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PubMed1995

Isoforms of platelet-derived growth factor and its receptors in epiretinal membranes: immunolocalization to retinal pigmented epithelial cells.

Epiretinal membranes (ERMs) form on the inner surface of the retina in conjunction with various ocular disease processes, but the factors controlling their development are not understood. The predominant cell types involved are retinal pigmented epithelial (RPE) cells and retinal glia. Cultured RPE cells secrete platelet-derived growth factor (PDGF), which is chemotactic and mitogenic for both RPE cells and retinal glia and, therefore, could be involved in the development of ERMs. In the present study, we performed immunohistochemical staining for PDGF A chain (PDGF-A), PDGF B chain (PDGF-B), and both types of PDGF receptors (PDGFr alpha and PDGFr beta) on ERMs associated with various disease processes. PDGF-A is detected in most ERMs, regardless of the associated disease process, and it appears to be localized predominantly in RPE cells, recognized by the presence of pigment and the immunohistochemical demonstration of some or all of the following RPE-associated epitopes: class III beta-tubulin, keratin, the 65-kDa microsomal protein recognized by the RPE9 antibody, and cellular retinaldehyde-binding protein. PDGF-B is found only in minor subpopulations of cells in about half of the ERMs evaluated and, with only occasional exceptions, appears to be localized almost entirely in blood-borne cells found in and around vessels in vascularized ERMs. Both PDGFr alpha and PDGFr beta are demonstrated in most ERMs with neither isotype consistently predominating: they are found predominantly on RPE cells with many cells expressing both receptor types. ERMs with little or no RPE cell component contain little or no PDGF and PDGF receptor, whereas those in which the RPE cell represents the major cell type, have widespread PDGF and PDGF receptor positivity. These findings show that RPE cells in ERMs produce PDGF-A and PDGF alpha and PDGF beta receptors and suggest that autocrine and paracrine stimulation with PDGF may be involved in ERM pathogenesis.

Eye Diseases↗
PubMed1995

Effects of Müller cell disruption on mouse photoreceptor cell development.

Müller cells have been proposed to play an important role in photoreceptor cell development during the final stages of retinal maturation. The effect of disrupting Müller cells during mouse retinal development was investigated using the specific glial cell toxin, DL-alpha-aminoadipic acid (AAA). By giving multiple systemic injections over several days, impairment of Müller cell function was maintained during the period of photoreceptor migration and differentiation. Following three consecutive days of AAA treatment [commencing on post-natal (P) day 3, 5, 7 or 9, and examined at P8-P14], clumps of photoreceptor nuclei were displaced through the inner segments, lying immediately beneath the retinal pigment epithelium (RPE). Apart from the scalloped appearance of the outer retina, the overall lamination pattern of the retina was relatively well preserved. Even when AAA treatment commenced as early as P3, several days prior to the formation of the outer nuclear layer, the majority of photoreceptors migrated to their correct position and formed inner and outer segments. Therefore, the signals for photoreceptor migration are either provided by the Müller cells prior to P3, or, alternatively, are derived from different intrinsic or extrinsic cues. Disruption of Müller cell function was evidenced by decreased glutamine synthetase activity as well as by increased glial fibrillary acidic protein (GFAP) and decreased cellular retinaldehyde-binding protein (CRALBP) immunoreactivity. Immunocytochemistry with an antibody to CD44, which labels the microvilli of Müller cells at the outer limiting membrane, coupled with electron microscopic analysis, demonstrated that the zonulae adherentes between Müller cells and photoreceptors were either irregular or absent in areas adjacent to displaced clumps of photoreceptors. Thus AAA treatment of early post-natal mice results in localized disruption of the contacts between Müller cells and photoreceptors. These pathologic changes persist into adulthood since at P28, while short stretches of photoreceptors appeared relatively normal with fully developed outer segments, periodic clumps of displaced photoreceptor nuclei were still present adjacent to the RPE. In conclusion, Müller cell processes at the outer limiting membrane appear to play a critical role in providing a barrier to aberrant photoreceptor migration into the subretinal space.

2-Aminoadipic Acid↗
PubMed1995

Class III beta-tubulin in human retinal pigment epithelial cells in culture and in epiretinal membranes.

