Affinage

ALDH1A2

Retinal dehydrogenase 2 · UniProt O94788

Length
518 aa
Mass
56.7 kDa
Annotated
2026-06-09
97 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH1A2 (RALDH2) is the principal embryonic retinoic acid (RA)-synthesizing enzyme, an NAD+-dependent retinaldehyde dehydrogenase that catalyzes oxidation of retinal to all-trans RA with highest catalytic efficiency for all-trans retinal (PMID:11983430, PMID:10570467), generating a diffusible RA signal that patterns multiple developing organs (PMID:9106168, PMID:11959834). Its catalytic mechanism centers on an active-site cysteine (Cys320/Cys319), which irreversible inhibitors such as WIN18,446 covalently modify, distorting the bound NAD cofactor and abolishing dehydrogenase activity (PMID:29240402, PMID:42124481). Genetic ablation eliminates nearly all embryonic RA synthesis and arrests development at midgestation (PMID:11959834), and RALDH2-derived mesodermal RA acts non-cell-autonomously to control posterior neural transformation, pharyngeal and enteric patterning, dorsal pancreatic budding, optic cup formation, limb initiation, and cardiopulmonary morphogenesis (PMID:11688558, PMID:12702665, PMID:16026781, PMID:15739227, PMID:15366004, PMID:15069081, PMID:15652703, PMID:34643182). Its enzymatic, RA-producing function is required for its biological output, as shown by loss of activity in catalytically dead variants (PMID:16166285). Expression is controlled by a wide regulatory network including WT1 in epicardium, Tbx5, HOXA13, and Foxc1a in developing mesoderm, Wnt/β-catenin repression, and—in dendritic cells—Sp1/RAR–RXR, RBPJ–Notch, and PU.1/IRF4, plus post-transcriptional control by tristetraprolin (PMID:21343363, PMID:34643182, PMID:25724646, PMID:23553814, PMID:32258025, PMID:24788806, PMID:28779023, PMID:30413670, PMID:32467605). In adult physiology, RALDH2-derived RA drives spermatogonial differentiation from Sertoli cells (PMID:35574006), tolerogenic dendritic-cell programs that favor Treg induction (PMID:28779023, PMID:32209473, PMID:39060515), cardiac protection after ischemia–reperfusion via RA→RAR→Bmp7 signaling (PMID:41689430), and cartilage homeostasis through a PPARγ-dependent suppression of mechanoflammation (PMID:36542696). Biallelic hypomorphic ALDH1A2 variants that reduce RA production cause a lethal multiple congenital anomaly syndrome with diaphragmatic, pulmonary, and cardiovascular defects (PMID:33565183), and reduced cartilage expression is linked to osteoarthritis risk (PMID:29732726).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Established the enzymatic identity of RALDH2 as a major embryonic RA-generating enzyme and revealed RA-dependent negative feedback on its own expression.

    Evidence In situ hybridization and RA administration in mouse embryos

    PMID:9106168

    Open questions at the time
    • Did not provide direct biochemical kinetics
    • Feedback mechanism at transcriptional level not molecularly dissected
  2. 1999 High

    Demonstrated in vivo that Raldh2 genuinely synthesizes RA and localized the protein to trunk mesodermal tissues, distinguishing it from non-RA-producing aldehyde dehydrogenases.

    Evidence Xenopus mRNA injection RA assay and whole-mount immunohistochemistry in mouse

    PMID:10570467

    Open questions at the time
    • Did not establish substrate kinetics
    • Did not test requirement by loss-of-function
  3. 2002 High

    Defined the biochemical parameters of catalysis, confirming retinal oxidation with substrate preference and inhibitor/activator sensitivity.

    Evidence In vitro kinetics with purified recombinant mouse RALDH2

    PMID:11983430

    Open questions at the time
    • Catalytic residue not yet mapped structurally
    • Oligomeric state not directly resolved
  4. 2002 High

    Genetic null established RALDH2 as responsible for nearly all embryonic RA synthesis and revealed residual non-Raldh1-3 RA activity in neural tube and heart.

    Evidence Raldh2 knockout mice with RA-reporter transgene and maternal RA rescue

    PMID:11959834

    Open questions at the time
    • Identity of residual RA-generating activity unresolved
    • Tissue-specific contributions not separated
  5. 2001 High

    Showed mesoderm-derived RALDH2 RA acts non-cell-autonomously on adjacent neural tissue, defining the signaling logic of RALDH2 patterning.

    Evidence Zebrafish neckless forward genetics, mosaic analysis, RA rescue

    PMID:11688558

    Open questions at the time
    • RA receptor effectors in neural tissue not defined here
    • Quantitative gradient not measured
  6. 2005 High

    Mapped organ-specific RALDH2 functions across pharyngeal, pancreatic, ocular, limb, and neural development, establishing it as a master source of patterning RA.

    Evidence Raldh2 knockout/conditional-rescue mice with RA reporters and maternal RA rescue across multiple organ systems

    PMID:12702665 PMID:15069081 PMID:15366004 PMID:15652703 PMID:16026781

    Open questions at the time
    • Downstream transcriptional targets of RA differ per organ and remain partial
    • Timing thresholds not fully defined
  7. 2005 Medium

    Linked ALDH1A2 enzymatic activity to tumor-suppressive function, showing the RA-synthesizing activity is required for growth suppression.

