of esterification of all-trans retinol in the RPE, the substrate for RPE65-dependent isomerization (Moiseyev et al., 2003), leads to a similar degeneration of cones as observed in the Rpe65-/- mouse.”

What the sources say

• ?Not checked — no full text of the sourcecites Fan et al., 2008 source
• Supported

  The Introduction reports that Lrat−/− mice have only trace amounts of retinyl esters, consistent with a block at the esterification step. The Results section reports cone loss in both Lrat−/− and Rpe65−/− mice, with no significant difference in their overall cone populations, although regional losses differ. The substrate detail is separately cited to Moiseyev et al. in the citing sentence. (LLM, conf=0.91)

  cites Zhang et al., 2008 source
• ?Not checked — no full text of the sourcecites Moiseyev et al., 2003 source

In the paper

“Salamander cones maintained within an isolated retina free of the RPE recover light sensitivity after bleaching; however, this recovery disappears in bleached cones disassociated from the retina (Wang et al., 2009).”

What the sources say

• Supported

  The Results section, “The Retina Promotes Cone Dark Adaptation,” reports that cones in a whole isolated salamander retina recovered sensitivity after bleaching without pigment epithelium or added chromophore. Under the same bleaching conditions, cones dissociated from the retina before bleaching showed persistent desensitization unless given exogenous chromophore. (LLM, conf=0.94)

  cites Wang et al., 2009 source

In the paper

“Knocking down the expression of CRALBP in the Müller cells of zebrafish larvae by using antisense morpholinos results in a substantial decrease in 11-cis retinal and reduction in light sensitivity, supporting the key role of this protein (Collery et al., 2008; Fleisch et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Collery et al., 2008 source
• Supported

  The section on 11-cis-retinal reports that knocking down Cralbp b, the Müller-cell paralog, reduced 11-cis-retinal to about 50% of control levels. The visual-performance section reports reduced light responsiveness in Cralbp-deficient larvae, with a more pronounced effect from Müller-cell Cralbp b deficiency. (LLM, conf=0.93)

  cites Fleisch et al., 2008 source

In the paper

“Mice whose RPE65 gene has been knocked out (Rpe65-/-) do not generate 11-cis retinal (Redmond et al., 1998) and exhibit rapid cone loss and cone opsin mistrafficking (Fan et al., 2008; Tang et al., 2010; Znoiko et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Redmond et al., 1998 source
• ?Not checked — no full text of the sourcecites Fan et al., 2008 source
• Supported

  The citation to Tang et al. supports the rapid cone loss and cone opsin mistrafficking portion of the sentence; the 11-cis retinal statement is separately cited to Redmond et al. Tang et al.’s Discussion reports significant cone loss by P30 in Rpe65−/− mice and describes disrupted trafficking of cone opsins before P30. Page numbers are not available in the supplied passages. (LLM, conf=0.91)

  cites Tang et al., 2010 source

In the paper

“Interestingly, 11-cis retinol is now known to act as an agonist to rod opsin, activating the rod opsins in a light-independent manner (Kono et al., 2008).”

What the sources say

• Supported

  The Results report that 11-cis retinol acts as an agonist of bovine rod opsin, increasing its activity sevenfold over opsin alone. The Discussion says that interaction with opsin could spuriously activate the signaling cascade in the dark, supporting the light-independent aspect of the claim. (LLM, conf=0.93)

  cites Kono et al., 2008 source

In the paper

“Subsequently, bis-retinoids enter the RPE through the daily phagocytosis of photoreceptor outer segments (Young, 1967), ending up in the lysosomal compartment where they accumulate in the form of lipofuscin.”

What the sources say

• Partly supported

  The Discussion (p. 68) places continual outer-segment renewal and removal of discs at the tip contacting the retinal pigment epithelium. It does not establish daily phagocytosis or show that bis-retinoids enter the RPE; the paper says evidence for labeled outer-segment protein in the pigment epithelium is equivocal. It also does not address lysosomal lipofuscin accumulation. (LLM, conf=0.84)

  cites Young, 1967 sourceExperimental — accuracy not yet measured

In the paper

“The kinetics of retinol formation, however, are faster in the cone than in the rod (Ala-Laurila et al., 2006), underlining the importance of the higher retinol dehydrogenase activity in the former.”

