Affinage

ALDH1A2

Retinal dehydrogenase 2 · UniProt O94788

Length
518 aa
Mass
56.7 kDa
Annotated
2026-04-28
96 papers in source corpus 41 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH1A2 (RALDH2) is the principal embryonic retinoic acid (RA)-synthesizing enzyme, catalyzing the NAD⁺-dependent oxidation of all-trans retinaldehyde to all-trans retinoic acid via a catalytic Cys320 residue, and functioning as a tetrameric dehydrogenase with highest catalytic efficiency for all-trans retinal (Km 0.66 µM) (PMID:11983430, PMID:29240402). In the embryo, ALDH1A2 expressed in mesoderm (somites, lateral plate, pharyngeal mesenchyme) generates a diffusible RA signal that patterns adjacent neural tube, endoderm, limb, heart, eye, and pancreas in a non-cell-autonomous manner; targeted disruption eliminates virtually all trunk RA synthesis and arrests development at midgestation (PMID:11959834, PMID:11688558, PMID:15069081, PMID:12702665). In the immune system, ALDH1A2 in dendritic cells—transcriptionally regulated by Sp1/RAR-RXR, Notch/Rbpj, PU.1/IRF4, and post-transcriptionally by TTP—produces RA that promotes regulatory T cell differentiation and gut homeostasis, while also acting as an autocrine brake on DC maturation (PMID:24788806, PMID:28779023, PMID:30413670, PMID:41491403). Biallelic hypomorphic ALDH1A2 variants in humans cause a lethal multiple congenital anomaly syndrome with diaphragmatic, pulmonary, and cardiovascular defects (PMID:33565183).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    The identity of the enzyme responsible for embryonic RA production was unknown; RALDH2 was identified as a major RA-generating enzyme expressed in mesodermal domains of the early mouse embryo, with exogenous RA downregulating its transcript, suggesting negative feedback.

    Evidence In situ hybridization and maternal RA administration in mouse embryos

    PMID:9106168

    Open questions at the time
    • No loss-of-function data yet
    • Negative feedback mechanism not molecularly defined
    • Enzymatic activity not directly measured
  2. 1999 High

    Whether RALDH2 was sufficient for in vivo RA synthesis was untested; injection of Raldh2 mRNA into Xenopus embryos demonstrated it can drive RA production in vivo, while immunohistochemistry showed trunk-restricted protein localization distinct from ALDH1.

    Evidence Xenopus mRNA injection with RA reporter assay; whole-mount immunohistochemistry in mouse embryos

    PMID:10570467

    Open questions at the time
    • No genetic loss-of-function in mammals yet
    • Quantitative RA output not measured
  3. 2001 High

    Whether mesodermal RA synthesis acts cell-autonomously or non-cell-autonomously on neural tube was unclear; zebrafish neckless (raldh2) mutants and mosaic analysis demonstrated that RA from paraxial mesoderm acts non-cell-autonomously to induce hoxb4 in the nervous system.

    Evidence Zebrafish genetic mutant with mosaic analysis and RA rescue

    PMID:11688558

    Open questions at the time
    • Mechanism of RA transport from mesoderm to neural tube not defined
    • Whether this non-cell-autonomous mechanism is conserved in mammals not yet shown
  4. 2002 High

    The biochemical parameters and substrate specificity of RALDH2 had not been quantified; purified recombinant enzyme showed highest efficiency for all-trans retinal (Km 0.66 µM) over 9-cis and 13-cis retinal, with pH optimum of 9.0 and sensitivity to citral inhibition and MgCl₂ activation.

    Evidence In vitro enzyme kinetics with purified recombinant mouse RALDH2

    PMID:11983430

    Open questions at the time
    • No crystal structure yet
    • In vivo cofactor requirements not validated
  5. 2002 High

    The relative contribution of RALDH2 versus other RALDHs to embryonic RA was unknown; Raldh2 knockout mice showed that RALDH2 is responsible for virtually all trunk RA synthesis, with only eye-associated RALDH3 activity remaining.