    Evidence Wild-type vs. catalytic mutant re-expression in DU145 prostate cancer cells, colony assay

    PMID:16166285

    Open questions at the time
    • Catalytic mutant only minimally characterized
    • Single cell line, mechanism downstream of RA not defined
  8. 2011 Medium

    Revealed context-dependent pro-tumor effects of ALDH1A2 overexpression and clarified Aldefluor/DEAB assay specificity across ALDH isoforms.

    Evidence Lentiviral overexpression, Aldefluor flow cytometry, DEAB inhibition in K562/H1299 cells

    PMID:22079344

    Open questions at the time
    • Opposite to tumor-suppressive role elsewhere; context determinants unknown
    • Single lab, drug-resistance mechanism not defined
  9. 2011 Medium

    Identified WT1 as a direct transcriptional activator linking epicardial cell identity to RALDH2-driven RA synthesis and PDGFRα expression.

    Evidence Wt1-null epicardial cells, RA reporter, transcriptional target analysis, rescue

    PMID:21343363

    Open questions at the time
    • Direct promoter binding inferred rather than fully mapped
    • Single lab
  10. 2018 High

    Resolved the structural basis of catalysis and inhibition, showing WIN18,446 covalently modifies Cys320 and distorts NAD into a catalytically incompetent conformation.

    Evidence X-ray crystallography of human ALDH1A2 with multiple inhibitor chemotypes

    PMID:29240402

    Open questions at the time
    • Apo and fully catalytic states resolved only later
    • Substrate-bound Michaelis complex not captured
  11. 2021 Medium

    Established direct human disease causation: biallelic hypomorphic variants reducing RA production cause a lethal multiple congenital anomaly syndrome.

    Evidence Exome sequencing in two families, in vitro RA synthesis assays, in silico modeling

    PMID:33565183

    Open questions at the time
    • Structural impact partly computational
    • Genotype-phenotype range not fully defined
  12. 2021 High

    Defined an upstream transcriptional cascade in which Tbx5 maintains aldh1a2 via a conserved intronic enhancer to coordinate cardiopulmonary development.

    Evidence Xenopus and mouse enhancer reporters, genetic epistasis, in situ hybridization

    PMID:34643182

    Open questions at the time
    • Other enhancer inputs in non-cardiac tissues not characterized
  13. 2018 High

    Dissected the dendritic-cell transcriptional control of RALDH2, identifying cooperative Sp1/RAR-RXR, RBPJ-Notch, and PU.1/IRF4 inputs plus PPARγ-directed pathway assembly governing tolerogenic RA production.

    Evidence ChIP, EMSA, reporter assays, siRNA, DC-specific knockouts, pathway reconstitution in DC subsets

    PMID:23833249 PMID:24788806 PMID:28779023 PMID:30413670

    Open questions at the time
    • Combinatorial integration of these inputs not fully reconstituted
    • Mostly mouse DC systems
  14. 2015 High

    Mapped repressive and restrictive transcriptional regulators (Foxc1a, HOXA13, Wnt/β-catenin) that spatially bound and tune aldh1a2 expression in developing tissues.

    Evidence ChIP, genetic nulls/epistasis, luciferase reporters in zebrafish, mouse, and kidney cells

    PMID:23553814 PMID:25724646 PMID:32258025

    Open questions at the time
    • Cross-talk among activators and repressors at the locus not integrated
  15. 2022 High

    Demonstrated cell-type-specific adult requirement: Sertoli-cell RALDH2-derived RA drives the initial round of spermatogonial differentiation, non-redundant with ALDH1A3.

    Evidence Global and cell-specific Cre-loxP knockout mice, histology

    PMID:35574006

    Open questions at the time
    • RA target genes in germ cells not fully defined
  16. 2022 High

    Established a cartilage-protective role through PPARγ-dependent suppression of mechanoflammation, linking reduced ALDH1A2/RA to osteoarthritis.

    Evidence RNA-seq of genotype-stratified human OA cartilage, talarozole treatment in vitro and in mouse joint-injury models, RNAi in chondrocytes

    PMID:29732726 PMID:36542696

    Open questions at the time
    • Direct enzyme-PPARγ mechanistic coupling not fully resolved
    • Therapeutic translation unproven
  17. 2020 Medium

    Expanded the regulatory and physiological repertoire to post-transcriptional control (TTP), a ROBO2 binding partner in ureter development, regeneration, ocular growth, milky-spot stroma, and paracrine immune circuits.

    Evidence Zfp36 knockout, Co-IP with ROBO2 and RA rescue, zebrafish regeneration, chick choroid RA quantification, cell ablation, DC pathway dissection

    PMID:19801676 PMID:22323456 PMID:32209473 PMID:32467605 PMID:32562756 PMID:36880532

    Open questions at the time
    • ROBO2-RALDH2 interaction is single Co-IP without reciprocal validation
    • Several roles are single-lab functional associations
  18. 2026 High

    Defined an autocrine RA brake on DC maturation and a cardioprotective RA→RAR→Bmp7 axis, and developed selective inhibitors enabling therapeutic targeting.

    Evidence Aldh1a2 DC and cardiomyocyte conditional knockouts/overexpression, small-molecule inhibitors, DC vaccine and I/R injury assays

    PMID:41491403 PMID:41689430

    Open questions at the time
    • Inhibitor selectivity over ALDH1A1/ALDH2 in vivo not fully resolved
    • Bmp7 regulation mechanism partial
  19. 2025 High

    Extended structural and mechanistic understanding with the apo structure and direct mass-spectrometric confirmation of the Cys319 covalent adduct underlying irreversible inhibition.

