*603687	Links
ALDEHYDE DEHYDROGENASE 1 FAMILY, MEMBER A2; ALDH1A2

Alternative titles; symbols

RETINALDEHYDE DEHYDROGENASE 2; RALDH2

Gene map locus Chr.15

TEXT

CLONING

Retinoic acid (RA), a developmental signal implicated in the formation of the neural axis, is present at high levels in the early embryonic trunk region, including the Hensen node. Retinaldehyde dehydrogenase converts retinaldehyde to RA. Zhao et al. (1996) cloned a cDNA, Raldh2, from mouse P19 teratocarcinoma cells that encoded an NAD-dependent aldehyde dehydrogenase with high substrate specificity for retinaldehyde. The cDNA encodes a 499-amino acid protein with 70% similarity to class 1 aldehyde dehydrogenases. The protein contains the conserved motifs characteristic of other aldehyde dehydrogenases: the NAD-binding domain containing the motif GXGXXXG, 2 conserved peptide motifs, and cys301, which is the critical residue for interaction with the aldehyde group. Transfection in COS-7 cells indicated that Raldh2 effectively catalyzed the synthesis of RA from retinaldehyde. Raldh2 did not oxidize any other substrate tested. Its pattern of expression during mouse development suggested that it may be responsible for embryonic RA synthesis. Wang et al. (1996) cloned the rat Raldh2 cDNA.

While studying the effect of TAL1 (187040) and LMO (see 186921) on T-cell acute lymphocytic leukemia (T-ALL), Ono et al. (1998) cloned the human RALDH2 cDNA. In normal T cells, GATA3 (131320) binds to the GATA site in the RALDH2 promoter but does not activate transcription. When TAL1 and LMO are ectopically expressed in T-ALL, a large complex containing TAL1, LMO, and GATA3 is formed on the GATA site in the RALDH2-T promoter to activate transcription from a downstream initiator.

The precise specification of left-right asymmetry is an essential process for patterning internal organs in vertebrates. In mouse embryonic development, the symmetry-breaking process in left-right determination is initiated by a leftward extraembryonic fluid flow on the surface of the ventral node. Tanaka et al. (2005) showed that fibroblast growth factor (FGF) signaling triggers secretion of membrane-sheathed objects 0.3 to 5 microns in diameter, termed 'nodal vesicular parcels' (NVPs), which carry Sonic hedgehog (Shh; 600725) and retinoic acid. These NVPs are transported leftward by the fluid flow and eventually fragment close to the left wall of the ventral node. The silencing effects of an FGF receptor (176943) inhibitor on NVP secretion and on a downstream rise in calcium were sufficiently reversed by exogenous Sonic hedgehog peptide or retinoic acid, suggesting that FGF-triggered surface accumulation of cargo morphogens may be essential for launching NVPs. Tanaka et al. (2005) proposed that NVP flow is a mode of extracellular transport that forms a left-right gradient of morphogens. Using time-lapse imaging, Tanaka et al. (2005) found that these NVPs were transported leftward once every 5 to 15 seconds.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the RALDH2 gene to chromosome 15 (RH76097).

ANIMAL MODEL

Niederreither et al. (1999) generated a targeted disruption of the mouse Raldh2 gene and found that Raldh2 -/- embryos, which died at midgestation without undergoing axial rotation, exhibited shortening along the anterioposterior axis, open neural tube, and absent limb buds. Their hearts consisted of a single, medial, dilated cavity. Their frontonasal regions were truncated and their otocysts were severely reduced. These defects resulted from a block of embryonic RA synthesis, as shown by the lack of activity of RA-responsive transgenes, the altered expression of an RA-target homeobox gene (Hoxa1; 142955), and the near full rescue of the mutant phenotype by maternal RA administration. The data established that RA synthesized by the postimplantation mammalian embryo is an essential developmental hormone whose lack leads to early embryonic death.

Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that acts in developing and adult tissues. The cytochrome p450, 26 (CYP26A1; 602239) metabolizes retinoic acid into more polar hydroxylated and oxidized derivatives. Cyp26a1 -/- mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development. If this is true, then the Cyp26a1 -/- phenotype could be 'rescued' under conditions in which embryonic retinoic acid levels are decreased. Niederreither et al. (2002) showed that these null mice are indeed phenotypically rescued by heterozygous disruption of the gene encoding Aldh1a2, which encodes a retinaldehyde dehydrogenase responsible for the synthesis of retinoic acid during early embryonic development. Aldh1a2 haploinsufficiency prevented the appearance of spina bifida and rescued the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1 -/- mice. Thus, some of these double-mutant mice could reach adulthood. This study was the first report of a mutation acting as a dominant suppressor of a lethal morphogenetic mutation in mammals. Niederreither et al. (2002) provided genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida. Perlmann (2002) referred to this relationship in retinoic metabolism as 'a balancing act.'

Vermot et al. (2003) generated mice bearing a hypomorphic allele of the RALDH2 gene. The resulting mutant mice, which died perinatally, exhibited features of DiGeorge syndrome (188400) with heart outflow tract septation defects and anomalies of the aortic arch-derived head and neck arteries, laryngeal-tracheal cartilage defects, and thyroid/parathyroid aplasia or hypoplasia. Analysis of Raldh2 hypomorph embryos showed selective defects of the posterior (third to sixth) branchial arches, including absence or hypoplasia of the corresponding aortic arches and pharyngeal pouches, and local downregulation of retinoic acid-targeted genes. Thus, a decreased level of embryonic retinoic acid (through genetic and/or nutritional causes) could represent a major modifier of the expressivity of human 22q11del-associated DiGeorge/velocardiofacial syndromes and, if severe enough, could on its own lead to the clinical features of the DiGeorge syndrome.

Keegan et al. (2005) presented a new mechanism for regulating the number of progenitor cells in organ development by limiting their density within a competent region. Using a zebrafish mutation that disrupts function of raldh2, they demonstrated that retinoic acid signaling restricted cardiac specification in the zebrafish embryo. Reduction of retinoic acid signaling caused formation of an excess of cardiomyocytes, via fate transformations that increased cardiac progenitor density within a multipotential zone. Thus, retinoic acid signaling creates a balance between cardiac and noncardiac identities, thereby refining the dimensions of the cardiac progenitor pool.

Vermot et al. (2005) found that Raldh2-null mice exhibit delayed somite formation on the right side. Asymmetric somite formation correlated with a left-right desynchronization of the segmentation clock oscillations. Vermot et al. (2005) concluded that their data implicated retinoic acid as an endogenous signal that maintains the bilateral synchrony of mesoderm segmentation, and therefore controls bilateral symmetry, in vertebrate embryos.

Kawakami et al. (2005) characterized a cascade of laterality information in the zebrafish embryo and showed that blocking the early steps of this cascade before it reaches the lateral plate mesoderm, using a morpholino-modified antisense oligonucleotide against Raldh2, results in random left-right asymmetric somitogenesis. They also uncovered a mechanism mediated by retinoic acid signaling that is crucial in buffering the influence of the flow of laterality information on the left-right progression of somite formation, and thus in ensuring bilaterally symmetric somitogenesis. The left-right axis in zebrafish embryos is controlled by 2 parallel mechanisms, one that depends on hydrogen/potassium ATPase activity and acts very early in development (before the start of zygotic transcription) and a second mechanism akin to the nodal flow of mouse embryos, which takes place in Kupffer's vesicle during early somitogenesis and depends on the expression of left-right dynein (lrd; 603339) and functional cilia.