    Evidence Raldh2 null mouse with RA-responsive transgene reporter

    PMID:11959834

    Open questions at the time
    • Maternal RA contribution complicates pre-midgestation analysis
    • Compound knockouts with Raldh1 and Raldh3 not yet done
  6. 2003 High

    Consolidating discoveries across organ systems, RALDH2-generated RA from specific mesodermal domains was shown to pattern pharyngeal arches, endoderm, limb buds, optic cup, dorsal pancreas, spinal cord, and craniofacial structures through non-cell-autonomous signaling, with RA acting on adjacent epithelia to regulate downstream targets including Pdx1, Tbx5, Fgf8, and Shh.

    Evidence Series of Raldh2-null mouse studies with stage-specific maternal RA rescue and molecular marker analysis across multiple organs

    PMID:12702665 PMID:15069081 PMID:15366004 PMID:15652703 PMID:16026781 PMID:16368932

    Open questions at the time
    • Direct RA receptor targets in each tissue not fully defined
    • Tissue-specific RA gradient concentrations not measured
    • Redundancy with RALDH1 in specific contexts unclear
  7. 2005 High

    Whether ALDH1A2 enzymatic activity was required for its tumor-suppressive function was untested; re-expression of wild-type but not catalytically dead ALDH1A2 reduced colony growth in prostate cancer cells, establishing that RA production mediates tumor suppression.

    Evidence Transfection of wild-type vs. catalytically dead ALDH1A2 in DU145 prostate cancer cells with colony formation assay

    PMID:16166285

    Open questions at the time
    • Downstream RA-dependent tumor suppression mechanism not identified
    • In vivo tumor suppression not tested
    • Epigenetic silencing mechanism not yet defined
  8. 2009 Medium

    Patient mutations and oligomeric state requirements were unexplored; ALDH1A2 variants (A151S, I157T) in Tetralogy of Fallot patients mapped to the tetramerization domain, with computational modeling predicting disrupted tetramer assembly.

    Evidence Patient exome sequencing with molecular mechanics simulation

    PMID:19886994

    Open questions at the time
    • No in vitro tetramerization or activity assay for these mutants
    • Causality for Tetralogy of Fallot not established
    • Small patient cohort
  9. 2014 High

    The transcriptional regulation of ALDH1A2 in dendritic cells was poorly understood; a series of studies defined multiple direct transcriptional inputs: Sp1/RAR-RXR cooperativity downstream of GM-CSF/ERK/p38, Notch/Rbpj binding to the promoter, and PU.1/IRF4 heterodimer binding an EICE motif, all converging to activate Aldh1a2 in gut DCs that produce RA for Treg generation.

    Evidence ChIP, EMSA, reporter assays, pathway inhibitors, conditional knockouts in DCs with functional Treg readouts

    PMID:24788806 PMID:28779023 PMID:30413670

    Open questions at the time
    • Hierarchy among these transcription factors not fully ordered
    • Enhancer landscape in human DCs incompletely mapped
    • Whether all these factors act simultaneously or sequentially on the same promoter unclear
  10. 2018 High

    The structural basis for ALDH1A2 inhibition was unknown; X-ray crystallography revealed that WIN18,446 covalently modifies catalytic Cys320, forming a chiral (R)-adduct that forces NAD into a contracted, catalytically suboptimal conformation, while a flexible loop orders over the active site upon inhibitor binding.

    Evidence X-ray crystallography with irreversible and reversible inhibitors bound to human ALDH1A2

    PMID:29240402

    Open questions at the time
    • No apo-structure available at this time
    • Dynamics of loop ordering not studied
    • Selectivity determinants over ALDH1A1/A3 not fully mapped
  11. 2018 High

    ALDH1A2 had been genetically linked to osteoarthritis but the mechanism was undefined; an OA risk SNP (rs12915901) was shown to reduce ALDH1A2 expression through altered Ets factor binding, and ALDH1A2 depletion changed chondrocyte gene expression including SOX9, establishing it as a chondrocyte regulator.

