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PubMed2001

The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain.

We describe a new zebrafish mutation, neckless, and present evidence that it inactivates retinaldehyde dehydrogenase type 2, an enzyme involved in retinoic acid biosynthesis. neckless embryos are characterised by a truncation of the anteroposterior axis anterior to the somites, defects in midline mesendodermal tissues and absence of pectoral fins. At a similar anteroposterior level within the nervous system, expression of the retinoic acid receptor a and hoxb4 genes is delayed and significantly reduced. Consistent with a primary defect in retinoic acid signalling, some of these defects in neckless mutants can be rescued by application of exogenous retinoic acid. We use mosaic analysis to show that the reduction in hoxb4 expression in the nervous system is a non-cell autonomous effect, reflecting a requirement for retinoic acid signalling from adjacent paraxial mesoderm. Together, our results demonstrate a conserved role for retinaldehyde dehydrogenase type 2 in patterning the posterior cranial mesoderm of the vertebrate embryo and provide definitive evidence for an involvement of endogenous retinoic acid in signalling between the paraxial mesoderm and neural tube.

Aldehyde Oxidoreductases↗
PubMed2004

Effects of methoprene, its metabolites, and breakdown products on retinoid-activated pathways in transfected cell lines.

Methoprene (isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) is an insect juvenile hormone agonist that blocks metamorphosis in some insects. Recent evidence suggests that a metabolite, methoprene acid, activates vertebrate retinoid X receptors (RXRs), and may interfere with retinoic acid-regulated developmental processes. Methoprene, methoxy-methoprene acid, and two major breakdown products were tested for their ability to interfere with retinoid-regulated pathways when using transfected cells. The CV-1 cells were transiently transfected with genes encoding RXRs and response elements attached to luciferase reporters, and retinoic acid-sensitive F9 cells were stably transfected with retinoic acid receptor (RAR)/RXR response elements attached a lacZ reporter (Sil-REM/beta-gal-NEO). Experiments confirmed that methoxy-methoprene acid acted as a ligand for RXRs and was capable of activating transcription through RAR/RXR response elements. However, neither methoprene nor the breakdown products, 7-methoxycitronellal and 7-methoxycitronellic acid, activated transcription in transfected CV-1 or F9 cells. Methoprene and methoxy-methoprene acid may interfere with the conversion of all-trans-retinol and all-trans-retinaldehyde to all-trans-retinoic acid in the F9-derived cell line. Methoprene was as effective as the retinol dehydrogenase inhibitor citral in blocking the retinol-induced transcription of RAR/RXR-regulated reporter genes, whereas methoxy-methoprene acid blocked transcription stimulated by retinaldehyde.

Acyclic Monoterpenes↗
PubMed2001

Immunocytochemical characterization of macular hole opercula.

OBJECTIVES: To immunocytochemically characterize the neural and glial elements of idiopathic full-thickness macular hole (FTMH) opercula excised during vitrectomy, and to correlate them with the outcome of surgery. METHODS: Opercula were collected from eyes undergoing vitrectomy for stage 3 FTMH and processed for transmission electron microscopy, light epifluorescence, and laser scanning confocal microscopy. Glia were identified using anti-glial fibrillary acid protein (GFAP), antivimentin, and anti-cellular retinaldehyde binding protein antibodies. Anti-phosphodiesterase gamma and antirhodopsin were used for cone and rod photoreceptors, and anticytokeratin was used for retinal pigment epithelium. The findings were correlated with the clinical data before and after surgery. For statistical analysis, data were combined with those of a previous study by the authors of 18 opercula. RESULTS: Opercula from 12 consecutive eyes of 12 patients were studied. In all opercula, GFAP, vimentin, and cellular retinaldehyde binding protein-positive glia were present. Six (50%) of 12 opercula contained more than 5 photoreceptors with somata and internal photoreceptor fibres, but lacking outer segments, demonstrating strong immunoreactivity to anti-phosphodiesterase gamma without antirhodopsin reactivity consistent with cones. Further, 2 (17%) of 12 opercula showed few cones (1-5 cones), and 4 (33%) of 12 contained only glia. Clinicopathologic correlation of the 30 opercula from the 2 studies showed that eyes with opercula containing more than 5 photoreceptors were associated with a worse anatomical closure rate after initial surgery, compared with those with fewer than 5 photoreceptors (P =.004). Once closure had been achieved with reoperation, median postoperative vision was similar in both groups (20/40 and 20/60, respectively). CONCLUSIONS: A spectrum of opercula occur in FTMH ranging from those containing only glia to those containing numerous cones. The extent of foveal neuroretinal tissue loss may affect the outcome of surgery.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Delayed dark-adaptation and lipofuscin accumulation in abcr+/- mice: implications for involvement of ABCR in age-related macular degeneration.