    Evidence Apo X-ray structure, LC-MS/MS adduct identification in human liver

    PMID:40829477 PMID:42124481

    Open questions at the time
    • No functional mutagenesis of apo structure reported
    • Isoform-selective targeting still limited by shared catalytic cysteine

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse activating and repressing transcription factors are combinatorially integrated at the ALDH1A2 locus to produce spatially precise RA gradients, and how RALDH2 inhibition can be made isoform-selective given the shared active-site cysteine, remain unresolved.
  • No unified model of cis-regulatory integration
  • No isoform-selective covalent inhibitor mechanism established
  • RA receptor effector logic differs across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016740 transferase activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
ROBO2

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RALDH2 (ALDH1A2) was identified as a major retinoic acid (RA)-generating enzyme in the early mouse embryo; its expression in mesoderm marks sites of endogenous RA synthesis, and exogenous RA administration downregulates RALDH2 transcript levels, suggesting a negative feedback mechanism on RA synthesis. In situ hybridization, RA administration experiments in mouse embryos Mechanisms of development High 9106168
2002 Kinetic analysis of purified recombinant mouse RALDH2 demonstrated that it catalyzes oxidation of retinal to retinoic acid with a pH optimum of 9.0, with highest catalytic efficiency for all-trans retinal (Km ~0.66 µM) compared to 9-cis retinal (Km ~2.25 µM); the enzyme is inhibited by citral and p-HMB, and activated by MgCl2. In vitro enzyme kinetics using purified recombinant RALDH2 Biochimica et biophysica acta High 11983430
1999 Injection of mouse Raldh2 mRNA into Xenopus embryos stimulates RA synthesis at high levels in vivo, whereas ALDH3 mRNA injection produces no detectable RA synthesis, establishing Raldh2 as a genuine RA-synthesizing enzyme in vivo. Immunohistochemistry showed RALDH2 protein is localized primarily in trunk tissues (paraxial mesoderm, somites, pericardium, midgut, mesonephros) at E7.5–E10.5. Xenopus mRNA injection with RA activity assay; whole-mount immunohistochemistry in mouse embryos Developmental genetics High 10570467
2002 Targeted disruption of Raldh2 in mice arrests development at midgestation and eliminates nearly all RA synthesis in the embryo (except RALDH3-dependent activity in the surface ectoderm of the eye field), demonstrating that RALDH2 is responsible for most embryonic RA synthesis. Conditional rescue by limited maternal RA revealed additional RA-generating activities in the neural tube and heart not corresponding to Raldh1–3. Raldh2 knockout mice, RA-responsive transgene reporter, maternal RA rescue Development (Cambridge, England) High 11959834
2001 The zebrafish neckless mutation inactivates Raldh2, causing truncation of the anteroposterior axis, midline mesendodermal defects, and absence of pectoral fins. Mosaic analysis showed that reduced hoxb4 expression in the nervous system is non-cell-autonomous, reflecting a requirement for RA signaling from adjacent paraxial mesoderm. Zebrafish forward genetics, mosaic analysis, RA rescue experiment Development (Cambridge, England) High 11688558
2003 Raldh2 is the enzyme responsible for RA synthesis in the posterior pharyngeal mesoderm; its inactivation (with early rescue) causes failure of posterior pharyngeal pouch formation, impaired neural crest migration, and agenesis of enteric ganglia resembling Hirschsprung's disease, establishing RALDH2-generated RA as a mesodermal signal patterning pharyngeal endoderm. Raldh2 conditional knockout mice (RA-rescued), in situ hybridization, in vivo phenotype analysis Development (Cambridge, England) High 12702665
2005 Raldh2 expressed in dorsal pancreatic mesenchyme provides RA signal to dorsal endoderm required for Pdx1 and Isl1 expression and dorsal pancreatic bud formation; Raldh2−/− embryos specifically lack dorsal but not ventral pancreatic development, and maternal RA supplementation rescues these defects. Raldh2 knockout mice, in situ hybridization, RA reporter transgene, maternal RA rescue Developmental biology High 15739227 16026781
2004 Raldh2 in the optic vesicle generates a RA signal required for retina invagination and optic cup formation; Raldh2−/− embryos fail to develop an optic cup, and maternal RA administration rescues this defect. RALDH3 activity in the lens placode is insufficient to substitute. Raldh2 knockout and Raldh1/Raldh2 double-knockout mice, RA reporter, maternal RA rescue Developmental dynamics High 15366004
2004 Raldh2 in lateral plate mesoderm controls two phases of RA signaling for limb development: an early phase (E8) upstream of Tbx5, Meis2, and dHand for forelimb bud initiation, and a late phase providing a proximodistal RA gradient for AER expansion. Raldh2−/− embryos fail to initiate forelimbs; selective RA rescue at E8 restores initiation but not full AER formation. Raldh2 knockout mice, RA reporter transgene, timed maternal RA administration, gene expression analysis The Journal of biological chemistry High 15069081
