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PubMed2004

hRDH-E2 gene polymorphisms, variable transcriptional start sites, and psoriasis.

hRDH-E2 is a member of the short-chain alcohol dehydrogenase/reductase (SDR) family that converts retinol to retinaldehyde as the first and rate-limiting step in the retinoic acid synthetic pathway. This pathway is critical for the maintenance of epidermal homeostasis in vivo. Previously, we reported that the mRNA levels of hRDH-E2 in psoriatic skin were elevated significantly compared with that in healthy individual skin and psoriatic unaffected skin. The gene encoding hRDH-E2 is located on Chromosome 8 close to a candidate region for psoriasis and therefore is a functional and positional candidate for this disorder. In the present study, the transcription start sites for hRDH-E2 gene transcription in the lung were found to be more upstream of those that were identified previously in keratinocytes. Consequently, differences in the nucleotide sequence were determined for all of the coding exons, untranslated regions, and at least 2850 bp of 5'-noncoding sequence of hRDH-E2 by direct sequencing of polymerase chain reaction (PCR)-amplified DNA samples obtained from 8 psoriatic patients and 8 healthy controls. One polymorphic microsatellite marker at the noncoding 3' end of the gene and six single nucleotide polymorphisms (SNPs) (three in the 5' flanking sequence, two in the coding sequence, and one in the intronic sequence) were identified. One of the SNPs was nonsynonymous in the second exon with an allelic variation between the amino acid sequences Arg and Trp. The microsatellite marker and the six SNPs were all genotyped in 100 Japanese psoriatic patients and 120 controls. However, there were no statistically significant differences in the genotype or allele frequency distributions between the cases and controls. On this basis, we conclude that the polymorphisms that we detected for the hRDH-E2 gene do not contribute to the etiology of psoriasis but may be important in diseases of other tissues.

Aldehyde Oxidoreductases↗
PubMed2000

OLN-93 oligodendrocytes synthesize all-trans-retinoic acid in vitro.

After traumatic injury to the central nervous system (CNS), various cytokines orchestrate the physiological responses of injured neurons and glial cells. The control of these intercellular signals is of major interest from a medical point of view. Since the transcriptional activator retinoic acid (RA) is known to regulate gene expression of cytokines in various cell culture systems we investigated the role of RA signaling in glial cells. The transcriptional activity of RA-induced genes is largely determined by the distribution of RA, which in turn depends on the local oxidation of retinaldehyde (RAL). This is synthesized from retinol or internalized as a component of vitamin A. Using high-pressure liquid chromatography and an RA-sensitive reporter cell line, we showed that OLN-93 cells, which serve as a model system for CNS oligodendrocytes, convert all-trans-RAL to the biologically active form all-trans-RA, but neither oxidize 9-cis-RAL nor isomerize RA enzymatically. The oligodendrocyte cell line expresses a cytosolic aldehyde dehydrogenase with an apparent molecular weight of 54-57 kDa and pI of 5.3-5.7. As indicated by a zymography bioassay, this enzyme is responsible for RA synthesis. The reaction requires NAD+ as cosubstrate and can be inhibited by disulfiram and citral. No other RA-producing enzyme activities were detected. These findings are in accordance with a putative role for retinoid signaling in neuroglial interactions in the CNS.

Aldehyde Dehydrogenase↗
PubMed1987

In vivo formation of tritium-labeled lactic acid from [2-3H]mannose or [15-3H]retinol by hamster intestinal epithelial cells.

