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PubMed1990

A water-soluble polylysine-retinaldehyde Schiff base. Stability in aqueous and nonaqueous environments.

In order to improve the existing models of retinal-protein Schiff bases, a water-soluble polylysine-retinaldehyde imine has been synthesized and its stability assessed under a variety of conditions through changes in the visible absorption spectrum. The compound absorbs at 342 nm and consists of a 90-kDa poly-L-lysine containing a retinal Schiff base in about 2% of the lysyl epsilon-amino ends. Retinal is mostly in the all-trans form; under no conditions is more than 15% of the 13-cis isomer detected. The absorption maximum exhibits a pH-dependent reversible shift to 402 nm, with an apparent pKa approximately 3.4. In the presence of the anionic surfactant sodium dodecyl sulfate, this pKa is shifted to approximately 8.9, probably because of electric neutralization of lysyl epsilon-amino groups. Other detergents (cetyltrimethylammonium bromide, Triton X-100) do not modify the Schiff base pKa, but rather promote its hydrolysis; in this case detergents act in the same way as certain solvent mixtures, by providing an amphiphillic environment to the imine that in turn stabilizes the products of hydrolysis. Our results suggest that once the surfactant reaches the Schiff base, preferential partition of retinal into detergent micelles is the main factor facilitating imine bond breakdown. The response of our synthetic Schiff base to changes in pH or solvent polarity point together to an important role of the supporting polypeptide in providing a suitable environment to the chromophore.

Hydrogen-Ion Concentration↗
PubMed1994

Molecular cloning and structural analysis of the human gene encoding cellular retinaldehyde-binding protein.

Cellular retinaldehyde-binding protein (CRALBP) appears to play a role in the vertebrate visual process as a substrate-routing protein, influencing the enzymatic partitioning of 11-cis-retinol at a key branch point in the visual cycle. Genomic clones spanning 29 kilobases and encompassing the human CRALBP gene have been isolated by screening two human genomic libraries and from polymerase chain reaction amplification of human leukocyte DNA. The sequence of 13,647 contiguous nucleotides has been determined, including 3130 and 516 bases from the 5'- and 3'-flanking regions, respectively. The human CRALBP gene exists as a single copy in the genome based on Southern analyses and localization to a single site on human chromosome 15 (Sparkes, R. S., Heinzmann, C., Goldflam, S., Kojis, T., Saari, J. C., Mohandes, T., Klisak, I., Bateman, J. B., and Crabb, J. W. (1992) Genomics 12, 58-62). The gene is composed of eight exons and seven introns with average lengths of 198 base pairs and 1.2 kilobases, respectively, and which exhibit conventional vertebrate splicing. Alu repetitive sequences exist in introns 4 and 5 as well as in the 5'- and 3'-flanking regions of the gene. RNase protection and primer extension analyses indicate that the human CRALBP gene transcription start site is 922 bases upstream of the initiation codon. The first exon is entirely untranslated and both exon 2 and exon 8 contain untranslated regions. The proximal 5'-flanking region lacks GC boxes and consensus TATA and CCAAT boxes at the usual positions. The 3'-untranslated region of CRALBP exon 8 is essentially identical to a partial cDNA clone reportedly isolated from a human hippocampus cDNA library, suggesting that the protein may be expressed in a wider spectrum of tissues than previously recognized. The human CRALBP genomic clones and structure provide valuable tools for studying the physiological role of the protein in vision and visual disorders.