2005 Raldh2 in somitic mesoderm is required for posterior neural transformation (spinal cord fate specification); Raldh2−/− embryos show loss of Pax6 and Olig2 in posterior neural plate, and RA generated by Raldh2 acts directly in neuroectoderm (not somitic mesoderm) to promote spinal cord differentiation while also suppressing Fgf8 in the tailbud. Raldh2 knockout mice, in situ hybridization, RA reporter transgene, maternal RA rescue Mechanisms of development High 15652703
2005 Transfection-mediated re-expression of wild-type ALDH1A2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 decreased colony growth, demonstrating that ALDH1A2 tumor-suppressive activity depends on its enzymatic (RA-synthesizing) function. Transfection of wild-type vs. catalytic mutant ALDH1A2 in DU145 cells, colony formation assay Cancer research Medium 16166285
2011 ALDH1A2 and ALDH2 enzymatic activity is detected by the Aldefluor assay; DEAB inhibits both isoenzymes (65–90% reduction), demonstrating that DEAB is not specific for ALDH1A1. Overexpression of ALDH1A2 in K562 and H1299 cells increased cell proliferation, clonal efficiency, and resistance to 4-hydroperoxycyclophosphamide and doxorubicin. Lentiviral overexpression, activity assay, Aldefluor flow cytometry, DEAB inhibition, Western blot Chemico-biological interactions Medium 22079344
2011 WT1 (Wilms Tumor 1) transcription factor directly activates Raldh2 transcription in epicardial cells; Wt1-null epicardial cells display decreased Raldh2 expression and reduced RA synthesis. WT1 was shown to be a direct transcriptional activator of Raldh2, and PDGFRα expression (but not RXRα) is rescued by RA addition to Wt1-null cells. In vivo and in vitro Wt1 knockout epicardial cells, RA-responsive reporter, ChIP (implied by 'direct transcriptional target' statement), rescue experiments Development (Cambridge, England) Medium 21343363
2018 X-ray crystal structures of human ALDH1A2 in complex with irreversible inhibitor WIN18,446 revealed that WIN18,446 covalently modifies the catalytic residue Cys320, forming a chiral adduct in (R) configuration that distorts the neighboring NAD cofactor into a contracted conformation suboptimal for the dehydrogenase reaction. Reversible inhibitors interact via hydrogen bonds near Cys320 without affecting NAD. A large flexible loop becomes ordered upon inhibitor binding, shielding the active site. X-ray crystallography, direct binding studies ACS chemical biology High 29240402
2009 Mutations Ala151Ser and Ile157Thr in the ALDH1A2 tetramerization domain (exon 4) found in Tetralogy of Fallot patients were shown by molecular mechanics simulation to hinder tetramerization of the enzyme, suggesting loss of functional oligomeric assembly as a disease mechanism. Sequencing of CHD patients, molecular mechanics simulation (AMBER 9), phylogenetic conservation analysis BMC medical genetics Low 19886994
2014 GM-CSF-induced RALDH2 expression in dendritic cells requires cooperative binding of the transcription factor Sp1 (activated via ERK and p38 MAPK) and the RAR/RXR complex (specifically RARα/RXRα) to the Aldh1a2 promoter; Sp1 binds GC-rich sites and RAR/RXR binds an RA response element (RARE) half-site near the TATA box. Inhibition of either Sp1 or RAR blocked GM-CSF-induced Aldh1a2 expression. Chromatin immunoprecipitation (ChIP), promoter-reporter luciferase assay, EMSA, pharmacological inhibitors, siRNA knockdown PloS one High 24788806
2017 Notch signaling (via RBPJ) directly regulates Aldh1a2 transcription in dendritic cells; RBPJ protein binds the Aldh1a2 promoter and its deficiency reduces RALDH2 expression, shifting DC function from iTreg induction toward Th17 promotion. Overexpression of Aldh1a2 in RBPJ-deficient DCs rescued iTreg-promoting ability. DC-specific Rbpj knockout mice, ChIP, Aldh1a2 overexpression rescue, in vivo colitis model Journal of immunology High 28779023
2018 PU.1 and IRF4 are transcriptional activators of the Aldh1a2 gene in dendritic cells; they form a heterodimer that binds an EICE motif at −1961/−1952 of the Aldh1a2 promoter. Knockdown of Spi1 (PU.1) or Irf4 reduced Aldh1a2 mRNA and RALDH2 enzyme activity; this binding was validated in freshly isolated splenic and mesenteric DCs. ChIP, reporter assay, EMSA, siRNA knockdown in BMDCs and primary DCs Journal of immunology High 30413670
2013 RALDH2 is a required component of PPARγ-directed all-trans retinoic acid (ATRA) synthesis in dendritic cells; RDH10, RALDH2, and CRABP2 form a linear pathway downstream of PPARγ activation for ATRA production. Only DC subsets expressing all three proteins produce ATRA efficiently. Gene expression analysis, PPARγ activation, functional ATRA production assay in DC subsets Journal of lipid research Medium 23833249