In studies designed to reexamine the in vivo occurrence of retinyl phosphate mannose we injected hamsters intraperitoneally with either [2-3H]mannose or [15-3H]retinol and sacrificed the animals 15 min later. The small intestine was removed, the epithelial cells were scraped, and a methanolic extract of the labeled cells was prepared and chromatographed on a Mono Q anion-exchange column. Intraperitoneal administration of either [2-3H]mannose or [15-3H]retinol lead to the formation of a tritium-labeled anionic compound with a retention time on the Mono Q column similar to that of standard retinyl phosphate mannose. However, the biochemical properties of this labeled anionic compound were those expected of an organic acid and not retinyl phosphate mannose. The compound was resistant to both strong acid hydrolysis and mild base hydrolysis, as well as digestion with alpha- or beta-mannosidase, phosphodiesterase I, nucleotide pyrophosphatase, or beta-glucuronidase. When chromatographed on an Aminex HPX-87H organic acid analysis column or a silicic acid column the labeled anionic compound derived from either [2-3H]mannose or [15-3H]retinol comigrated with standard lactic acid. Treatment of the anionic compound derived from [2-3H]mannose with lactate oxidase or L-lactate 2-monooxygenase resulted in the formation of a tritium-labeled product that cochromatographed, respectively, with pyruvate or acetate on the Aminex HPX-87H column. However, treatment of the anionic compound derived from [15-3H]retinol with these same two enzymes resulted in a labeled product that migrated on the Aminex column at the same position as tritiated water. This result demonstrated that the labeled hydrogen was removed during enzymatic digestion and suggested that it was present on the second carbon of lactic acid. During the course of these studies no evidence for the in vivo labeling of a compound with the properties of retinyl phosphate mannose was found. Since [2-3H]mannose leads to labeled lactic acid in vivo the tritium label must not always be lost, as expected, during the entry step into glycolysis in which mannose 6-phosphate is converted to fructose 6-phosphate. The results suggest that an intramolecular hydrogen transfer from the C-2 position of mannose 6-phosphate to the C-1 position of fructose 6-phosphate can occur during the phosphomannose isomerase reaction. The finding that the position of the tritium label on lactic acid derived from [15-3H]retinol is on the second carbon is consistent with it coming from NADH labeled with tritium in the transferable hydrogen which was formed intracellularly during the NAD+-linked oxidation of retinol to retinaldehyde.

Animals↗
PubMed1975

Biochemical aspects of the visual process. XXVIII. Classification of sulfhydryl groups in phodopsin and other photoreceptor membrane proteins.

Reaction of isolated bovine rod outer segment membrane with radioactive N-ethylmaleimide, both in the presence and absence of 1% dodecyl sulfate followed by dodecyl sulfate-polyacrylamide gel electrophoresis, shows that six sulfhydryl groups (96% of total sulfhydryl in this membrane) are located on the rhodopsin molecule. On the basis of their reactivity towards rho-chloromercuribenzoate and rho-chloromercuribenzene sulfonate in suspensions of outer segment membranes, the sulfhydryl groups of rhodopsin can be divided into three pairs. One pair is rapidly modified, both in light and darkness. This modification does not impair the recombination capacity of opsin with 11-cis retinaldehyde under regeneration of rhodopsin. A second pair is modified upon prolonged interaction with the rho-chloromercuriderivatives in darkness. Modification of this pair leaves the typical rhodopsin absorbance at 500 nm intact, but a proportional loss of recombination capacity does occur. The third pair is only modified after illumination and isprobably located in the vicinity of the chromophoric center. The differences between these results and those obtained by modification with dithiobis-(2-nitrobenzoic acid) or N-ethylmaleimide in suspension, where even upon prolonged exposure to light as well as in darkness only two sulfhydryl groups of rhodopsin are modified, is explained by the detergent-like character of the rho-chloromercuri-derivatives.

Animals↗
PubMed1995

Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics.

In this report we have characterized the photopigments mediating circadian phase shifts in retinal degenerate (rd) mice. In aged rd/rd mice, which lack detectable opsin, high performance liquid chromatography (HPLC) was used to quantify the photopigment chromophore 11-cis-retinaldehyde. This chromophore was photoisomerized in whole eyes, suggesting the presence of a functional opsin-based photopigment system. We also analyzed the spectral sensitivity of phase shifting circadian locomotor rhythms. Our data implicate a photopigment that is consistent with the involvement of the middle wavelength-sensitive cone photoreceptors (M-cones; lambda(max) = 511 nm) found in the mouse retina. In addition, discrete near-ultraviolet (UV-A) pulses were capable of eliciting large phase shifts in circadian locomotor activity rhythms. This result is consistent with the involvement of the short wavelength-sensitive cone photoreceptors (UV-cones; lambda(max) = 359 nm) in photoentrainment. Collectively, these data suggest that both cone classes of the mouse may mediate the photic regulation of circadian rhythms. If this is the case, circadian sensitivity can be maintained by very few degenerate cones. Alternatively, an unknown class of ocular photoreceptor may fulfill this function.