Animals↗
PubMed1993

Primary structure of alpha-tocopherol transfer protein from rat liver. Homology with cellular retinaldehyde-binding protein.

alpha-Tocopherol transfer protein (alpha TTP) present in rat liver cytosol specifically binds this vitamin and enhances its transfer between separate membranes. We previously reported purification of alpha TTP and showed that two isoforms exist in rat liver, of which the isoelectric points are 5.0 and 5.1, respectively (Sato, Y., Hagiwara, K., Arai, H., and Inoue, K. (1991) FEBS Lett. 288, 41-45). In the present paper, we have isolated a cDNA clone with 2194 base pairs encoding alpha TTP from a rat liver cDNA library. The amino acid sequence deduced from the cDNA contained all the sequences of the peptide fragments obtained by digestion of the purified protein with endoproteinase Lys-C. The isolated cDNA was found to encode the isoform with a pI of 5.0 on the basis of the cross-reactivity of the recombinant protein expressed in Escherichia coli with the isoform-specific monoclonal antibody. From the longest open reading frame of the cloned cDNA, one isoform of rat liver alpha TTP is predicted to be composed of 278 amino acid residues of calculated molecular weight 31,845. Both Western and Northern blot analyses revealed that alpha TTP is expressed exclusively in the liver in rats. alpha TTP has been found to exhibit a structural homology with the cellular retinaldehyde-binding protein present only in visual tissues.

Amino Acid Sequence↗
PubMed1998

Molecular characterization of the mouse gene encoding cellular retinaldehyde-binding protein.

PURPOSE: To clone and characterize the mouse gene encoding cellular retinaldehyde-binding protein (CRALBP). CRALBP appears to modulate enzymatic generation and processing of 11-cis-retinol and regeneration of visual pigment in the vertebrate visual cycle. Mutations in human CRALBP segregate with autosomal recessive retinitis pigmentosa. METHODS: A genomic clone encompassing the 5' end of the CRALBP gene through exon 6 was isolated from a mouse 129/Sv genomic DNA library. Exons 7 and 8 were PCR amplified from mouse eye cDNA and 129/SvJ genomic DNA. The gene structure was determined by automated DNA sequence analysis. RESULTS: The sequence of 6855 nucleotides was determined, including all 8 exons, 3 introns plus 3932 and 629 bases from the 5'- and 3'-flanking regions, respectively. The lengths of introns 3-6 were determined by PCR amplification. Northern analysis identifies a approximately 2.1 kb transcript in mouse eye; Southern analysis supports a single copy gene. CONCLUSIONS: The mouse CRALBP gene is similar to the human gene; the coding sequence is approximately 87% identical, the non-coding sequence approximately 65% identical. In contrast to the human gene, the mouse gene contains a consensus TATA box. One of two photoreceptor consensus elements important for CRALBP expression in human retinal pigment epithelium is also present in the mouse gene. Additional conserved and species-specific consensus sequences are identified. The mouse CRALBP genomic clones and structure provide valuable tools for developing an in vivo model to study protein function and gene regulation.

Animals↗
PubMed2006

Localization of retinaldehyde dehydrogenases and retinoid binding proteins to sustentacular cells, glia, Bowman's gland cells, and stroma: potential sites of retinoic acid synthesis in the postnatal rat olfactory organ.

Work from our laboratory suggests that retinoic acid (RA) influences neuron development in the postnatal olfactory epithelium (OE). The studies reported here were carried out to identify and localize retinaldehyde dehydrogenase (RALDH) expression in postnatal rat OE to gain a better understanding of potential in vivo RA synthesis sites in this continuously regenerating tissue. RALDH 1, 2, and 3 mRNAs were detected in postnatal rat olfactory tissue by RT-PCR analysis, but RALDH 1 and 2 transcripts were predominant. RALDH 1 immunoreactivity was localized to sustentacular cells in the OE and to Bowman's gland cells, and GFAP(+)/p75(-) olfactory ensheathing cells (OECs) in the underlying lamina propria (LP). RALDH 2 did not colocalize with RALDH 1, but appeared to be expressed in GFAP(-)/RALDH 1(-) OECs as well as in unidentified structures in the LP. Cellular RA binding protein (CRABP II) colocalized with RALDH 1. Cellular retinol/retinaldehyde binding protein (CRBP I) was localized to RALDH 1(+) sites in the OE and LP and RALDH 2(+) sites, primarily surrounding nerve fiber bundles in the LP. Vitamin A deficiency altered RALDH 1, but not RALDH 2 protein expression. The isozymes and binding proteins exhibited random variability in levels and areas of expression both within and between animals. These findings support the hypothesis that RA is synthesized in the postnatal OE (catalyzed by RALDH 1) and underlying LP (differentially catalyzed by RALDH 1 and RALDH 2) at sites that could influence the development, maturation, targeting, and/or turnover of olfactory receptor neurons throughout the olfactory organ.