What the sources say

• Supported

  The Results report faster retinol production in salamander red- and blue-sensitive cones than in the rods compared with them. The Discussion (Retinol Clearance) identifies a faster retinol dehydrogenase (RDH) reaction in cones as one reason for their faster retinol production. (LLM, conf=0.92)

  cites Ala-Laurila et al., 2006 source

In the paper

“Parker et al. (Parker et al., 2009) found a reduction in cone ERG responses in Irbp-/- mice having the Met450 variant of RPE65 but observed no change in cone density or cone opsin levels and distribution.”

What the sources say

• Supported

  Materials and Methods (Animals; page unavailable) says the strains were genotyped to confirm the Leu450Met Rpe65 variant. The Results sections on photopic ERGs, cone density, and cone opsins (pages unavailable) report reduced cone responses in Irbp−/− mice relative to WT, similar cone densities and opsin levels, and normal opsin localization. (LLM, conf=0.94)

  cites Parker et al., 2009 source

In the paper

“The isoform of RPE65 appears to affect the phenotype of Irbp-/- mice as Jin et al. (Jin et al., 2009) reported cones in Irbp-/- mice with the Leu450 variant of RPE65 also had reduced outer segment length, partially mislocalized cone opsin, and underwent progressive degeneration.”

What the sources say

• Supported

  The Introduction identifies the studied Irbp−/− mice as carrying Leu450 Rpe65 and explains why Rpe65 genotype matters when interpreting their phenotype. The Discussion reports 2.2-fold shorter cone outer segments, partial M-opsin mislocalization, and reduced cone numbers rather than a developmental deficit, supporting the cited description of cone degeneration. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites Jin et al., 2009 source

In the paper

“Using isolated Nrl-/-Rpe65-/-retinas, IRBP was shown to deliver 11-cis retinol for oxidation in cones and to enhance the efficiency of the oxidation reaction (Parker et al., 2011).”

What the sources say

• Supported

  The Introduction states that oxidation assays in isolated Nrl−/−Rpe65−/− retinas showed IRBP improves the efficiency of 11-cis retinal production. The Results describe IRBP delivering 11-cis retinol to those retinas for oxidation, and the Discussion summary identifies IRBP as an effective vehicle for delivery to cones. Page numbers are not available in our copy. (LLM, conf=0.95)

  cites Parker et al., 2011 source

In the paper

“The rates of sensitivity recovery (Perry and McNaughton, 1991) and visual pigment regeneration (Schnapf et al., 1990) are greater in cones than in rods (Baylor et al., 1979; Baylor et al., 1984).”

What the sources say

• ?Not checked — no full text of the sourcecites Perry and McNaughton, 1991 source
• ?Not checked — no full text of the sourcecites Schnapf et al., 1990 source
• ?Not checked — no full text of the sourcecites Baylor et al., 1979 source

In the paper

“In humans, RPE65 appears to be selectively expressed in the OS regions of cones that detect green/red light, but not in blue cones (Tang et al., 2011a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Tang et al., 2011a

In the paper

“chromophore has been demonstrated to be exchanged in the dark with cone pigments, but not rhodopsin (Crescitelli, 1984; Matsumoto et al., 1975).”

What the sources say

• ?Not checked — no full text of the sourcecites Crescitelli, 1984 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Matsumoto et al., 1975

In the paper

“Bleached cones, but not bleached rods, were first demonstrated to regenerate resting dark current and light-sensitivity after the addition of 11-cis retinol in single salamander cell electrophysiological recordings (Jones et al., 1989).”

What the sources say

• ?Not checked — no full text of the sourcecites Jones et al., 1989 source

In the paper

“Recently, the Travis group identified the presence of dihydroceramide desaturase-1 (DES1) in Müller cells and reported that this protein mediates a direct isomerization of all-trans retinol to 11-cis retinol (Kaylor et al., 2012).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kaylor et al., 2012

In the paper

“We have localized RPE65 to cones although, interestingly, there does not appear to be a common location within cones for RPE65 among the cones of different species that we have studied.”

In the paper

“Surprisingly, the RPE65-based complex is not specific for the 11-cis isomer, but may be driven by a mass action effect of the binding protein(s) (Redmond et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Redmond et al., 2010 source

In the paper

“In vitro studies had demonstrated up to nine oxygens could be detected on A2E exposed to oxidizing conditions (Ben-Shabat et al., 2002b); however, the tissue profiling studies only detected A2E with an addition of a maximum of 3 oxygens.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ben-Shabat et al., 2002b

In the paper

“There is growing evidence to show that two separate retinoid cycles exist, one that supplies both rods and cones with chromophore (classic visual cycle) and another that specifically supplies cones (cone visual cycle), possibly as a supplemental source.”