    Evidence RNA interference in primary human chondrocytes, allelic expression imbalance by pyrosequencing, promoter analysis

    PMID:29732726

    Open questions at the time
    • RA-dependent vs RA-independent mechanisms in cartilage not distinguished
    • Downstream chondrocyte RA targets not comprehensively mapped
  12. 2020 High

    How upstream signaling pathways converge to regulate ALDH1A2 beyond direct transcription factors was emerging; CD137-TAK1-AMPK-PGC-1α was identified as a signaling cascade activating Aldh1a2 in intestinal DCs, while Wnt/β-catenin was shown to directly repress ALDH1A2 via promoter and intronic element binding, and TTP (ZFP36) was identified as a post-transcriptional destabilizer of RALDH2 mRNA.

    Evidence DC-specific CD137 knockout mice with pathway inhibitors; ChIP and reporter assays for β-catenin; Zfp36-knockout mice with gut immune phenotyping

    PMID:32209473 PMID:32258025 PMID:32467605

    Open questions at the time
    • TTP binding site on RALDH2 mRNA not precisely mapped
    • Whether AMPK directly phosphorylates ALDH1A2 promoter regulators unknown
    • Integration of Wnt repression with other activating signals not modeled
  13. 2021 Medium

    Direct human disease causation by ALDH1A2 loss-of-function was unproven; biallelic hypomorphic missense variants were identified in patients with lethal congenital anomaly syndrome, and in vitro assays confirmed reduced RA production.

    Evidence Exome sequencing of affected families, in vitro RA production assay, in silico structural modeling

    PMID:33565183

    Open questions at the time
    • Small number of families
    • No animal model rescue with patient-specific variants
    • Genotype-phenotype correlation across variants not established
  14. 2021 High

    The upstream transcriptional activator linking limb/cardiopulmonary Tbx5 to RA signaling was undefined; Tbx5 was shown to directly maintain aldh1a2 expression via a conserved intronic enhancer, and the resulting RA signal activates shh through a MACS1 enhancer, establishing a Tbx5-ALDH1A2-RA-Shh cascade.

    Evidence ChIP and enhancer reporter assays in Xenopus and mouse embryos

    PMID:34643182

    Open questions at the time
    • Whether Tbx5 regulation of ALDH1A2 is direct or involves co-factors not fully resolved
    • Quantitative RA threshold for Shh activation unknown
  15. 2022 High

    The mechanism linking ALDH1A2 to OA mechanoflammation and a therapeutic strategy were unknown; reduced ALDH1A2 and RA were shown to derepress inflammatory genes, while pharmacological RA restoration via talarozole suppressed mechanoflammation through PPARγ and reduced cartilage degradation in vivo.

    Evidence RNA-seq of patient cartilage stratified by genotype; talarozole treatment in vitro and in mouse OA model; PPARγ inhibitor experiments

    PMID:36542696

    Open questions at the time
    • Direct PPARγ-RA receptor crosstalk mechanism not defined
    • Long-term therapeutic efficacy not assessed
  16. 2022 High

    Whether Sertoli cells or germ cells are the essential RA source for spermatogenesis was unknown; cell-type-specific knockouts showed Sertoli cell Aldh1a1/Aldh1a2 RA synthesis is required for spermatogonial differentiation, with Aldh1a3 unable to compensate.

    Evidence Cell-type-specific Cre-loxP conditional knockout mice

    PMID:35574006

    Open questions at the time
    • Individual contributions of ALDH1A1 vs ALDH1A2 in Sertoli cells not separated
    • RA target genes in spermatogonia not identified
  17. 2026 High

    Whether cardiomyocyte-autonomous ALDH1A2 plays a protective role in ischemia-reperfusion injury was untested; cardiomyocyte-specific knockout aggravated and overexpression protected against I/R injury through an RA-RAR-Bmp7 transcriptional axis inhibiting cell death and fibrosis.

    Evidence Cardiomyocyte-specific Aldh1a2 knockout and overexpression in mice with I/R surgery

    PMID:41689430

    Open questions at the time
    • Whether Bmp7 is a direct RAR transcriptional target not confirmed by ChIP
    • Relevance to human cardiac ischemia not tested
  18. 2026 High

    Whether DC-intrinsic ALDH1A2 limits or promotes DC immunogenicity was debated; genetic knockout and pharmacological inhibition showed that autocrine RA from ALDH1A2 acts as a brake on DC maturation, and its removal enhances antigen-specific T cell responses and DC vaccine efficacy.