PURPOSE: To examine the ocular phenotype in mice heterozygous for a null mutation in the abcr gene. METHODS: Retinas and retinal pigment epithelia (RPE) were prepared from wild-type, abcr+/-, and abcr-/- mice. Fresh tissues were homogenized and analyzed by normal phase high-performance liquid chromatography (HPLC) for the presence of retinoids and phospholipids. In another study, fixed tissues were sectioned and analyzed by light and electron microscopy. Finally, anesthetized mice were studied by electroretinography (ERG) at different times after exposure to strong light. RESULTS: A2E, the major fluorophore of lipofuscin, and its precursors, A2PE-H(2) and A2PE, were approximately fourfold more abundant in 8-month-old abcr+/- than in the wild-type retina and RPE. The levels of these substances in abcr+/- mice were approximately 40% those in abcr-/- mice. Lipofuscin pigment-granules were also visible in abcr+/- RPE cells by electron microscopy. Accumulation of A2PE-H(2) and A2E in abcr+/- retina and RPE, respectively, was strongly dependent on light exposure. Heterozygous mutants also exhibited delayed recovery of rod sensitivity by ERG. This delay was correlated with elevated levels of all-trans-retinaldehyde (all-trans-RAL) in retina after a photobleach and was not caused by a reduction in quantum-catch due to depletion of 11-cis-retinaldehyde (11-cis-RAL). CONCLUSIONS: Partial loss of the ABCR or rim protein is sufficient to cause a phenotype in mice similar to recessive Stargardt's disease (STGD) and age-related macular degeneration (AMD) in humans. These data are consistent with the suggestion that the STGD carrier-state may predispose to the development of AMD.

ATP-Binding Cassette Transporters↗
PubMed1967

Effect of light on extraction of lipid from retinal rods.

Chloroform-methanol 2:1 removes a significantly greater quantity of lipid from bleached bovine retinal rods than from a dark-adapted counterpart. The extracts contain phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, and an unknown substance which, it is proposed, may be a combination of phospholipid and retinaldehyde. The difference between extracts of light-and dark-adapted rods is quantitative rather than qualitative. The data tend to confirm a model of rhodopsin suggested by Kropf and Hubbard in which isomerization of the retinaldehyde chromophore causes its displacement and opens a path to the interior of the molecule.

Journal Article↗
PubMed1995

Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase.

PURPOSE: Identification of a 32-kd protein in the bovine retinal pigment epithelium. METHODS: A bovine retinal pigment epithelium cDNA library was constructed in the bacteriophage lambda ZAP Express. A monoclonal antibody, designated 21-C3/AV, was used to isolate the cDNA encoding the 21-C3/AV antigen. A positive full-length clone, designated 21-C3RDH/CD, was sequenced. Northern blot analysis was used to determine the length of the mRNA and the tissue expression pattern. The entire open reading frame of clone 21-C3RDH/CD was used to isolate a recombinant baculovirus clone and expressed in Spodoptera frugiperda insect cells. Enzymatic activity toward 11-cis retinaldehyde was investigated. RESULTS: The complete nucleotide sequence of 21-C3RDH/CD was obtained. The deduced amino acid sequence reveals homology with short-chain alcohol dehydrogenases. Northern blot analysis detected a 1.2-kb transcript. Although the monoclonal antibody used to isolate 21-C3RDH/CD also reacts with other ocular and nonocular tissues, the authors were unable to demonstrate any reactivity with RNA samples isolated from different (non)ocular tissues. Recombinant baculovirus-infected insect cells synthesized the 21-C3/AV antigen. This protein showed 11-cis retinol dehydrogenase activity. CONCLUSIONS: Homology to the human D-beta-hydroxybutyrate dehydrogenase precursor and other alcohol dehydrogenases shows that 21-C3RDH/CD encodes a short-chain alcohol dehydrogenase. Furthermore, tissue specificity and molecular weight of the antigen suggest that 21-C3RDH/CD encodes the bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Direct proof came from experiments in which we used the baculovirus-based expression system for in vitro synthesis of the protein encoded by 21-C3RDH/CD. Protein extracts obtained from recombinant baculovirus-infected insect cells were found capable of reducing 11-cis retinaldehyde.

Alcohol Dehydrogenase↗
PubMed1996

Endogenous retinoids in the zebrafish embryo and adult.