The class III beta-tubulin isotype (beta III) is expressed exclusively by neurons within the normal human retina and is not present in normal retinal pigment epithelial (RPE) cells in situ or in 1 day-old primary cultures; however, beta III is present in RPE cells in 5-day primary cultures and in passaged RPE cells grown in monolayer cultures as determined by immunohistochemistry and Western blotting. beta III-positivity in cultured RPE cells is not affected by cell density or hydroxyurea- or retinoic-acid-mediated growth inhibition, but only a few cells weakly express beta III in cyclohexamide-treated cultures and RPE cells maintained in serum-free medium fail to produce beta III. When monolayer-cultured RPE cells grown in normal, serum-containing medium, are transferred to irradiated bovine vitreous, beta III is undetectable in most cells. Cultured RPE cells coexpress beta III with keratin and cellular retinaldehyde-binding protein (both RPE cell markers), but not with glial fibrillary acidic protein. Some cultured RPE cells also express neuron-specific (gamma) enolase, which is neuron-associated but not neuron-specific, and occasional cells in confluent or super-confluent cultures contain the 200-kDa neurofilament protein. Retinal glia, fibroblasts, endothelial cells, and smooth muscle cells do not express beta III under the same culture conditions. We have detected beta III in 45 of 56 epiretinal membranes, frequently in cells with a bipolar or dedifferentiated morphology, where its expression coincides with other RPE cell-associated antigens. Cells with morphological features resembling normal RPE cells in epiretinal membranes are usually negative for beta III, but RPE cells appearing to be in the early stages of dedifferentiation express the isotype weakly. Electron microscopic immunocytochemistry localizes beta III to microtubules, ribosomes and cytoplasm. beta III may be a useful marker for recognizing the fraction of RPE cells in epiretinal membranes that are no longer identifiable by morphological criteria or other RPE cell markers. These findings demonstrate that mature human RPE cells have the capacity to express a neuron-associated gene in response to conditions that promote dedifferentiation.

Cells, Cultured↗
PubMed1987

Uveoretinitis in rabbits following immunization with interphotoreceptor retinoid-binding protein.

Interphotoreceptor retinoid-binding protein (IRBP) is a glycoprotein found in the interphotoreceptor matrix between the neurosensory retina and the retinal pigment epithelium and is thought to shuttle retinol among cells that border the interphotoreceptor space. Immunization of rabbits with bovine IRBP caused subsequent photoreceptor degeneration, as documented by light- and electron microscopy. Beginning on post-injection day 18, scattered regions had photoreceptor outer segments that were disorganized and shortened or absent. Macrophages were found between the retinal pigment epithelium and neurosensory retina and within choroidal interstitium and blood vessels. Labeling of these cells with a marker specific for monocytic macrophages (RAM11) and absence of labeling with a marker for retinal pigment epithelium (rabbit anti-bovine cellular retinaldehyde-binding protein) suggest that these macrophages were hematogenous in origin. Staining of retinas with fluorescein isothiocyanate (FITC)-conjugated sheep anti-rabbit IgG revealed leakage of rabbit IgG into the interphotoreceptor matrix on and after day 18 in experimental animals but not in controls, suggesting breakdown of the outer blood-retinal barrier. Indirect immunofluorescence with anti-glial fibrillary acidic protein revealed labeling of Müller cells in experimental retinas on and after day 18, but not in control or shorter survival experimental retinas. There were foci of increased cellularity in the choroid on days 18, 26 and 39. From days 26 through 67, the retinal pathology became more widespread. Varying degrees of outer-segment degeneration were present in all parts of the retina and in many areas there was total loss of outer segments and loss of some photoreceptor-cell bodies. The inner retina appeared unaffected in all experimental and control retinas. These results demonstrate that injection of rabbits with bovine IRBP causes retinal photoreceptor degeneration as anti-IRBP titers increase and breakdown of the outer blood-retinal barrier ensues. Further studies will be required to elucidate factor(s) that control accessibility of the neurosensory retina to circulating antibodies against IRBP and other intrinsic retinal proteins.

Animals↗
PubMed2002

Human pancreas protein 2 (PAN2) has a retinal reductase activity and is ubiquitously expressed in human tissues.

Human gene for pancreas protein 2 (PAN2) is a novel member of the short-chain dehydrogenase/reductase gene superfamily. The properties of PAN2 protein have not yet been characterized. We present the first evidence that human PAN2 is a ubiquitously expressed microsomal enzyme that recognizes retinoids but not steroids as substrates with the apparent K(m) values between 0.08 microM and 0.4 microM. PAN2 is approximately 4-fold more efficient in the reductive than in the oxidative direction. The apparent K(m) values for NADP(+) and NADPH are 0.65 microM and 0.32 microM versus 1200 microM and 1060 microM for NAD(+) and NADH, respectively. Kinetic constants and expression pattern of PAN2 suggest that it is likely to function as a reductase in vivo and might contribute to the reduction of retinaldehyde to retinol in most human tissues.