Aldehyde Oxidoreductases↗
PubMed2006

Conditional (loxP-flanked) allele for the gene encoding the retinoic acid-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2).

Retinoic acid, the active vitamin A derivative, has pleiotropic functions during vertebrate development and postnatal life. Retinaldehyde dehydrogenase 2 (RALDH2) acts as the main retinoic acid-synthesizing enzyme during development. Mouse Raldh2 germline null mutants are early embryonic lethal and exhibit complex abnormalities that include defective heart looping morphogenesis. To investigate later functions of this enzyme, we have engineered a "floxed" (loxP-flanked) allele allowing Cre-mediated somatic gene inactivations. Mice heterozygous or homozygous for the floxed Raldh2 allele are viable and fertile. We tested whether the novel Raldh2 allele behaves as a null mutation after Cre-mediated in vivo excision by crossing the conditional mutants with CMV-Cre transgenic mice. An embryonic lethal phenotype indistinguishable from that of germline mutants was obtained. The conditional allele described herein is a genetic tool for studying tissue-specific, RALDH2-dependent functions of retinoic acid during development and in adult life.

Aldehyde Oxidoreductases↗
PubMed2005

Distribution and onset of retinaldehyde dehydrogenase (zRalDH) expression in zebra finch brain: lack of sex difference in HVC and RA at early posthatch ages.

Using in situ hybridization to detect the expression of the retinoic acid synthesizing enzyme (retinaldehyde dehydrogenase: zRalDH) mRNA, we mapped the distribution of its expression in adult zebra finch brain. In the neural song circuit, strong expression was found in high vocal center (HVC), para-HVC, and at a very low level in the robust nucleus of the arcopallium (RA). The expression in HVC and RA was found in both males and females. Outside of the song system, major areas of expression were in medial nidopallium (N), hyperpallium apicale (HA), mesopallium ventrale (MV), taenial amygdala (TnA), cerebellar Purkinje cells, and nucleus isthmo-opticus (IO). In nestlings, we found zRalDH mRNA expression in HVC and RA as early as posthatch day 4 or 5 (P4-5), although the expression varied among individuals. Thus, retinoic acid synthesis in HVC and RA could participate in song system formation and development. However, we found no sex difference in volume or intensity of zRalDH and androgen receptor (AR) expression in HVC and RA at P11 prior to the development of significant size dimorphisms in these nuclei. The size of HVC in females at P11 defined by zRalDH expression was greater than that in adult females, suggesting that HVC might experience net cell loss between P11 and adulthood.

Age Factors↗
PubMed1997

Cellular retinaldehyde binding protein in developing retinal astrocytes.

Cellular retinaldehyde binding protein (CRALBP) is present in Müller glia and in cells of the retinal pigment epithelium, but we have recently observed CRALBP-like immunoreactivity near the inner limiting membrane in the newborn mouse retina. The present study has examined whether this protein is present in developing retinal astrocytes. Retinal tissue was collected at various embryonic and postnatal ages and in adulthood. Tissue for immunohistochemistry was fixed by immersion in 4% paraformaldehyde and immunostained using rabbit polyclonal antisera to CRALBP or glial fibrillary acidic protein (GFAP), while fresh tissue was homogenized for Western analysis. Specificity of the antiserum for the 33 kDa protein was shown in retinal homogenates by immunoblotting, with expression of the protein increasing steadily from E15.5 through adulthood. Immunostaining of sections from fetal eye-cups revealed faint labeling of cells in the optic nerve, with progressive migration of CRALBP-immunoreactive cells into the retina at the inner limiting membrane during the perinatal period. By the day of birth, these cells were intensely immunoreactive, showing a morphology characteristic of migrating astrocytes. These CRALBP-immunoreactive cells mimicked the progressive infiltration of GFAP-positive astrocytes which are known to migrate into the retina from the optic nerve head, many of which were double-labeled with GFAP. Their distribution across the retina is distinct from that of the lighter-staining Müller glial somata during these stages, and they are not misidentified Müller glial endfeet. Astrocytes are only transiently CRALBP-immunoreactive, no longer containing the protein after the second post-natal week. Preincubation of the antiserum with purified CRALBP abolished all staining of astrocytes. Coupled with the fact that only a single (approximately 33 kDa) molecular weight protein is labeled by the antiserum, it was concluded that retinal astrocytes contain CRALBP during a limited period of development.