    Evidence Aldh1a2 genetic knockout in DCs, ALDH1A2 inhibitor, DC vaccine functional assays

    PMID:41491403

    Open questions at the time
    • RA receptor mediating the autocrine brake not identified
    • Whether this applies to in vivo tumor immunotherapy settings not fully shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full structural dynamics of the ALDH1A2 tetramer (apo vs. substrate-bound conformational changes), the identity of direct RAR/RXR target genes mediating ALDH1A2's effects in each tissue context, and how the multiple transcriptional and post-transcriptional inputs are integrated to fine-tune RA output in space and time.
  • Apo-enzyme structure only recently solved; no full conformational dynamics study
  • Tissue-specific RA gradient quantification lacking
  • Systematic identification of direct RA receptor targets downstream of ALDH1A2 in each organ not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 10 R-HSA-162582 Signal Transduction 8 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-168256 Immune System 7 R-HSA-1430728 Metabolism 5
Partners
IRF4RBPJROBO2SPI1TBX5WT1ZFP36

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RALDH2 (ALDH1A2) was identified as a major retinoic acid-generating enzyme in the early mouse embryo, with expression domains in mesoderm that indicate regions of endogenous RA synthesis; exogenous RA administration at E8.5 downregulates RALDH2 transcript levels in caudal regions, suggesting a negative feedback mechanism on RA synthesis. In situ hybridization, maternal RA administration in mouse embryos Mechanisms of development High 9106168
2002 Kinetic characterization of purified recombinant mouse RALDH2 showed it catalyzes oxidation of retinal to retinoic acid with pH optimum of 9.0, preferentially converting all-trans retinal (highest efficiency) over 13-cis and 9-cis retinal substrates; Km for all-trans retinal is 0.66 µM; citral and p-hydroxymercuribenzoic acid inhibit activity while MgCl2 activates it. In vitro enzyme kinetics with purified recombinant RALDH2 Biochimica et biophysica acta High 11983430
1999 Injection of mouse Raldh2 mRNA into Xenopus embryos stimulates high-level RA synthesis in vivo, establishing that RALDH2 can perform RA synthesis in vivo; RALDH2 protein is localized primarily in trunk tissue (paraxial mesoderm, somites, pericardium, midgut, mesonephros) at E7.5–E10.5, distinct from ALDH1 which is in cranial tissues. Xenopus mRNA injection with RA reporter assay; whole-mount immunohistochemistry in mouse embryos Developmental genetics High 10570467
2002 Targeted disruption of Raldh2 in mice arrests development at midgestation and eliminates virtually all RA synthesis in the embryo except that associated with Raldh3 in surface ectoderm of the eye field, demonstrating RALDH2 is responsible for most RA synthesis in trunk mesodermal derivatives and spinal cord. Raldh2 null mouse knockout with RA-responsive transgene reporter Development (Cambridge, England) High 11959834
2001 The zebrafish neckless mutation inactivates retinaldehyde dehydrogenase type 2 (raldh2), causing loss of retinoic acid biosynthesis; mosaic analysis demonstrates that reduced hoxb4 expression in the nervous system is non-cell autonomous, requiring RA signaling from adjacent paraxial mesoderm. Zebrafish genetic mutant analysis, mosaic analysis, RA rescue experiments Development (Cambridge, England) High 11688558
2003 RALDH2 in posterior pharyngeal mesoderm produces RA required for development of posterior branchial arches, pharyngeal pouches, vagal neural crest, and enteric ganglia; RA synthesized by RALDH2 diffuses to both pharyngeal endoderm and mesoderm, acting as a mesodermal signal patterning the pharyngeal endoderm. Raldh2 null mouse with RA supplementation rescue; in situ hybridization of RA target genes (Hoxa1, Hoxb1) Development (Cambridge, England) High 12702665