Alcohol Oxidoreductases↗
PubMed2003

Neuropsin (Opn5): a novel opsin identified in mammalian neural tissue.

We have cloned and characterised the expression of a new opsin gene, neuropsin (Opn5), in mice and humans. Neuropsin comprises seven exons on mouse chromosome 17. Its deduced protein sequence suggests a polypeptide of 377 amino acids in mice (354 in humans), with many structural features common to all opsins, including a lysine in the seventh transmembrane domain required to form a Schiff base link with retinaldehyde. Neuropsin shares 25-30% amino acid identity with all known opsins, making it the founding member of a new opsin family. It is expressed in the eye, brain, testis and spinal cord.

Amino Acid Sequence↗
PubMed1998

The visual cycle retinol dehydrogenase: possible involvement in the 9-cis retinoic acid biosynthetic pathway.

The 11-cis-retinol dehydrogenase (11-cis-RoDH) gene encodes the short-chain alcohol dehydrogenase responsible for 11-cis-retinol oxidation in the visual cycle. The structure of the murine 11-cis-RoDH gene was used to reinvestigate its transcription pattern. An 11-cis-RoDH gene transcript was detected in several non-ocular tissues. The question regarding the substrate specificity of the enzyme was therefore addressed. Recombinant 11-cis-RoDH was found capable of oxidizing and reducing 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinaldehyde, respectively. Dodecyl-beta-1-maltoside used to solubilize the enzyme was found to affect the substrate specificity. This is the first report on a visual cycle enzyme also present in non-retinal ocular and non-ocular tissues. A possible role in addition to its role in the visual cycle is being discussed.

Alcohol Oxidoreductases↗
PubMed1994

Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus.

BACKGROUND: Fundus flavimaculatus (Stargardt disease) is a group of inherited macular dystrophies in which central vision usually decreases in the first two decades of life. Previous histopathologic studies used light, scanning, and transmission electron microscopy to characterize the retinal pigment epithelium (RPE) in fundus flavimaculatus. The authors describe in detail the pathologic changes in the neurosensory retina, including use of specific immunocytochemical markers. METHODS: The eyes of a patient with fundus flavimaculatus were processed using Medcast and JB-4 plastic for light and electron microscopy, and cryomicrotomy and LR-white resin for immunocytochemistry. RESULTS: Changes in the RPE occurred in a peripheral/central gradient and included increased lipofuscin content and cell loss toward the macula. The changes in the retina paralleled those in the RPE, including accumulation of lipofuscin in photoreceptor inner segments, loss of photoreceptors, and reactive Müller cell hypertrophy. Immunocytochemistry using rod- and cone-specific markers showed abnormal photoreceptor morphology but qualitatively normal immunoreactivity, and there was strong reactivity for glial fibrillary acid protein in reactive Müller cells. Labeling for cellular retinaldehyde-binding protein was qualitatively normal in Müller cells, but was reduced in RPE cells that were engorged with lipofuscin. CONCLUSIONS: The histopathologic changes in the retina correlate with clinical progression of the disease process. Although abnormal lipofuscin metabolism has been implicated in the loss of vision in fundus flavimaculatus and other macular diseases, the mechanism is not understood. Based on the authors' observations and a review of recent literature on lipofuscin, the authors propose that all-trans-retinol dehydrogenase, a photoreceptor outer segment enzyme, may be defective in fundus flavimaculatus.

Female↗
PubMed2001

Sources and sink of retinoic acid in the embryonic chick retina: distribution of aldehyde dehydrogenase activities, CRABP-I, and sites of retinoic acid inactivation.