Animals↗
PubMed1991

Effect of light on endogenous ligands carried by interphotoreceptor retinoid-binding protein.

Interphotoreceptor retinoid-binding protein (IRBP) is a vitamin A carrier present only in the extracellular material lying between the neural retina and the retinal pigment epithelium of vertebrate eyes. The amount of retinol bound endogenously by IRBP in this interphotoreceptor space is known to increase upon illumination. This finding led to the hypothesis that IRBP may act as a shuttle for vitamin A during the visual cycle that regenerates rhodopsin. In the present work, we separated IRBP from other retinoid-binding proteins in bovine interphotoreceptor matrix preparations by means of size-exclusion chromatography. IRBP's endogenous ligands were retained during this procedure and were then extracted into hexane and analysed by normal-phase HPCL. We found that IRBP carries, in a light-dependent manner, all the retinoid isomers involved in the visual cycle. For dark-adapted eyes the amounts of bound ligands are (in nmol per eye) 0.09 all-trans retinol, 0.11 11-cis retinol, 0.04 all-trans retinal, 0.16 11-cis retinal, and 0.07 retinyl esters. For light-adapted eyes the amount of all-trans retinol was found to increase by a factor of five, and that of 11-cis retinal to decrease by a factor of four. (These eyes contain 3.1 nmol of IRBP, which does not change in amount with lighting conditions). Thus, the major endogenous ligand of IRBP is 11-cis retinaldehyde in the dark and all-trans retinol in the light. The data are consistent with a role for IRBP as a non-selective scavenger and stabilizer of retinoids released from photoreceptors and pigment epithelial cells. However, it cannot be concluded from these data that IRBP is involved in directed transport of retinoids across the interphotoreceptor matrix, since there is no evidence for the appropriate spatial gradients in the ligands bound to the protein.

Adaptation, Ocular↗
PubMed1991

Uptake and isomerization of all-trans retinol by isolated bovine retinal pigment epithelial cells: further clues to the visual cycle.

The site and substrate for all-trans to 11-cis isomerization in the visual cycle have remained obscure for several decades. Only recently studies on a subcellular level have begun to shed some light on these phenomena. We have addressed this system on a cellular level by utilizing intact isolated bovine retinal pigment epithelial cells, maintained during short-term incubation in vitro. Supplementation with labeled all-trans retinol incorporated in a lipid vesicle carrier, in a range of 1-6 nmol per 10(6) cells, resulted in a rapid uptake of retinol. The majority of the internalized retinol was processed prior to mixing with endogenous retinoid pools and most of it was converted into all-trans retinylester. Up to 10% of the incorporated label was isomerized yielding 11-cis retinol, 11-cis retinaldehyde and 11-cis retinylester. The kinetics of the 11-cis retinoid formation indicated that 11-cis retinol is the first isomerization product. The level of 11-cis retinol apparently 'triggered' further processing into other 11-cis retinoids. An updated model with discussion topics is presented for the retinoid pathway relevant to the visual cycle.

Animals↗
PubMed1984

Dynamic processes of visual transduction.

Rhodopsin is one of those rare macromolecules whose inherent chromophore, 11-cis retinaldehyde, allows one to naturally observe triggered macromolecular changes on the timescale of picoseconds to minutes. Investigations of these molecular processes have been carried out with laser monochromatic light under conditions where the photon flux used for photolysis was carefully measured. The formation of bleaching intermediates has been examined as a function of fluence. Under conditions where the formation of intermediates is unaffected by photon reversal the following observations hold: Upon the absorption of a photon, the initial photochemical event results in production of metastable bathorhodopsin within 6 psec. Artificial rhodopsin regenerated with 9-cis retinal forms a distinct bathorhodopsin which must reflect distortions at the active site differing from those generated with 11-cis retinal. Bathorhodopsin thermally decays through lumirhodopsin and meta I-rhodopsin, to meta II-rhodopsin through a series of coupled equilibria. The final meta I-meta II equilibrium is stable for seconds. The process provides a unique model for utilization of energy to drive (trigger) a biological cascade of events.

Animals↗
PubMed1994

Photoreceptor and glial markers in human embryonic retina and in human embryonic retinal transplants to rat retina.