Animals↗
PubMed2003

The so-called "testis-specific aldehyde dehydrogenase" corresponds to type 2 retinaldehyde dehydrogenase in the mouse.

The distribution pattern of "testis-specific aldehyde dehydrogenase" in mouse tissues was investigated. Because of the broad substrate specificity and the high degree of sequence identity of the large aldehyde dehydrogenase family a specific detection of single isoforms is not possible by histochemical means. Therefore, the technique of native isoelectric focusing was used. Thus, the expression of four to five banded "testis-specific aldehyde dehydrogenase" in the mouse testis was confirmed. However, the activity of this enzyme with the same pattern of multiplicity was found not only in the testis but also in the uterus and in embryonic tissues. At 9.5 and 10.5 days of embryonic development the enzyme activity was restricted to tissues of the embryonic trunk and absent in extracts from cranial tissues. The tissue distribution as well as substrate specificity and isoelectric points indicate that the "testis-specific aldehyde dehydrogenase" corresponds to mouse type 2 retinaldehyde dehydrogenase.

Aldehyde Oxidoreductases↗
PubMed2006

Expression of retinaldehyde dehydrogenase (RALDH)2 and RALDH3 but not RALDH1 in the developing anterior pituitary glands of rats.

Retinoic acid (RA) plays an important role in cell growth and tissue development and is also a regulating factor of pituitary function. However, whether RA is generated in the pituitary gland and plays a role as a paracrine and/or autocrine hormone is generally unknown. RA is synthesized from retinoids through oxidation processes. Dehydrogenases catalyzing the oxidation of retinal to RA are members of the retinaldehyde dehydrogenase (RALDH) family. In this study, we examined the expression of RALDH1, RALDH2, and RALDH3 mRNA in the rat embryonic pituitary gland. By in situ hybridization with digoxigenin-labeled cRNA probes, we detected mRNA expression for RALDH2 and RALDH3, but not RALDH1. The expression of RALDH2 and RALDH3 was located in Rathke's pouch at embryonic day 12.5 (E12.5) and subsequently in the developing anterior pituitary gland. We also used quantitative real-time polymerase chain reaction to analyze RALDH2 and RALDH3 mRNA expression levels during the development of the pituitary gland. We found that pituitary RALDH2 and RALDH3 mRNA levels were high at E17.5 and decreased markedly after birth. Our study is the first to show that RALDH2 and RALDH3, but not RALDH1, are expressed in the embryonic anterior pituitary gland of the rat.

Aldehyde Dehydrogenase 1 Family↗
PubMed2006

Cloning and characterization of a novel, human cellular retinaldehyde-binding protein CRALBP-like (CRALBPL) gene.

Cellular retinaldehyde-binding protein (CRALBP) plays a role in the vertebrate visual process as a substrate-routing protein. It belongs to a widespread lipid-binding SEC14-like protein family. All the members of the family have the lipid-binding domain called CRAL-TRIO. Here we have isolated a new human CRAL-TRIO domain containing a CRALBP-like (CRALBPL) gene from the cDNA library of human adult brain. The CRALBPL gene consisted of 1,694 bp and had an ORF encoding putatively 354 amino acids with a CRAL-TRIO domain from 118 to 279 aa. The expression pattern in 18 human tissues indicated that CRALBPL gene was mainly expressed in brain. The alignment of CRAL-TRIO domain showed that CRALBPL had 45% identity with human CRALBP. Subcellular location revealed that CRALBPL protein was located in the cytoplasm of HeLa cells. Western blotting indicated that the CRALBPL had a molecular weight of about 40 kDa.