2021 Tbx5 transcription factor directly maintains aldh1a2 expression in foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer, establishing a Tbx5→Aldh1a2→RA→Shh→Wnt signaling cascade coordinating cardiopulmonary development. This was demonstrated in both Xenopus and mouse embryos. Xenopus and mouse embryo experiments, enhancer reporter assays, genetic epistasis, in situ hybridization eLife High 34643182
2015 Foxc1a transcription factor directly binds the aldh1a2 promoter and restricts its expression in paraxial mesoderm; in foxc1a knockout zebrafish, aldh1a2 expression is significantly increased, elevating RA levels and reducing myod1 expression by suppressing fgf8a and deltaC. Knockdown of aldh1a2 in foxc1a nulls partially rescues myod1 expression. TALEN-mediated foxc1a knockout zebrafish, chromatin immunoprecipitation (ChIP) on zebrafish embryos, aldh1a2 morpholino knockdown, gene expression analysis The Journal of biological chemistry High 25724646
2013 HOXA13 directly regulates Aldh1a2 expression by binding a conserved cis-regulatory element in the Aldh1a2 locus; in Hoxa13 mutant mice, Aldh1a2 expression, RA signaling, and interdigital programmed cell death are reduced. Maternal RA supplementation partially rescues digit separation defects. Hoxa13 knockout mice, ChIP (HOXA13 binding to Aldh1a2 locus), RA reporter, maternal RA rescue Developmental dynamics High 23553814
2020 Wnt/β-catenin signaling directly represses ALDH1A2 expression in fetal kidney (WiT49) cells; β-catenin is recruited to the ALDH1A2 promoter and intron 1 (intron1G enhancer element) as shown by ChIP, and luciferase assays confirmed these elements mediate repression. Ectopic Wnt1, Wnt3a, Wnt4, and Wnt9b all repressed ALDH1A2, and this effect required β-catenin. ChIP, luciferase reporter assay, Wnt overexpression, β-catenin inhibition, immunohistochemistry in rat kidney Frontiers in cell and developmental biology High 32258025
2009 Aldh1a2 is the primary aldehyde dehydrogenase acting during pancreas development in zebrafish; a null allele (glycine-to-arginine change in the catalytic domain) produces a similar but less severe phenotype than the DEAB inhibitor treatment, revealing that maternal Aldh1a2 activity persists in zygotic null embryos. Translation-blocking (but not splice-blocking) morpholinos phenocopy DEAB treatment, confirming maternal protein contribution. Zebrafish forward genetics, morpholino knockdown, DEAB pharmacological inhibition, gene expression analysis PloS one High 20011517
2009 Comparative regeneration analysis identified raldh2 as one of the most highly induced genes across adult caudal fin, adult heart, and larval fin regeneration in zebrafish; loss-of-function studies showed raldh2 expression is critical for wound epithelium and blastema formation. raldh2 expression during regeneration is regulated by Wnt and FGF/ERK signaling. Comparative microarray, in situ hybridization, functional loss-of-function studies in zebrafish regeneration model The Journal of biological chemistry Medium 19801676
2012 RALDH2 is the predominant retinaldehyde dehydrogenase in the chick choroid (>100-fold higher than RALDH3) and is upregulated during recovery from form-deprivation myopia, leading to increased all-trans retinoic acid synthesis. Choroid conditioned medium from recovering eyes inhibited scleral proteoglycan synthesis, suggesting RALDH2-derived RA acts as a signal for ocular growth regulation. qRT-PCR, in situ hybridization, immunohistochemistry, LC-tandem MS quantification of atRA in organ cultures, (35)SO4 incorporation assay Investigative ophthalmology & visual science Medium 22323456
2022 Global deletion of Aldh1a1 and Aldh1a2 in mice blocks spermatogenesis without affecting viability. Cell-specific deletion showed that RALDH2 synthesis of RA in Sertoli cells (but not germ cells) is required for the initial round of spermatogonial differentiation. ALDH1A3 activity cannot compensate for loss of both ALDH1A1 and ALDH1A2. Global and cell-specific (Sertoli cell and germ cell) Cre-loxP conditional knockout mice, histological analysis of spermatogenesis Frontiers in endocrinology High 35574006
2021 Biallelic hypomorphic missense variants in ALDH1A2 in two unrelated human families cause a lethal multiple congenital anomaly syndrome (diaphragmatic, pulmonary, cardiovascular defects). In vitro studies of the variants showed reduced RA production, and in silico modeling indicated probable impairment of ALDH1A2 function for three of four substitutions. Exome sequencing, in vitro RA synthesis assay, in silico protein modeling Human mutation Medium 33565183
2020 In intestinal CD11b−CD103+ dendritic cells, CD137 engagement activates TAK1 and the AMPK-PGC-1α axis, which enhances Aldh1a2 transcription and RALDH2 expression. RALDH2-derived RA then acts on adjacent CD11b+CD103− DCs to induce SOCS3, suppressing p38MAPK and IL-23 production, defining a paracrine immunoregulatory circuit. DC-specific CD137 knockout mice, pathway inhibitors, RA administration rescue, gene expression analysis, in vivo colitis model Cell reports Medium 32209473