The purpose of this study was to compare the development of photoreceptor and glial cells in human embryonic retinal transplants with the development of normal human embryonic retina (13-20 weeks postconception). Human embryonic retinal cells (donor age 6-11 weeks postconception) were transplanted to the retinas of adult immunosuppressed rat hosts. Host animals were killed when the transplants were of 13-37 weeks total age (donor age+survival time after surgery). Immunohistochemistry was performed with antibodies specific for neuron-specific enolase (NSE), synaptophysin (SYN), cone-specific opsins, rhodopsin, rod alpha-transducin, S-antigen, vimentin, cellular retinaldehyde-binding protein (CRALBP) and glial fibrillary acidic protein (GFAP). With regards to photoreceptors, NSE and SYN immunoreactive cones were seen in transplants from 14-16 weeks of age, but cone opsin immunoreactivity was not seen until 25 weeks. Developing graft rods became S-antigen immunoreactive at 17-18 weeks. At 20 weeks, inner segments and some cell somas of graft rods stained faintly for alpha-transducin and rhodopsin. At 31 and 37 weeks, inner and outer rod segments were intensely labelled for the rod-specific antigens. The grafts exhibited areas of varying maturation with different staining intensities. Concerning the glial cells, vimentin immunoreactivity was seen in the earliest transplants studied (total age 14-16 weeks), but only in stages older than 19 weeks was the immunoreactivity of graft Müller cells comparable in intensity to those of the host retina. Host Müller cells were immunoreactive for GFAP near the lesion site at all times. At 20 weeks, some GFAP immunoreactive processes were seen inside the graft, apparently coming from the host retina. At 25 weeks, faintly stained Müller cells intrinsic to the graft were observed, indicating a gliosis within the graft. Graft Müller cells were first seen to express CRALBP immunoreactivity at 19-20 weeks and, at 25 weeks, intense immunoreactivity was seen in the transplant, mostly in regions near the host. In the transplants only the Müller cells were stained, whereas both Müller and retinal pigment epithelium cells were CRALBP immunoreactive in the host retina. The development of human embryonic retinal transplants appears to parallel approximately normal in utero development. Transplant cones, rods and Müller cells all express their cell-specific proteins. The photoreceptors develop both inner and outer segments and contain several essential proteins for processing light. The transplants can reach a degree of maturity comparable to newborn retina.

Animals↗
PubMed1996

Influence of the choroid plexus on cerebellar development: analysis of retinoic acid synthesis.

The choroid plexus of the fourth ventricle is conspicuous both in location and size: it protrudes over the outer hindbrain, closely apposed to the caudal external surface of the cerebellum, and it is disproportionately large early on. While the developing cerebellum is known to respond to retinoic acid (RA), it does not express significant levels of RA synthesizing enzyme. Retinaldehyde dehydrogenase levels in the choroid plexus, however, are very high, with maxima during the pre- and postnatal periods of cerebellar morphogenesis. Explants assays demonstrate release of a neurite-outgrowth promoting activity from the choroid plexus, whose levels parallel the levels of RA synthesizing enzyme here, and which can be mimicked by RA. These observations characterize the choroid plexus as a paracrine, growth-promoting organ for the developing cerebellum, with the effects mediated through temporally regulated RA production.

Aldehyde Oxidoreductases↗
PubMed1990

GTP hydrolysis by transitional endoplasmic reticulum from rat liver inhibited by all-trans-retinol.

GTP hydrolysis by an endoplasmic reticulum fraction from rat liver enriched in part-rough, part-smooth transition elements was inhibited by all-trans-retinol half maximally at a concentration of about 10 micrograms/ml. Similar results were obtained with GTPase activity partially purified by ion-exchange (DE-52) chromatography. The inhibition was non-competitive and given by both retinol and retinaldehyde but not by retinoic acid or alpha-tocopheryl acetate. The hydrolysis of other nucleoside di- and triphosphates was much less affected by retinol. The activity was inhibited by detergents but at much higher concentrations than by retinol. The results suggest that enhancement of cell-free transfer from endoplasmic reticulum to Golgi apparatus by retinol observed previously at low concentrations of cytosol may be mediated through an interaction with GTP.

Animals↗
PubMed1996

Determination of retinoids by reversed-phase capillary liquid chromatography with amperometric electrochemical detection.