In the paper

“the unexpected distribution of the retinoid metabolite N-retinylidene-N-retinylethanolamine (A2E) ((Ablonczy et al., 2012a) and see Fig. 12) in the human RPE pose challenges to previously accepted mechanisms.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ablonczy et al., 2012a

In the paper

“Unlike in the RPE, the role of RPE65 in cones remains unclear.”

In the paper

“Using suction electrodes to mask the OS of isolated salamander rods and cones, 11-cis retinal presented to the cell bodies of bleached photoreceptors restored light sensitivity in cones, but had no effect on rods (Jin et al., 1994).”

What the sources say

• ?Not checked — no full text of the sourcecites Jin et al., 1994 source

In the paper

“This last finding is likely the basis of some controversy over the presence of RPE65 in cones (summarized in (Tang et al., 2011b)) as RPE65 is highest in the C57BL/6 mice (low levels of RPE65 in the RPE) and undetectable by immunostaining in BALB/c and 129Sv mouse eyecups where RPE65 is high in the RPE.”

In the paper

“It has been shown that cones are capable of carrying out 11-cis retinol oxidation, whereas rods cannot.”

In the paper

“Its involvement in promoting the cone visual cycle is supported by evidence that IRBP binds 11-cis retinol endogenously (Saari et al., 1985), is co-localized with Müller cell processes surrounding the cone cell body (Uehara et al., 1990), and is found in high concentrations around the cones (Carter-Dawson and Burroughs, 1992a, 1992b).”

What the sources say

• ?Not checked — no full text of the sourcecites Saari et al., 1985 source
• ?Not checked — no full text of the sourcecites Uehara et al., 1990 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Carter-Dawson and Burroughs, 1992a, 1992b

In the paper

“Thus, Müller cells are capable of converting all-trans retinol to 11-cis retinol similar to what is observed in the RPE with the exception of the final oxidation reaction to generate 11-cis retinal.”

In the paper

“This may be due to a requirement of green and red cones for a supplemental source of retinoids for rapid chromophore turnover, as they are the only subtypes that appear within the fovea.”

In the paper

“By not performing the final oxidation step in the Müller cells, 11-cis retinol becomes a source of chromophore usable only by cones.”

In the paper

“We thus propose that RPE65 is acting as a retinol binding protein, and the distribution within the cones of various species may vary depending on the localization of the hydrolysis/oxidation reactions.”

In the paper

“Both rods and cones apparently receive 11-cis retinal from the RPE, and we are referring to this as the classic visual cycle to distinguish it from a more recently identified cone visual cycle involving the Müller cells that appears to be exclusive to cones”

In the paper

“A cone-specific visual cycle involving the Müller cells (Kaylor et al., 2012) has been proposed and an isomerase identified which is localized in Müller cells.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Kaylor et al., 2012

In the paper

“Third, lipofuscin accumulation requires the phagocytosis of the photoreceptor OS by the RPE, and in the absence of phagocytosis, retinoid-derived fluorescent material accumulates in the photoreceptors (Katz et al., 1987).”

What the sources say

• ?Not checked — no full text of the sourcecites Katz et al., 1987 source

In the paper

“Finally, all-trans retinal can form A2PE in rod OS membranes. This includes the formation of A2PE from all-trans retinal added exogenously to membranes (Liu et al., 2000), as well as from retinal released endogenously from rhodopsin following bleaching (Ben-Shabat et al., 2002b).”

What the sources say

• ?Not checked — no full text of the sourcecites Liu et al., 2000 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ben-Shabat et al., 2002b

In the paper

“First, lipofuscin levels are greatly decreased in mice that lack RPE65 (Katz and Redmond, 2001), indicating that lipofuscin formation requires the generation of 11-cis retinal.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Katz and Redmond, 2001

In the paper

“The lack of correlation between A2E and lipofuscin in the human eye clearly shows that further study is needed.”

In the paper

“As IRBP protects the isomeric state of 11-cis retinol, even in the presence of light (Crouch et al., 1992), the protein is likely to have a critical role in the delivery of 11-cis retinol to cones and to facilitate cone function.”

What the sources say

• ?Not checked — no full text of the sourcecites Crouch et al., 1992 source

In the paper

“It would allow cone photoreceptors to recycle the chromophore faster than rods, so they can support faster visual pigment regeneration.”

In the paper

“This is in agreement with the faster release of retinal from the photoactivated visual pigment, and the higher retinol dehydrogenase activity in cones (Miyazono et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Miyazono et al., 2008 source