2018 ALDH1A2 depletion by RNA interference in primary human chondrocytes altered expression of chondrogenic markers including SOX9, establishing a functional role for ALDH1A2 in chondrocyte biology. The OA-risk allele rs12915901 is associated with reduced ALDH1A2 expression in cartilage through allelic expression imbalance, with Ets transcription factors identified as potential mediators. RNAi knockdown in primary human chondrocytes, allelic expression imbalance by pyrosequencing, in silico and in vitro analysis of SNP function Arthritis & rheumatology Medium 29732726
2022 Cartilage injury upregulates inflammatory genes (mechanoflammation) with concomitant reduction of atRA-inducible genes; talarozole (a RAMBA that blocks RA catabolism, thereby boosting atRA) reverses both responses via a PPARγ-dependent mechanism. Talarozole suppressed mechano-inflammatory genes in articular cartilage in vivo 6 hours after joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days in mice. RNA sequencing of human OA cartilage stratified by genotype, cartilage injury model, talarozole treatment in vitro and in vivo, PPARγ pathway analysis Science translational medicine High 36542696
2023 Aldh1a2+ fibroblastic reticular cells (FRCs) in omental milky spots regulate lymphocyte recruitment by controlling CXCL12 display on high endothelial venules (HEVs). Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs reduced milky spot size and cellularity and altered peritoneal lymphocyte composition. Cell-specific diphtheria toxin ablation (Aldh1a2-DTR mouse), flow cytometry, immunofluorescence, CXCL12 expression analysis The Journal of experimental medicine Medium 36880532
2026 GM-CSF-IL-4-induced differentiating dendritic cells express ALDH1A2 and produce retinoic acid that inhibits DC maturation (autocrine brake). Genetic knockout of Aldh1a2 in DCs enhances DC function and antigen-specific T cell responses. A selective ALDH1A2 small-molecule inhibitor with high potency was developed and shown to improve DC vaccine efficacy. Genetic Aldh1a2 knockout in DCs, ALDH1A2 inhibitor development and testing, DC vaccine efficacy assays, antigen-specific T cell response measurement Nature immunology High 41491403
2025 Identification and characterization by mass spectrometry of a WIN18,446 aldehyde metabolite (M-54) and a WIN18,446-derived protein adduct of mass 292.07 Da on Cys319 of ALDH1A2, confirming covalent modification of the active-site cysteine as the mechanism of irreversible inhibition. Analogous adducts were detected on ALDH1A1 and ALDH2 active-site cysteines in human liver samples. Mass spectrometry (proteomics), crystal structure, LC-MS/MS, human liver samples Drug metabolism reviews High 42124481
2025 First apo-ALDH1A2 crystal structure (without bound ligand/cofactor) was obtained from nanolitre sitting-drop crystallisation, expanding the structural basis for drug discovery studies on this isoform. X-ray crystallography (nanolitre sitting-drop crystallisation) Biochemical and biophysical research communications Medium 40829477
2026 Cardiomyocyte-specific ALDH1A2 ablation aggravated heart dysfunction and fibrosis after ischemia-reperfusion injury in mice, whereas ALDH1A2 overexpression provided protection. The cardioprotective mechanism depends on ALDH1A2-catalyzed RA production, which activates RA receptors to regulate Bmp7 transcription, inhibiting cell death and cardiac fibrosis. Cardiomyocyte-specific Aldh1a2 knockout and overexpression in mouse I/R model, transcriptional profiling, RA receptor pathway analysis, Bmp7 expression measurement Cardiovascular research Medium 41689430
2020 RALDH2 mRNA is a direct post-transcriptional target of the RNA-binding protein tristetraprolin (TTP/ZFP36) in intestinal dendritic cells; Zfp36−/− mice show increased vitamin A metabolism by gut DCs and expanded colonic Treg numbers, a phenotype linked to elevated RALDH2 activity. Zfp36 knockout mice, colonic DC analysis, vitamin A metabolism assay, Treg quantification Mucosal immunology Medium 32467605
2020 ROBO2 binds RALDH2 as a novel binding partner in the common nephric duct (CND) and primitive bladder; loss of Robo2 impairs CND migration and fusion with the primitive bladder, delayed apoptosis, and abnormal ureter connection. Retinoic acid administration rescued ureter anomalies in Robo2−/− embryos, establishing a ROBO2-RALDH2-RA pathway in ureter development. Robo2 knockout mice, Co-IP (ROBO2-RALDH2 interaction), in situ hybridization, RA rescue experiment Developmental biology Medium 32562756
2024 Non-canonical NF-κB signaling (RelB:p52) in intestinal DCs activates Axin1 transcription, thereby destabilizing β-catenin and reducing β-catenin-dependent Raldh2 expression, which suppresses tolerogenic DC function. DC-specific inactivation of non-canonical NF-κB signaling reinforces β-catenin→Raldh2 axis and increases colonic Tregs and IgA+ B cells. β-catenin haploinsufficiency in DCs lacking non-canonical NF-κB reinstates colitogenic sensitivity. DC-specific RelB knockout mice, β-catenin haploinsufficiency mouse model, genetic epistasis, transcription analysis, colitis model The EMBO journal High 39060515