A method for separating and detecting retinoids by reversed-phase capillary liquid chromatography with amperometric electrochemical detection is described. Packed columns with an inner diameter of 180 microns were employed for the separation using C18 stationary phase and a mobile phase containing acetonitrile-water methanol (65:32.5:2.5, v/v/v) with 1% tetrabutylammonium perchlorate and 0.174 M acetate buffered at pH 5. The detection cell consisted of a carbon fiber barrel electrode held at 0.9 V versus an Ag/AgCl reference. Injection volumes of 2 microliters produced detection limits of 2.73, 0.472, 0.428, and 0.267 fmol (or 410, 64.1, 60.9, and 38.2 pg ml-1) for 13-cis-retinoic acid, all-trans-retinoic acid, retinaldehyde, and retinol, respectively. This represents an improvement in detection limits of at least three orders of magnitude for similar analyses using liquid chromatography and UV absorbance detection. The detector signal was linear over two orders of magnitude of analyte concentration. Retinoid concentrations in bovine serum were determined and found to be in good agreement with previously reported values.

Animals↗
PubMed1989

Effects of a vitamin-A-free diet on tissue vitamin A concentration and dark adaptation of aging rats.

Changes in serum, hepatic, and ocular vitamin A levels were followed in 9-month-old Long Evans rats fed either a vitamin-A-free or vitamin-A-sufficient diet for up to 18 months. After 18 months, hepatic total vitamin A fell exponentially from 2542 +/- 433 to 48 +/- 12 micrograms/g wet weight, but these stores maintained normal serum retinol and ocular total vitamin A concentrations in vitamin-A-deprived rats. However, retinal dark-adaptation time, a functional indicator of photoreceptor integrity, was prolonged in elderly vitamin-A-deprived rats as compared to vitamin-A-sufficient controls (p less than 0.05). Aging appeared to be the most important factor that depressed the rate of dark adaptation, with vitamin A status having a secondary effect. The proportion of total ocular retinaldehyde decreased (p less than 0.05) and the concentration of retinyl ester increased (p less than 0.05) in the eyes of 27-month-old vitamin-A-deprived rats compared to age-matched vitamin-A-sufficient animals. Possible mechanisms of visual dysfunction include abnormal retinal rhodopsin recycling caused by a dependence on newly absorbed dietary vitamin A (e.g., chylomicron). Alternatively, in the vitamin-A-deprived rat, decreased hepatic oxidation of pentobarbital (used for electroretinographic anesthesia) could prolong retinal anesthetic exposure and either directly depress neural transmission or indirectly alter transmission by affecting rhodopsin recycling.

Aging↗
PubMed2005

Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia.

Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.

Animals↗
PubMed2004

Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum.

Several characteristics of fetal alcohol syndrome (FAS) are similar to the teratogenic effects of retinoic acid (RA) exposure. It has been suggested that FAS may result from ethanol-induced alteration in endogenous RA synthesis, leading to abnormal embryonic concentrations of this morphogen. We examined whether ethanol may interfere with RA synthesis in the postnatal cerebellum, as a region of the developing CNS particularly vulnerable to both ethanol and RA teratogenesis. It was found that astrocytes are the predominant source of postnatal RA synthesis in the cerebellum. They express both retinaldehyde dehydrogenase 1 and 2. In vitro cytosolic preparations of astrocytes, as well as live cell preparations, have an increased capacity to synthesize RA in the presence of ethanol. A mechanism by which ethanol could stimulate RA synthesis is via the ethanol-activated short-chain retinol dehydrogenases, which we show to be present in the postnatal cerebellum. To determine whether ethanol stimulated RA synthesis in vivo, a sensitive and highly specific HPLC/MSn technique was used to measure cerebellar RA after administration of ethanol to postnatal day 4 rat pups. Cerebellar RA levels climbed significantly after such treatment. These results suggest that the cerebellar pathology exerted by ethanol may occur, at least in part, through increased production of RA.

Alcohol Dehydrogenase↗
PubMed2004

Short-term study of retinal pigment epithelium sheet transplants onto Bruch's membrane.