Retinoic acid and its isoforms are considered to be endogenous compounds which regulate embryonic development. In the work reported here we have determined which retinoids are present in zebrafish embryos and how their levels change throughout development and into adulthood. All-trans-RA is present and its level does not change significantly during embryogenesis. We failed to detect other retinoic acid isomers such as 9-cis-RA and 4-oxo-RA, but we did observe a rapid rise in the level of didehydroretinol after gastrulation. The most striking result is that the zebrafish embryo, like Xenopus and tunicates, contains a vast excess of t-retinal whereas the embryos of higher vertebrates have an excess of t-retinol. However, as the zebrafish grows, the levels of t-retinol rise so that by adulthood t-retinol and t-retinal concentrations are more equivalent, indicating a changing pattern of retinoid metabolism with growth. To examine the significance of the use of t-retinal as a precursor of t-RA we treated embryos with disulphiram, an inhibitor of retinaldehyde dehydrogenase. This resulted in embryos with an undulating notochord and correspondingly abnormal somites and ventral floor plate. In contrast to this effect, 4-methylpyrazole, which inhibits alcohol dehydrogenases, had no effect on development. This effect of disulphiram suggests that t-RA may be involved in the establishment of the anteroposterior axis of the embryo.

Alcohol Dehydrogenase↗
PubMed1988

Analysis of retinoids by direct exposure probe mass spectrometry.

Recently, our laboratory has investigated the depletion of Vitamin A and its metabolites in experimental animals. High Pressure Liquid Chromatography (HPLC) was used to measure retinal oxidase activity by monitoring the conversion of retinaldehyde (RALD) to retinoic acid (ROIC). In order to obtain more information about these compounds, a Direct Exposure Probe mass spectrometric method was developed to confirm the presence of ROIC and RALD in HPLC peaks. A rapid negative ion chemical ionization (NICI) method using ammonia as reagent gas was developed to detect the presence of ROIC and RALD with picogram sensitivity. The ROIC and RALD peaks were collected from HPLC, extracted with hexane, evaporated under nitrogen and reconstituted in ethanol before placing onto a rhenium filament with current programmed from 0-1.3 A at 50 mA/sec. The instrument employed was a Finnigan 4510 operated in the NICI mode and scanned from m/z 100-650 with a source temperature of 80 C. Other parameters were electron energy 140 eV and filament current at 0.25 mA. Prominent ions were generated at m/z 284 and m/z 300 for RALD and ROIC which were subsequently monitored in the selected ion monitoring mode. In summary, we have developed a rapid retinoid identification method (2.5 minutes) which is more sensitive (pg vs ng) than HPLC and does not require elaborate sample preparation or derivitization. This method can be used as an important adjunct to HPLC enzyme studies.

Chromatography, High Pressure Liquid↗
PubMed1993

Corneal endothelial cell matrix promotes expression of differentiated features of retinal pigmented epithelial cells: implication of laminin and basic fibroblast growth factor as active components.

Human retinal pigmented epithelial (RPE) cells cultured on plastic, unlike RPE in situ, often fail to density arrest, do not produce melanin, and do not express mRNA for cellular retinaldehyde binding protein (CRALBP). When human RPE are cultured on the extracellular matrix produced by bovine corneal endothelial cells for 1 week or human RPE for 3 weeks, they density arrest, assume a differentiated morphology, and produce pigment and mRNA for CRALBP (all differentiated features of RPE). Human RPE grown on a laminin substratum or grown in media supplemented with basic fibroblast growth factor (basic FGF), assume a differentiated morphology for up to 3 weeks, and this is maintained for several months when the cells are grown on laminin in the presence of basic FGF and heparin. With the latter conditions, the cells also produce mRNA for CRALBP. Human RPE grown on bovine corneal endothelial cell matrix treated with neutralizing antibodies to basic FGF or laminin or agents that displace FGF from extracellular matrix (suramin or protamine), do not assume a differentiated morphology and express less CRALBP mRNA than RPE grown on bovine corneal endothelial cell matrix treated with antibodies to type IV collagen. These data suggest that the extracellular matrix may facilitate RPE expression of differentiated features and that laminin and basic FGF may be important components.

Aged↗
PubMed1997

Retinol kinetics in the isolated retina determined by retinoid extraction and HPLC.