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mechanisms of development 414 9106168
2001 The zebrafish neckless mutation reveals a requirement for raldh2 in mesodermal signals that pattern the hindbrain. Development (Cambridge, England) 314 11688558
2002 Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development (Cambridge, England) 214 11959834
2005 Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Developmental biology 195 16026781
2002 Experimental studies on the spatiotemporal expression of WT1 and RALDH2 in the embryonic avian heart: a model for the regulation of myocardial and valvuloseptal development by epicardially derived cells (EPDCs). Developmental biology 190 12086469
2003 The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development (Cambridge, England) 177 12702665
2011 The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chemico-biological interactions 164 22079344
2005 Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Developmental dynamics : an official publication of the American Association of Anatomists 163 15739227
2003 A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field. Development (Cambridge, England) 150 13129847
1999 Differential distribution of retinoic acid synthesis in the chicken embryo as determined by immunolocalization of the retinoic acid synthetic enzyme, RALDH-2. Developmental biology 147 10357892
2005 The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer. Cancer research 127 16166285
1999 Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways. Developmental genetics 125 10570467
2014 Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nature genetics 118 24728293
2011 Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2. Development (Cambridge, England) 111 21343363
2006 Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development (Cambridge, England) 104 16368932
2002 Retinaldehyde dehydrogenase 2 (RALDH2)- independent patterns of retinoic acid synthesis in the mouse embryo. Proceedings of the National Academy of Sciences of the United States of America 98 12454286
2005 Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation. Mechanisms of development 83 15652703
2004 Retinoic acid synthesis controlled by Raldh2 is required early for limb bud initiation and then later as a proximodistal signal during apical ectodermal ridge formation. The Journal of biological chemistry 77 15069081
2004 Raldh2 expression in optic vesicle generates a retinoic acid signal needed for invagination of retina during optic cup formation. Developmental dynamics : an official publication of the American Association of Anatomists 77 15366004
2015 Retinoic acid homeostasis through aldh1a2 and cyp26a1 mediates meiotic entry in Nile tilapia (Oreochromis niloticus). Scientific reports 76 25976364
2009 Comparative expression profiling reveals an essential role for raldh2 in epimorphic regeneration. The Journal of biological chemistry 66 19801676
2018 Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS chemical biology 60 29240402
2003 Expression of Raldh2, Cyp26 and Hox-1 in normal and retinoic acid-treated Ciona intestinalis embryos. Gene expression patterns : GEP 56 12799071
2016 Secretory IgA in complex with Lactobacillus rhamnosus potentiates mucosal dendritic cell-mediated Treg cell differentiation via TLR regulatory proteins, RALDH2 and secretion of IL-10 and TGF-β. Cellular & molecular immunology 51 26972771
2013 IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. Journal of immunology (Baltimore, Md. : 1950) 50 23960232
2004 Early transcriptional changes of retinal and choroidal TGFbeta-2, RALDH-2, and ZENK following imposed positive and negative defocus in chickens. Molecular vision 50 15343149
2002 Kinetic analysis of mouse retinal dehydrogenase type-2 (RALDH2) for retinal substrates. Biochimica et biophysica acta 49 11983430
2005 Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth defects research. Part A, Clinical and molecular teratology 46 16237707
2002 Alveolar proliferation, retinoid synthesizing enzymes, and endogenous retinoids in the postnatal mouse lung. Different roles for Aldh-1 and Raldh-2. American journal of respiratory cell and molecular biology 43 11751205
2018 Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant. Arthritis & rheumatology (Hoboken, N.J.) 41 29732726
2009 ALDH1A2 (RALDH2) genetic variation in human congenital heart disease. BMC medical genetics 40 19886994
2022 Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis. Science translational medicine 38 36542696
2010 A human ALDH1A2 gene variant is associated with increased newborn kidney size and serum retinoic acid. Kidney international 38 20375987
2006 Expression of retinaldehyde dehydrogenase (RALDH)2 and RALDH3 but not RALDH1 in the developing anterior pituitary glands of rats. Cell and tissue research 36 17180597
2009 Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. Biochemical pharmacology 34 19549509
2012 RALDH2, the enzyme for retinoic acid synthesis, mediates meiosis initiation in germ cells of the female embryonic chickens. Amino acids 33 22733143
2019 ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer. Cancers 30 31615043
2012 Identification of RALDH2 as a visually regulated retinoic acid synthesizing enzyme in the chick choroid. Investigative ophthalmology & visual science 30 22323456
2009 Maternal and zygotic aldh1a2 activity is required for pancreas development in zebrafish. PloS one 27 20011517
2004 Hair cycle-specific immunolocalization of retinoic acid synthesizing enzymes Aldh1a2 and Aldh1a3 indicate complex regulation. The Journal of investigative dermatology 27 15245423
2014 Retinoic acid and GM-CSF coordinately induce retinal dehydrogenase 2 (RALDH2) expression through cooperation between the RAR/RXR complex and Sp1 in dendritic cells. PloS one 26 24788806
2008 Expression of the retinoic acid-metabolizing enzymes RALDH2 and CYP26b1 during mouse postnatal testis development. Asian journal of andrology 25 18478160
2021 Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development. eLife 24 34643182
2015 Zebrafish foxc1a plays a crucial role in early somitogenesis by restricting the expression of aldh1a2 directly. The Journal of biological chemistry 24 25724646
2013 RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells. Journal of lipid research 24 23833249
2018 ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3. OncoTargets and therapy 23 29430185
2013 Duplication of the ALDH1A2 gene in association with pentalogy of Cantrell: a case report. Journal of medical case reports 23 24377748
2010 Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer. Development (Cambridge, England) 23 20081195
2009 Positive association between ALDH1A2 and schizophrenia in the Chinese population. Progress in neuro-psychopharmacology & biological psychiatry 23 19703508
2001 Expression and regulation of the retinoic acid synthetic enzyme RALDH-2 in the embryonic chicken wing. Developmental dynamics : an official publication of the American Association of Anatomists 23 11507765
2000 Mouse type-2 retinaldehyde dehydrogenase (RALDH2): genomic organization, tissue-dependent expression, chromosome assignment and comparison to other types. Biochimica et biophysica acta 23 10858567