The purpose of this study is to investigate the survival and behaviour of retinal pigment epithelium sheets transplanted onto hydraulically debrided Bruch's membrane. Uncultured retinal pigment epithelium sheets obtained from male cats and sandwiched between two gelatin sheets were transplanted onto the tapetal area of female cats after native retinal pigment epithelium was debrided. For controls, the gelatin carrier was transplanted after debridement. Each transplant or control specimen was analyzed histologically and immunohistochemically. Transplanted male retinal pigment epithelial cells were identified by in situ labelling of the cat Y chromosome. Over half of the transplants appeared as retinal pigment epithelium multilayers in the subretinal space. Retinal pigment epithelium pigment dispersion into the subretinal space was seen in most of the transplants, and retinal pigment epithelium pigment infiltration into the neural retina was seen in all 7-day survival transplants. A few condensed darkly stained retinal pigment epithelium nuclei and Terminal Transferase dUTP Nick End Labelling-positive retinal pigment epithelium cells were observed in all transplants. Cellular retinaldehyde-binding protein was present up to day-7 in most transplanted RPE cells. In both transplant and control specimens, the antibody against the Ki-67 nuclear antigen labelled a few retinal pigment epithelium cells at day-3. Terminal Transferase dUTP Nick End Labelling-positive outer nuclear layer nuclei were most frequently observed at day-1 but were much less frequent at day-3 in both transplants and controls. The survival and effectiveness of retinal pigment epithelium sheet transplants appeared similar to the retinal pigment epithelium microaggregates transplants conducted previously in this model.

Animals↗
PubMed2005

Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation.

Studies in amphibian embryos have suggested that retinoic acid (RA) may function as a signal that stimulates posterior differentiation of the nervous system as postulated by the activation-transformation model for anteroposterior patterning of the nervous system. We have tested this hypothesis in retinaldehyde dehydrogenase-2 (Raldh2) null mutant mice lacking RA synthesis in the somitic mesoderm. Raldh2(-/-) embryos exhibited neural induction (activation) as evidenced by expression of Sox1 and Sox2 along the neural plate, but differentiation of spinal cord neuroectodermal progenitor cells (posterior transformation) did not occur as demonstrated by a loss of Pax6 and Olig2 expression along the posterior neural plate. Spinal cord differentiation in Raldh2(-/-) embryos was rescued by maternal RA administration, and during the rescue RA was found to act directly in the neuroectoderm but not the somitic mesoderm. RA generated by Raldh2 in the somitic mesoderm was found to normally travel as a signal throughout the mesoderm and neuroectoderm of the trunk and into tailbud neuroectoderm, but not into tailbud mesoderm. Raldh2(-/-) embryos also exhibited increased Fgf8 expression in the tailbud, and decreased cell proliferation in tailbud neuroectoderm. Our findings demonstrate that RA synthesized in the somitic mesoderm is necessary for posterior neural transformation in the mouse and that Raldh2 provides the only source of RA for posterior development. An important concept to emerge from our studies is that the somitic mesodermal RA signal acts in the neuroectoderm but not mesoderm to generate a spinal cord fate.

Aldehyde Oxidoreductases↗
PubMed2004

Complementary expression patterns of retinoid acid-synthesizing and -metabolizing enzymes in pre-natal mouse inner ear structures.

Retinoic acid (RA) plays a pivotal role in patterning and differentiation of the embryonic inner ear. Despite its documented effects during embryonic development, the cellular sites that synthesize or metabolize RA in the inner ear have yet to be determined. Here we describe the distribution of three synthesizing enzymes, retinaldehyde dehydrogenases 1, 2 and 3 (RALDH1, RALDH2 and RALDH3) and two catabolizing enzymes (CYP26A1 and CYP26B1) in the mouse inner ear at embryonic day 18.5 when active cell differentiation is underway. Two detection methods, radioactive and non-radioactive in situ hybridization, were employed to elucidate the tissue distribution and cellular localization of these enzymes, respectively. All of the five enzymes examined, with the exception of CYP26A1, were expressed in both vestibular and cochlear end organs. While expression of the three RALDHs was observed in various cell types, CYP26B1 expression was found only in supporting cells of the vestibular and cochlear end organs. In the cochlea, expression domains of RALDH1-3 and CYP26B1 were complementary to one another. These results reveal specific tissue- and cellular expression patterns of RA synthesizing and catabolizing enzymes in the pre-natal inner ear, and suggest that a precise control of RA concentrations in various cell types of the inner ear is achieved by the balance between RALDHs and CYP26B1 activities.

Aldehyde Oxidoreductases↗