2005 Raldh2 expressed in dorsal pancreatic mesenchyme provides a RA signal required for dorsal endodermal pancreas development, specifically activating Pdx1 expression in dorsal but not ventral endoderm; maternal RA supplementation rescues dorsal pancreas development and restores endodermal Pdx1 and mesenchymal Isl1 expression. Raldh2 knockout mouse with RA reporter transgene, maternal RA rescue, in situ hybridization Developmental biology High 15739227 16026781
2005 Raldh2 expressed in somitic mesoderm generates RA that travels as a signal throughout the mesoderm and neuroectoderm but not tailbud mesoderm; this RA is required for posterior neural transformation (spinal cord differentiation), acting directly in the neuroectoderm rather than in the mesoderm; loss of Raldh2 increases Fgf8 expression in the tailbud. Raldh2 null mouse, maternal RA rescue, RA reporter transgene, gene expression analysis Mechanisms of development High 15652703
2004 Raldh2 expressed in optic vesicle generates RA required for retina invagination and optic cup formation; RA synthesis in the optic vesicle initiates retinal development and cannot be compensated by Raldh3 activity in lens placode alone; maternal RA rescue restores optic cup formation in Raldh2-/- embryos. Raldh2-/- and Raldh1-/-;Raldh2-/- double knockout mouse, RA-reporter transgene, maternal RA rescue Developmental dynamics High 15366004
2004 Raldh2 in lateral plate mesoderm controls two phases of RA signaling required for limb development: an early phase upstream of Tbx5, Meis2, and dHand needed for forelimb bud initiation, and a late phase needed to expand the apical ectodermal ridge along distal ectoderm. Raldh2-/- mouse with stage-specific maternal RA administration windows, gene expression analysis The Journal of biological chemistry High 15069081
2006 RALDH2 is responsible for RA synthesis in the craniofacial region and forebrain between the 8- and 15-somite stages; loss of Raldh2 causes decreased FGF signaling in the craniofacial region and impaired sonic hedgehog signaling in the ventral diencephalon, demonstrating RALDH2-mediated RA regulates FGF and Shh signaling crosstalk. Raldh2-/- knockout mouse, gene expression analysis, signaling pathway analysis Development (Cambridge, England) High 16368932
2005 Wild-type ALDH1A2, but not a catalytically dead mutant, reduces colony growth when re-expressed in DU145 prostate cancer cells, demonstrating that the enzymatic (RA-synthesizing) activity is required for tumor suppressor function. Transfection of wild-type vs. catalytically dead ALDH1A2 mutant in prostate cancer cells, colony formation assay Cancer research High 16166285
2018 X-ray crystal structures of human ALDH1A2 with irreversible and reversible inhibitors revealed that WIN18,446 covalently reacts with the catalytic residue Cys320, forming a chiral adduct in (R) configuration that induces a contracted NAD conformation suboptimal for dehydrogenase activity; reversible inhibitors interact through hydrogen bonding near Cys320 without affecting NAD; inhibitor binding causes a large flexible loop to assume regular structure shielding the active site. X-ray crystallography, direct binding studies (Tier 1 structural analysis) ACS chemical biology High 29240402
2011 ALDH1A2 enzyme activity is detected by the Aldefluor assay and inhibited by DEAB (diethylaminobenzaldehyde) and disulfiram; overexpression of ALDH1A2 in K562 and H1299 cancer cell lines increases cell proliferation, clonal efficiency, and drug resistance to 4-hydroperoxycyclophosphamide and doxorubicin, demonstrating DEAB is not specific for ALDH1A1. Lentiviral overexpression, ALDH activity assay, Aldefluor assay, Western blot, drug resistance assays Chemico-biological interactions High 22079344
2011 Wt1 transcription factor directly activates Raldh2 transcription in epicardial cells; Wt1-null epicardial cells show decreased Raldh2 expression and reduced RA synthesis; PDGFRα expression is downstream of this WT1-RALDH2-RA axis. Wt1 null in vivo and in vitro; RA-responsive reporter; ChIP/direct transcription target analysis Development (Cambridge, England) High 21343363
2009 ALDH1A2 mutations Ala151Ser and Ile157Thr found in Tetralogy of Fallot patients are located in the tetramerization domain; molecular mechanics simulations show these mutations hinder RALDH2 tetramerization, implicating the oligomeric state in normal function. Patient sequencing, molecular mechanics simulation of protein structure BMC medical genetics Medium 19886994