Suzuki et al. [Vis. Res. 26, 425-9 (1986); Vis. Res. 28, 1061-70 (1988)] have described a formaldehyde-based (HCHO-based) extraction procedure that efficiently recovers 11-cis retinal initially present as rhodopsin chromophore in photoreceptor membranes. Using the isolated retina of the toad (Bufo marinus), we tested whether this procedure ('HCHO' method), in combination with a formaldehyde-free extraction procedure ('i/h' method) and the analysis of extracted retinoids by high performance liquid chromatography (HPLC), can account quantitatively for light-induced changes in retinoid levels and thus serve as an alternative to spectrophotometry for tracking the formation of all-trans retinol in this intact rod preparation. Initially dark-adapted retinas were incubated in bright light or in darkness and then analysed by homogenization and extraction using the HCHO and i/h methods. Combined data obtained using the two extraction procedures indicated a near-conservation of total retinoid recovered from dark-incubated and illuminated retinas, and thus accounted for light-induced changes in retinoid levels. The HCHO procedure, employing formaldehyde, isopropanol and hexane, was similar to that described by Suzuki et al. and recovered retinaldehydes including chromophoric 11-cis retinal. The i/h procedure utilized isopropanol and hexane and, unlike the HCHO method, efficiently recovered all-trans retinol. Illumination (onset at time zero) that produced an approximately exponential decline of 11-cis retinal (time constant of 24 s) led to an increase and then a gradual decline in all-trans retinal. The normalized peak level of all-trans retinal, representing about 0.54 of the total molar quantity of recovered retinoid, developed with illumination periods of 10-80 s. The normalized level of all-trans retinol reached approximately 0.3 in retinas illuminated for 1 min and, with longer illuminations (up to 30 min), exhibited an approximately exponential further growth to approximately 0.9 with a time constant of 9.2 min. The results indicate the workability of the HCHO and i/h extraction procedures for tracking the in situ conversion of all-trans retinal to all-trans retinol, a reaction thought to be important for both operation of the retinoid visual cycle and shut-off of the phototransduction cascade.

Animals↗
PubMed1980

Kinetic and mechanistic studies of oxidation of vitamin A alcohol to vitamin A aldehyde by horse liver alcohol dehydrogenase. The inhibition by ethanol and pyrazole.

The present investigation shows that all-trans retinol (Vitamin A alcohol), an alcohol of great physiological importance, is efficiently oxidized to all-trans retinaldehyde by the enzyme horse liver alcohol dehydrogenase. We observe a Km retinol value of 145 microM and a turnover number of 0.45s-1 for the oxidation of all-trans retinol in the presence of Triton X-100, a surfactant used as a solubilizer. Over the concentration range of surfactant used (up to 0.1% Triton X-100) our studies on the oxidation of ethanol and all-trans retinol show that turnover numbers for both reactions remain constant as does the value for Km ethanol. On increasing the concentration of Triton X-100 from 0.025% to 0.10%, however, the Km retinol value increases by a factor of two. This behavior for retinol oxidation can be attributed to the partitioning of retinol between enzyme and surfactant. Pyrazole, a known inhibitor of alcohol oxidation by horse liver alcohol dehydrogenase, is a competitive inhibitor of both all-trans retinol and ethanol, with observed Ki values of 3.3 X 10(-7) M and 3.9 x 10(-7) M, respectively. We also find that ethanol inhibits all-trans retinol oxidation in a complex fashion, an observation which may have important consequences in view of the physiological role of retinol and its oxidation products. Our present studies indicate that all-trans retinol binds in the same region of the enzyme as does ethanol and is oxidized with an efficiency approaching that of ethanol itself.

Alcohol Oxidoreductases↗
PubMed1999

Detection of mRNA for proteins involved in retinol metabolism in iris pigment epithelium.

BACKGROUND: To investigate in iris pigment epithelium (IPE) the expression of mRNA for proteins involved in retinol metabolism we used a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) technique. METHODS: RNA was prepared from freshly isolated bovine IPE and retinal pigment epithelium (RPE) cells and reverse transcribed. The expression of mRNA for cellular retinaldehyde binding protein (CRALBP), p63 (RPE63), the presumed retinal pigment epithelial membrane receptor for retinoids, and 11-cis-dehydrogenase (11cisRDH) was determined by RT-PCR using specific primers. Semi-quantitative expression data were obtained by using a series of fivefold dilution of each cDNA with a fixed number of PCR cycles. RESULTS: Bovine IPE and RPE cells express mRNA for CRALBP, 11cisRDH, and RPE63. The mRNA expression for CRALBP and 11cisRDH is high and equal in both cell types. However, RPE63 mRNA expression in IPE cells is relatively low compared with the expression in RPE cells. CONCLUSIONS: The presence of mRNA for CRALBP, RPE63, and 11cisRDH suggests that IPE cells may be able to metabolize retinol.

Aldehyde Oxidoreductases↗
PubMed1980

Cell fusion, haemolysis and mitochondrial swelling induced by retinol and derivatives.