Previous experiments in mice and zebrafish led to the hypothesis that an asymmetric distribution of the transcriptional activator retinoic acid (RA) causes ventral-dorsal polarity in the vertebrate eye anlage. A high concentration of RA in the ventral retinal neuroepithelium has been suggested to induce developmental events that finally establish topographic order in the retinotectal projection along the vertical eye axis. In the present study we have investigated potential sources and sinks of RA during embryonic development of the chick retina. At embryonic day (E)1 to E2, when the spatial determination of the eye primordia takes place, no RA synthesis by aldehyde dehydrogenases was detectable, and neither immunoreactivity for retinaldehyde dehydrogenase RALDH-2 nor for cellular retinoic acid binding protein CRABP-I was observed. These components of RA signal transduction appeared in the eye between E3 and E5. At later stages, RA-measurements with a reporter cell line showed highest synthesis in the retinal pigment epithelium (RPE) and at the ventral and dorsal poles of the retina. RA degradation occurred mostly in a horizontal region in the middle of the retina with only small differences along the nasal-temporal axis. CRABP-I immunoreactivity appeared first in differentiating retinal ganglion cells with no indication of a spatial gradient across the ventral-dorsal eye axis. RA-production depended on three NAD+-dependent enzyme activities, which could be competitively inhibited by citral. One enzyme, located in the dorsal retina (corresponding to mouse RALDH-1), and one enzyme in the RPE (RALDH-2) were aldehyde dehydrogenases of the same molecular weight (monomers about 55 kDa) but with different isoelectric points (6.5-6.9; 4.9-5.4). The third RA-synthesizing activity (pI 6.0-6.3) was limited to the ventral retina, and likely corresponded to mouse RALDH-3. The restricted localization of retinoid-metabolizing activities along the dorsal-ventral axis of the embryonic chick retina does support the idea that RA is involved in dorsal-ventral eye patterning. However, the late time of appearance of aldehyde dehydrogenase activities and CRABP-I points to functions in cellular differentiation that are distinct from the initiation of the dorsal-ventral polarity.

Aldehyde Dehydrogenase↗
PubMed2000

Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase.

Lipocalin-type prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), a potent endogenous somnogen and nociceptive modulator, in the presence of sulfhydryl compounds. PGDS is an N-glycosylated monomeric protein with an M(r) of 20000-31000 depending on the size of the glycosyl moiety. PGDS is localized in the central nervous system and male genital organs of various mammals and in the human heart and is secreted into the cerebrospinal fluid, seminal plasma, and plasma, respectively, as beta-trace. The PGDS concentrations in these body fluids are useful for the diagnosis of several neurological disorders, dysfunction of sperm formation, and cardiovascular and renal diseases. The cDNA and gene for PGDS have been isolated from several animal species, and the tissue distribution and cellular localization have also been determined. This enzyme is considered to be a dual functional protein; i.e. it acts as a PGD(2)-producing enzyme and also as a lipophilic ligand-binding protein, because the enzyme binds biliverdin, bilirubin (K(d)=30 nM), retinaldehyde, retinoic acid (K(d)=80 nM) with high affinities. X-ray crystallographic analyses revealed that PGDS possesses a beta-barrel structure with a hydrophobic pocket in which an active thiol, Cys(65), the active center for the catalytic reaction, was located facing to the inside of the pocket. Gene-knockout and transgenic mice for PGDS were generated and found to have abnormalities in the regulation of nociception and sleep.

Amino Acid Sequence↗
PubMed2001

Molecular targets of disulfiram action on song maturation in zebra finches.

Disulfiram, an aldehyde dehydrogenase inhibitor, interferes with normal song maturation when applied to brain nucleus HVC of male zebra finches. We present here evidence from Western blots and enzymatic assays showing that known disulfiram targets other than retinaldehyde-specific aldehyde dehydrogenase (zRalDH) are absent in HVC. These findings are consistent with the conclusion that disulfiram disrupts song maturation by interfering with retinoic acid production.

Aldehyde Dehydrogenase↗
PubMed1997

Human liver fatty aldehyde dehydrogenase: microsomal localization, purification, and biochemical characterization.

To better understand the genetic disorder Sjogren-Larsson syndrome which is caused by a deficiency of fatty aldehyde dehydrogenase activity, we determined the subcellular localization of the enzyme and investigated its biochemical properties. Using density gradient centrifugation, we found that fatty aldehyde dehydrogenase activity was predominantly localized in the microsomal fraction in human liver. This fatty aldehyde dehydrogenase was solubilized from human liver microsomes and purified by chromatography on columns consisting of omega-aminohexyl-agarose and 5'-AMP-Sepharose 4B. The enzyme had an apparent subunit molecular weight of 54000, required NAD+ as cofactor, had optimal activity at pH 9.8, and was thermolabile at 47 degrees C. Fatty aldehyde dehydrogenase had high activity towards saturated and unsaturated aliphatic aldehydes ranging from 6 to 24 carbons in length, as well as dihydrophytal, a 20-carbon branched chain aldehyde. In contrast, acetaldehyde, propionaldehyde, crotonaldehyde, glutaraldehyde, benzaldehyde, and retinaldehyde were poor substrates. The enzyme was inhibited by disulfiram, iodoacetamide, alpha,p-dibromoacetophenone, and p-chloromercuribenzoate. These results indicate that microsomal fatty aldehyde dehydrogenase is a distinct human aldehyde dehydrogenase isozyme that acts on a variety of medium- and long-chain aliphatic substrates.