Amino Acid Sequence↗
PubMed2001

The distribution of retinaldehyde dehydrogenase-2 in rat and human orodental tissues.

Retinoic acid is an important signalling molecule in embryological development and continues to be important in the adult animal because it modulates growth and differentiation in many epithelial tissues. The distribution of the enzyme retinaldehyde dehydrogenase-2 (RALDH 2), which is involved in the synthesis of retinoic acid, was studied using immunocytochemical techniques in: (1) the developing orodental region of rats aged between 15 days in utero and 6 months; and (2) in archival human autopsy material consisting of abdominal skin and mucosa from various regions of the mouth. In developing tooth germs, RALDH 2 was absent in the enamel organ and dental papilla, its presence only being noted at the periphery of the dental follicle adjacent to parts of the developing alveolar crypt. In adult teeth, the presence of RALDH 2 was limited to blood vessels in the periodontal ligament. In embryos, the connective tissue beneath the nasal epithelium and the meninges stained strongly positively for RALDH 2, as did the connective tissue beneath nasal epithelium in an adult rat. Both keratinized and non-keratinized human oral epithelia and abdominal skin stained positively for RALDH 2. Staining was present throughout the stratified epithelium, except in the keratinized layer and in the basal layer associated with the dorsal surface of the tongue. In addition, the adnexia as well as the ductal lining of mucous glands stained positively for RALDH 2.

Adult↗
PubMed2000

Mouse type-2 retinaldehyde dehydrogenase (RALDH2): genomic organization, tissue-dependent expression, chromosome assignment and comparison to other types.

Retinaldehyde dehydrogenase (RALDH) isozymes catalyze the formation of an essential developmental modulator, retinoic acid. We determined the structural organization of mouse type-2 Raldh2 by isolation of overlapping genomic DNA clones from a phage library. The gene consists of 14 exons spanning more than 70 kb of genomic DNA. It was localized to mouse chromosome 6. Northern blot analysis revealed testis-specific expression. The RALDH genes belong to the aldehyde dehydrogenase (ALDH) multi-gene family. Three types of RALDH genes (e.g. human ALDH1/mouse Ahd2/rat RalDH(I), human ALDH11/mouse Raldh2/rat RalDH(II) and human ALDH6) are highly conserved during evolution, sharing about 70% identity at the amino acid level between any two gene types and 90% identity between any two mammalian genes of the same type. Different RALDH types show specific tissue and developmental expression patterns, suggesting (i) a regulatory mechanism of retinoic acid synthesis via different promoters of RALDH genes, and (ii) distinctive biological roles of different isozymes in embryogenesis and organogenesis.

Aldehyde Oxidoreductases↗
PubMed1997

Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development.

Retinaldehyde dehydrogenase type 2 (RALDH-2) was identified as a major retinoic acid generating enzyme in the early embryo. Here we report the expression domains of the RALDH-2 gene during mouse embryogenesis, which are likely to indicate regions of endogenous retinoic acid (RA) synthesis. During early gastrulation, RALDH-2 is expressed in the mesoderm adjacent to the node and primitive streak. At the headfold stage, mesodermal expression is restricted to posterior regions up to the base of the headfolds. Later, RALDH-2 is transiently expressed in the undifferentiated somites and the optic vesicles, and more persistently along the lateral walls of the intraembryonic coelom and around the hindgut diverticulum. The RALDH-2 expression domains in differentiating limbs, which include presumptive interdigital regions, coincide with, but slightly precede, those of the RA-inducible RAR beta gene. The RALDH-2 gene is also expressed in specific regions of the developing head, including the tooth buds, inner ear, meninges and pituitary gland, and in several viscera. Administration of a teratogenic dose of RA at embryonic day 8.5 results in downregulation of RALDH-2 transcript levels in caudal regions of the embryo, and may reflect a mechanism of negative feedback regulation of RA synthesis.