2020 Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells. The Journal of allergy and clinical immunology 22 33378690
2001 Specific expression of the retinoic acid-synthesizing enzyme RALDH2 during mouse inner ear development. Mechanisms of development 22 11472854
2018 CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features. Blood advances 21 30381402
2021 Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Human mutation 19 33565183
2023 Aldh1a2 + fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots. The Journal of experimental medicine 18 36880532
2017 The rs4238326 polymorphism in ALDH1A2 gene potentially associated with non-post traumatic knee osteoarthritis susceptibility: a two-stage population-based study. Osteoarthritis and cartilage 18 28089900
2016 Expression of retinoic acid-metabolizing enzymes, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1 and CYP26C1 in canine testis during post-natal development. Reproduction in domestic animals = Zuchthygiene 18 27569851
2003 Patterning of forelimb bud myogenic precursor cells requires retinoic acid signaling initiated by Raldh2. Developmental biology 18 14623241
2022 Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis. Frontiers in endocrinology 17 35574006
2013 Retinoic acid homeostasis regulates meiotic entry in developing anuran gonads and in Bidder's organ through Raldh2 and Cyp26b1 proteins. Mechanisms of development 17 24056063
2017 Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by Regulating Aldh1a2 Expression. Journal of immunology (Baltimore, Md. : 1950) 16 28779023
2012 New sources of retinoic acid synthesis revealed by live imaging of an Aldh1a2-GFP reporter fusion protein throughout zebrafish development. Developmental dynamics : an official publication of the American Association of Anatomists 16 22592974
2018 The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell-Specific Expression of RALDH2. Journal of immunology (Baltimore, Md. : 1950) 15 30413670
2022 ALDH1A2-related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway. American journal of medical genetics. Part A 13 36263470
2021 The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment. Cells 13 34572134
2020 CD137 Signaling Regulates Acute Colitis via RALDH2-Expressing CD11b-CD103+ DCs. Cell reports 13 32209473
2013 HOXA13 regulates Aldh1a2 expression in the autopod to facilitate interdigital programmed cell death. Developmental dynamics : an official publication of the American Association of Anatomists 13 23553814
2006 Conditional (loxP-flanked) allele for the gene encoding the retinoic acid-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2). Genesis (New York, N.Y. : 2000) 12 16496350
2020 Age-Dependent Decrease in the Induction of Regulatory T Cells Is Associated With Decreased Expression of RALDH2 in Mesenteric Lymph Node Dendritic Cells. Frontiers in immunology 11 32849526
2016 Beta 1-integrin ligation and TLR ligation enhance GM-CSF-induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties. Scientific reports 11 27897208
2013 Methylation of a CpG site near the ALDH1A2 gene is associated with loss of control over drinking and related phenotypes. Alcoholism, clinical and experimental research 11 24236815
2024 The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling. Molecular medicine (Cambridge, Mass.) 10 39521994
2010 prep1.2 and aldh1a2 participate to a positive loop required for branchial arches development in zebrafish. Developmental biology 9 20423710
2018 The Microenvironment in Barrett's Esophagus Tissue Is Characterized by High FOXP3 and RALDH2 Levels. Frontiers in immunology 8 29967615
2006 Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells. Differentiation; research in biological diversity 8 17177861
2020 Inhibition of GSK3 Represses the Expression of Retinoic Acid Synthetic Enzyme ALDH1A2 via Wnt/β-Catenin Signaling in WiT49 Cells. Frontiers in cell and developmental biology 7 32258025
2019 Cux2 refines the forelimb field by controlling expression of Raldh2 and Hox genes. Biology open 7 30651234
2024 Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies. The EMBO journal 6 39060515
2023 Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy. Neuroscience research 5 37146794
2022 Inhibitor of Growth 4 (ING4) Plays a Tumor-repressing Role in Oral Squamous Cell Carcinoma via Nuclear Factor Kappa-B (NF-kB)/DNA Methyltransferase 1 (DNMT1) Axis-mediated Regulation of Aldehyde Dehydrogenase 1A2 (ALDH1A2). Current cancer drug targets 5 35388759
2020 The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis. Mucosal immunology 5 32467605
2026 Targeting autocrine retinoic acid signaling by ALDH1A2 inhibition enhances antitumor dendritic cell vaccine efficacy. Nature immunology 4 41491403
2024 A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population. International journal of immunogenetics 3 38441233
2009 Opossum aldehyde dehydrogenases: evidence for four ALDH1A1-like genes on chromosome 6 and ALDH1A2 and ALDH1A3 genes on chromosome 1. Biochemical genetics 3 19455414
2005 Molecular cloning and expression of retinoic-acid synthesizing enzyme raldh2 from Takifugu rubripes. Comparative biochemistry and physiology. Part D, Genomics & proteomics 3 20483243
2022 An eQTL variant of ALDH1A2 is associated with Kashin-Beck disease in Chinese population. Journal of bone and mineral metabolism 2 35059888
2020 ROBO2-mediated RALDH2 signaling is required for common nephric duct fusion with primitive bladder. Developmental biology 2 32562756
2026 PTPN2 alleviates Silicotic pulmonary fibrosis by inhibiting senescence of type II alveolar epithelial cells via retinol metabolism regulated by ALDH1A2. International immunopharmacology 1 41558294
2025 Intratracheal administration of mesenchymal stem cells ameliorates hyperoxia-induced bronchopulmonary dysplasia by inhibiting NLRP3 inflammasome activation: the critical role of Aldh1a2. Stem cell research & therapy 1 41382115
2024 Single-cell RNA sequencing data locate ALDH1A2-mediated retinoic acid synthetic pathway to glomerular parietal epithelial cells. Experimental biology and medicine (Maywood, N.J.) 1 39360029
2010 [Effects of 5-Aza-2'-deoxycitydine and trichostatin A on expression and apoptosis of ALDH1a2 gene in human bladder cancer cell lines]. Zhonghua wai ke za zhi [Chinese journal of surgery] 1 20450613
2026 Identification of ALDH1A2-mediated cardioprotective benefits in myocardial ischaemia-reperfusion injury. Cardiovascular research 0 41689430
2026 Identification and characterization of a novel aldehyde metabolite of WIN18,446 and associated WIN18,446-ALDH1A2 protein adducts using mass spectrometry. Drug metabolism reviews 0 42124481
2025 Uncovering the Role of ALDH1A2 in Prostate Cancer: Insights from Genetic and Expression Analyses. Journal of Cancer 0 39781359
2025 ZBTB12 promotes breast cancer progression through transcriptional activation of the DNMT3B/ALDH1A2 axis. Biochemical and biophysical research communications 0 40543226
2025 Exploiting ALDH1A2 and ALDH1A3 isoform variability for crystallisation screening. Biochemical and biophysical research communications 0 40829477

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