A comparative study has been made of the abilities of retinol and its derivatives to induce cell fusion and haemolysis of hen erythrocytes and to cause swelling of rat liver mitochondria. Retinol, retinaldehyde, alpha-retinoic acid, iso-13-retinol and to a lesser extent retinyl acetate were active in all three systems. Iso-13-retinoic acid was extremely membranolytic but did not produce stable fused cells. By contrast retinoic acid, its cyclopentyl derivative RO8-7699, and the long chain fatty acid esters of retinol, viz. the oleate, linoleate and palmitate esters, were neither fusogenic nor haemolytic, nor did they affect mitochondria.

Animals↗
PubMed1993

Adult rabbit brain synthesizes retinoic acid.

Tissues of adult rabbit brain were shown to enzymatically oxidize retinol and retinaldehyde to retinoic acid, a potent stimulator of gene expression. Rates of retinoic acid synthesis by the cerebrum, cerebellum, and meninges were comparable to, or exceeded, rates measured with rat liver, an organ known to have a relatively high capacity to synthesize retinoic acid. These results, taken together with previous observations that the adult brain contains retinoic acid-activated transcription factors and cellular retinoid-binding proteins, suggest that retinoids may play an important role in the adult central nervous system.

Animals↗
PubMed1988

An immunocytochemical comparison of Müller cells and astrocytes in the cat retina.

Immunocytochemical localization, at the light and electron microscopic levels, of five different known glial proteins was used to compare Müller cells with astrocytes in the adult cat retina. Retina from two different areas of the eye was examined. A region of retina on the border of the optic nerve was used because of its large population of astrocytes, and a region away from the optic nerve was used to examine Müller cells (astrocytes are sparse in this region). Antibodies to cellular retinaldehyde binding protein and glutamine synthetase labeled the Müller cells but not the astrocytes, while labeling with anti-carbonic anhydrase C, anti-alpha crystallin and anti-glial fibrillary acidic protein was found in both Müller cells and astrocytes.

Animals↗
PubMed1988

An immunocytochemical study of cat retinal Müller cells in culture.

Müller cells, the specialized radial glia found in vertebrate retinas, were enzymatically dissociated from adult cat retinas and grown in culture. The cells were processed for immunofluorescence microscopy at times ranging from 4 hr to 3 months in culture. Labeling with antibodies specific to glial fibrillary acidic protein, cellular retinaldehyde binding protein, glutamine synthetase, carbonic anhydrase C and alpha crystallin, all proteins known to be found in Müller cells, was detected in the cultured cells. Immunoblot analysis of the cultured cells showed single protein bands corresponding to the appropriate molecular weights of the antigens.

Animals↗
PubMed1989

Changes in the expression of specific Müller cell proteins during long-term retinal detachment.

Retinal detachments were produced in domestic cats by injecting fluid between the retinal pigment epithelium and neural retina. Retinas were allowed to remain detached for 30 or 60 days at which time the animals were killed. Tissue areas from detached and attached retinal regions from the same eye were processed for correlative biochemical and structural analysis, i.e. SDS-PAGE and Western blots of tissue homogenates were correlated with tissue processed for postembedding immunoelectron microscopy. Antibodies to six proteins were used as probes. Glial fibrillary acidic protein in Müller cells has previously been shown to increase after retinal detachment; here we show that vimentin, another intermediate filament protein present in Müller cells, also increases after detachment. In contrast, cellular retinaldehyde binding protein, cellular retinol binding protein, glutamine synthetase, and carbonic anhydrase C--all normally found in Müller cells--decrease after detachment. The results of this study indicate that retinal Müller cells dramatically alter their expression of proteins in response to retinal detachment.

Animals↗
PubMed1994

9-cis-retinoyl-beta-D-glucuronide is a major metabolite of 9-cis-retinoic acid.

The in vivo metabolism of 9-cis-retinoic acid (9-c-RA), an endogenous ligand of retinoid X receptors (RXRs), which can also bind to retinoic acid receptors (RARs), was examined in pregnant mice and rats following a single oral dose of 100 mg 9-cis-retinaldehyde (9-c-RAL)/kg body weight. 9-Cis-retinoyl-beta-D-glucuronide (9-c-RAG), a metabolite not found in vivo before, was a major metabolite of 9-c-RA in mouse plasma and was also present in all mouse tissues examined as well as in rat plasma. In both species putative oxidation products of retinoic acids and high levels of retinyl esters were found. Concentrations of retinoic acid isomers and retinoyl-beta-D-glucuronides in the mouse plasma greatly exceeded those of the rat plasma. The finding of high levels of 9-c-RAG underlines the importance of glucuronidation in the metabolism of retinoids.

Animals↗