Aldehyde Oxidoreductases↗
PubMed2000

A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse.

Most retinoic acid (RA) in the embryonic mouse is generated by three retinaldehyde dehydrogenases (RALDHs). RALDH1 (also called E1, AHD2 or ALDH1) is expressed in the dorsal retina, and RALDH2 (V2, ALDH11) generates most RA in the embryonic trunk. The third one, RALDH3 (V1), synthesizes the bulk of RA in the head of the early embryo. We show here that RALDH3 is a mouse homologue to ALDH6, an aldehyde dehydrogenase cloned from adult human salivary gland (Hsu, L.C., Chang, W.-C., Hiraoka, L., Hsien, C.-L., 1994. Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6. Genomics 24, 333-341), which was recently reported to act as a RALDH (Yoshida, A., Rzhetsky, A., Hsu, L.C., Chang, C., 1998. Human aldehyde dehydrogenase gene family. Eur. J. Biochem. 251, 549-557). RALDH3 expression begins in the surface ectoderm over the optic recess. In rapidly changing expression patterns it labels the appearance of several ectodermal structures: it marks the formation of the lens and the olfactory organ from ectodermal placodes, and it delineates the beginning eyelid field. Within the optic vesicle, RALDH3 is expressed in the ventral retina and the dorsal pigment epithelium. In the telencephalon, RALDH3 is expressed at high levels in the lateral part of the ganglionic eminence. From here it extends via the piriform cortex into the lower part of the septum. Of the three RALDHs, RALDH3 shows the strongest predilection for epithelia.

Aldehyde Dehydrogenase↗
PubMed2001

Specific expression of the retinoic acid-synthesizing enzyme RALDH2 during mouse inner ear development.

Retinoid binding proteins and nuclear receptors are expressed in the developing mouse inner ear. Here, we report that the retinaldehyde dehydrogenase 2 (Raldh2) gene, whose product is involved in the enzymatic generation of retinoic acid (RA), exhibits a restricted expression pattern during mouse inner ear ontogenesis. The Raldh2 gene is first expressed at embryonic day (E) 10.5 in a V-shaped medio-dorsal region of the otocyst outer epithelium, which evolves as two separate domains upon otocyst morphogenesis. At E14.5, Raldh2 is expressed in two areas of the utricle epithelium and specific regions of the saccule and cochlear mesenchyme. Later, Raldh2 transcripts are restricted to two cochlear areas, the stria vascularis and Reissner membrane. Raldh2 mesenchymal expression did not correlate with migrating neural crest-derived melanoblasts. These restricted expression domains may correspond to specific sites of RA synthesis during inner ear morphogenesis.

Aldehyde Oxidoreductases↗
PubMed2003

Retinoic acid signaling regulates murine bronchial tubule formation.

Treatment of pseudoglandular stage fetal lungs in vitro with the pan-retinoic acid receptor (pan-RAR) antagonist, BMS493, reduces retinoic acid receptor beta (Rarb) gene expression within the proximal bronchial tubules and increases explant bud formation. Treatment with retinoic acid (RA) increases Rarb expression and reduces explant bud formation through a signaling mechanism involving RARbeta. Together these data suggest that RA through RARbeta provides morphogenetic stabilizing activity to the proximal tubules during lung branching morphogenesis. Here we further investigate RA-mediated morphogenetic stabilization of the proximal respiratory tubules during fetal lung development. We demonstrate that Rarb isoform transcripts are the only known Rar transcripts to specifically localize to the proximal tubules and that RAREhsp68lacZ reporter transgene activity reveals endogenous RA signaling activity within these same proximal tubules. Furthermore, the expression patterns of the RA-producing enzyme retinaldehyde dehydrogenase 1 (Raldh1), as well as of transforming growth factor-3beta (Tgfb3), Foxa2, and the cystic fibrosis transmembrane conductance regulator (Cftr) within the proximal tubules are all altered by the application of either RA or BMS493 in vitro. We therefore discuss an interbud/proximal tubule signaling niche involving feedback between Rarb expression and Raldh1-mediated synthesis of RA. We suggest that this feedback favors interbud morphogenetic stability by increasing expression of morphoregulatory molecules such as TGFbeta3 and Foxa2, thus promoting bronchial tubule formation rather than continual budding and branching. The relationship between this RAR signaling center and the previously described distal bud signaling center is also addressed.