Vermot and Pourquie (2005) reported that blocking the production of retinoic acid in chicken embryos with an inhibitor of Raldh2 led to a desynchronization of somite formation between the 2 embryonic sides, demonstrated by a shortened left segmented region. This defect was linked to a loss of coordination of the segmentation clock oscillations. The lateralization of this defect led the authors to investigate the relation between somitogenesis and the left-right asymmetry machinery in RA-deficient embryos. Reversal of the situs in chick or mouse embryos lacking retinoic acid resulted in a reversal of the somitogenesis laterality defect. Vermot and Pourquie (2005) concluded that retinoic acid is important in buffering the lateralizing influence of the left-right machinery, thus permitting synchronization of the development of the 2 embryonic sides.

REFERENCES

1. Kawakami, Y.; Raya, A.; Raya, R. M.; Rodriguez-Esteban, C.; Izpisua Belmonte, J. C. :

Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435: 165-171, 2005.
PubMed ID : 15889082

2. Keegan, B. R.; Feldman, J. L.; Begemann, G.; Ingham, P. W.; Yelon, D. :

Retinoic acid signaling restricts the cardiac progenitor pool. Science 307: 247-249, 2005.
PubMed ID : 15653502

3. Niederreither, K.; Abu-Abed, S.; Schuhbaur, B.; Petkovich, M.; Chambon, P.; Dolle, P. :

Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nature Genet. 31: 84-88, 2002.
PubMed ID : 11953746

4. Niederreither, K.; Subbarayan, V.; Dolle, P.; Chambon, P. :

Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genet. 21: 444-448, 1999.
PubMed ID : 10192400

5. Ono, Y.; Fukuhara, N.; Yoshie, O. :

TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3. Molec. Cell. Biol. 18: 6939-6950, 1998.
PubMed ID : 9819382

6. Perlmann, T. :

Retinoid metabolism: a balancing act. Nature Genet. 31: 7-9, 2002. Note: Erratum: Nature Genet. 31: 221 only, 2002.
PubMed ID : 11953747

7. Tanaka, Y.; Okada, Y.; Hirokawa, N. :

FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435: 172-177, 2005.
PubMed ID : 15889083

8. Vermot, J.; Llamas, J. G.; Fraulob, V.; Niederreither, K.; Chambon, P.; Dolle, P. :

Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science 308: 563-566, 2005.
PubMed ID : 15731404

9. Vermot, J.; Niederreither, K.; Garnier, J.-M.; Chambon, P.; Dolle, P. :

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proc. Nat. Acad. Sci. 100: 1763-1768, 2003.
PubMed ID : 12563036

10. Vermot, J.; Pourquie, O. :

Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature 435: 215-220, 2005.
PubMed ID : 15889094

11. Wang, X.; Penzes, P.; Napoli, J. L. :

Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli: recognition of retinal as substrate. J. Biol. Chem. 271: 16288-16293, 1996.
PubMed ID : 8663198

12. Zhao, D.; McCaffery, P.; Ivins, K. J.; Neve, R. L.; Hogan, P.; Chin, W. W.; Drager, U. C. :

Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Europ. J. Biochem. 240: 15-22, 1996.
PubMed ID : 8797830

CONTRIBUTORS

Ada Hamosh - updated : 5/25/2005
Ada Hamosh - updated : 5/3/2005
Ada Hamosh - updated : 1/27/2005
Victor A. McKusick - updated : 3/27/2003
Victor A. McKusick - updated : 4/22/2002
Joanna S. Amberger - updated : 4/2/2001

CREATION DATE

Ada Hamosh : 3/31/1999

EDIT HISTORY

tkritzer : 6/2/2005
tkritzer : 5/26/2005
terry : 5/25/2005
alopez : 5/4/2005
terry : 5/3/2005
wwang : 2/7/2005
wwang : 2/2/2005
terry : 1/27/2005
terry : 3/18/2004
cwells : 4/1/2003
terry : 3/27/2003
alopez : 6/6/2002
alopez : 4/24/2002
terry : 4/22/2002
carol : 4/3/2001
joanna : 4/2/2001
alopez : 5/9/2000
alopez : 4/1/1999
alopez : 3/31/1999
alopez : 3/31/1999

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