Aldehyde Oxidoreductases↗
PubMed2004

Genetic segregation of brain gene expression identifies retinaldehyde binding protein 1 and syntaxin 12 as potential contributors to ethanol preference in mice.

Genetic strains of mice represent an important resource for research on the biological determinants of complex diseases and behavioral phenotypes. To date, the approaches used have had little success in identifying causal genes. We have evaluated brain gene expression in C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains using differential display to identify a number of sequences showing significant expression differences between the two strains. These differences were confirmed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. Knowing that B6 and D2 mouse strains differ for a number of behavioral phenotypes, we asked whether this difference in brain gene expression could explain any of these traits. Here, we show that the expression of two of these genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), co-segregate with the ethanol preference phenotype in a B6D2 F2 population. Our results suggest a potential role for Rlbp1 and Stx12 in ethanol preference in mice, a conclusion supported by the location of these genes in quantitative trait loci (QTL) regions for this phenotype. This experimental approach has the potential for a broad application in the assessment of the roles of differentially expressed genes in a variety of complex phenotypes, with the advantage of identifying novel and potentially causal candidate genes directly.

Animals↗
PubMed2006

Regulation of expression of the retinoic acid-synthesising enzymes retinaldehyde dehydrogenases in the uteri of ovariectomised mice after treatment with oestrogen, gestagen and their combination.

The active metabolite of vitamin A, retinoic acid (RA), plays an important role in the female reproductive system. The synthesis of RA is tightly regulated by the activity of retinaldehyde dehydrogenases (Raldh). Among these, Raldh1 and Raldh2 exhibit specific temporal and spatial expression patterns in the mouse uterus, both during the oestrous cycle and early pregnancy. In the present study, we have assessed whether oestradiol and progesterone directly influence the uterine expression of Raldh1 and Raldh2 in ovariectomised mice. We investigated the effect of gestagen (promegestone 0.3 mg kg(-1) bodyweight), oestrogen (oestradiol 3 microg kg(-1) bodyweight) and their combination on the uterine expression of Raldh2. Expression was analysed using in situ hybridisation and quantified using real-time detection reverse transcription-polymerase chain reaction. The results show that the expression of Raldh2 is rapidly (within 1-4 h) induced in stromal cells by oestrogen, but not by gestagen, treatment, whereas combined oestrogen + gestagen treatment leads to a more prolonged (48 h) response. In contrast, oestrogen, but not progesterone, treatment downregulates (within 4-24 h) Raldh1 expression in the uterine glandular epithelium. We conclude that the uterine RA concentrations are regulated by oestrogens via an effect on the expression of the Raldh synthesising enzymes. Such a regulation is consistent with the natural fluctuations of Raldh expression during the oestrous cycle, early pregnancy and blastocyst implantation.

Aldehyde Oxidoreductases↗
PubMed2003

A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment.

The retinoic acid (RA) signal, produced locally from vitamin A by retinaldehyde dehydrogenase (Raldh) and transduced by the nuclear receptors for retinoids (RA receptor and 9-cis-RA receptor), is indispensable for ontogenesis and homeostasis of numerous tissues. We demonstrate that Raldh3 knockout in mouse suppresses RA synthesis and causes malformations restricted to ocular and nasal regions, which are similar to those observed in vitamin A-deficient fetuses and/or in retinoid receptor mutants. Raldh3 knockout notably causes choanal atresia (CA), which is responsible for respiratory distress and death of Raldh3-null mutants at birth. CA is due to persistence of nasal fins, whose rupture normally allows the communication between nasal and oral cavities. This malformation, which is similar to isolated congenital CA in humans and may result from impaired RA-controlled down-regulation of Fgf8 expression in nasal fins, can be prevented by a simple maternal treatment with RA.

Aldehyde Oxidoreductases↗