Aldehyde Oxidoreductases↗
PubMed1999

Dorsal and ventral retinal territories defined by retinoic acid synthesis, break-down and nuclear receptor expression.

Determination of the dorso-ventral dimension of the vertebrate retina is known to involve retinoic acid (RA), in that high RA activates expression of a ventral retinaldehyde dehydrogenase and low RA of a dorsal dehydrogenase. Here we show that in the early eye vesicle of the mouse embryo, expression of the dorsal dehydrogenase is preceded by, and transiently overlaps with, the RA-degrading oxidase CYP26. Subsequently in the embryonic retina, CYP26 forms a narrow horizontal boundary between the dorsal and ventral dehydrogenases, creating a trough between very high ventral and moderately high dorsal RA levels. Most of the RA receptors are expressed uniformly throughout the retina except for the RA-sensitive RARbeta, which is down-regulated in the CYP26 stripe. The orphan receptor COUP-TFII, which modulates RA responses, colocalizes with the dorsal dehydrogenase. The organization of the embryonic vertebrate retina into dorsal and ventral territories divided by a horizontal boundary has parallels to the division of the Drosophila eye disc into dorsal, equatorial and ventral zones, indicating that the similarities in eye morphogenesis extend beyond single molecules to topographical patterns.

Aldehyde Oxidoreductases↗
PubMed1999

Dorsal and ventral rentinoic territories defined by retinoic acid synthesis, break-down and nuclear receptor expression.

Determination of the dorso-ventral dimension of the vertebrate retina is known to involve retinoic acid (RA), in that high RA activates expression of a ventral retinaldehyde dehydrogenase and low RA of a dorsal dehydrogenase. Here we show that in the early eye vesicle of the mouse embryo, expression of the dorsal dehydrogenase is preceded by, and transiently overlaps with, the RA-degrading oxidase creating a trough between very high ventral and moderately high dorsal RA levels. Most of the RA receptors are expressed uniformly throughout the retina except for the RA-sensitive RARbeta, which is down-regulated in the CYP26 stripe. The orphan receptor COUP-TFII, which modulates RA responses, colocalizes with the dorsal dehydrogenase. The organization of the embryonic vertebrate retina into dorsal ventral territories divided by a horizontal boundary has parallels to the division of the Drosophila eye disc into dorsal, equatorial and ventral zones, indicating that the similarities in eye morphogenesis extend beyond single molecules to topographical patterns.

Animals↗
PubMed2003

Expression pattern and biochemical characteristics of a major epidermal retinol dehydrogenase.

The biological functions of vitamin A in the epidermis are mediated by all-trans retinoic acid, which is biosynthesized from retinol in two oxidative reactions. The first step involves enzymatic conversion of retinol to retinaldehyde. The physiological significance and relative contributions of the various retinol dehydrogenases to the oxidation of retinol in epidermal cells remain unclear. We report the characterization of a retinol dehydrogenase/reductase of the SDR superfamily, hRoDH-E2, which is abundantly expressed in the epidermis, epidermal appendages and in cultured epidermal keratinocytes. Both in live keratinocytes and in isolated keratinocyte microsomes, where the enzyme normally localizes, hRoDH-E2 functions as a bona fide retinol dehydrogenase. In the prevailing oxidative reaction it recognizes both free- and CRBP-bound retinol, and shows preference toward NADP as a co-substrate. In comparison, hRoDH-E2 retinol dehydrogenase activity in the simple epithelial HEK 293 cells is much lower and in CHO cells is non-existent. hRoDH-E2 transcripts are distributed throughout the epidermal layers but are more abundant in the basal cells. In contrast, the protein is detected predominantly in the basal and the most differentiated living layers. Its synthesis is negatively regulated by retinoic acid. The biochemical properties and the differential expression of hRoDH-E2 in the strata where retinoic acid signaling is critical for epidermal homeostasis support a conclusion that hRoDH-E2 bears the characteristics of the major microsomal retinol dehydrogenase activity in the epidermal keratinocytes in physiological circumstances.

Alcohol Oxidoreductases↗