2021 Tbx5 directly maintains aldh1a2 expression in foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer; Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in adjacent foregut endoderm through a conserved MACS1 enhancer, establishing a RA-Hedgehog-Wnt signaling cascade in cardiopulmonary development. Xenopus and mouse embryo genetic analysis, ChIP, enhancer reporter assays eLife High 34643182
2018 Depletion of ALDH1A2 in primary human chondrocytes changes expression of chondrogenic markers including SOX9; the OA risk SNP rs12915901 reduces ALDH1A2 expression in cartilage through altered Ets transcription factor binding at an intronic element, establishing ALDH1A2 as a regulator of chondrocyte gene expression. RNA interference in primary chondrocytes, allelic expression imbalance (pyrosequencing), in silico/in vitro promoter analysis Arthritis & rheumatology (Hoboken, N.J.) High 29732726
2022 ALDH1A2 risk variants associate with lower ALDH1A2 mRNA in OA cartilage; ALDH1A2 depletion (via low atRA) and cartilage injury both upregulate inflammatory genes (mechanoflammation); talarozole (RAMBA) restores atRA and suppresses mechanoflammation via a PPARγ-dependent mechanism; talarozole suppressed mechano-inflammatory genes in mouse joint in vivo and reduced cartilage degradation and osteophyte formation. RNA-seq of patient cartilage stratified by genotype; in vitro/in vivo pharmacological manipulation with talarozole; PPARγ inhibitor experiments Science translational medicine High 36542696
2014 GM-CSF-induced RALDH2 expression in dendritic cells requires cooperative binding of Sp1 (activated by ERK and p38 MAPK downstream of GM-CSF) and the RAR/RXR complex to GC-rich Sp1-binding sites and an RARE half-site near the TATA box in the mouse Aldh1a2 promoter. ChIP, reporter assay, EMSA, ERK/p38 inhibitors, RAR antagonist, Sp1 inhibitor in bone marrow-derived DCs PloS one High 24788806
2017 Rbpj (Notch signaling effector) directly regulates Aldh1a2 transcription in dendritic cells by binding to its promoter; Rbpj-deficient DCs lack ALDH1A2 and lose ability to generate regulatory T cells; overexpression of Aldh1a2 in Rbpj-deficient DCs rescues their Th17-promoting phenotype. Rbpj conditional knockout in CD11c+ cells, ChIP, Aldh1a2 overexpression rescue, in vivo colitis model Journal of immunology High 28779023
2018 PU.1 and IRF4 transcription factors form a heterodimer that synergistically transactivates the Aldh1a2 gene in dendritic cells via an EICE motif at -1961/-1952 of the gene; GM-CSF upregulates IRF4 expression and PU.1 recruitment to the Aldh1a2 promoter. ChIP, reporter assay, EMSA, siRNA knockdown of PU.1 and IRF4, ex vivo DCs Journal of immunology High 30413670
2009 Aldh1a2 is the primary retinaldehyde dehydrogenase acting during zebrafish pancreas development; a glycine-to-arginine mutation in the catalytic domain of aldh1a2 causes loss of endocrine pancreas markers; maternal Aldh1a2 activity persists in zygotic null mutants, demonstrated by translation-blocking morpholinos producing a more severe phenotype than splice-blocking morpholinos. Zebrafish genetic mutant (null allele), morpholino knockdown (translation-blocking vs splice-blocking), gene expression analysis PloS one High 20011517
2009 Zebrafish raldh2 is one of the most highly induced genes across three epimorphic regeneration platforms (adult caudal fin, adult heart, larval fin); raldh2 expression is required for wound epithelium and blastema formation; raldh2 expression during regeneration is regulated by Wnt and FGF/ERK signaling. Comparative microarray, in situ hybridization, functional knockdown studies in zebrafish regeneration models The Journal of biological chemistry Medium 19801676
2013 HOXA13 directly binds a conserved cis-regulatory element in the Aldh1a2 locus to promote its expression in the autopod; loss of HOXA13 reduces Aldh1a2 expression, RA signaling, and interdigital programmed cell death; maternal RA supplementation partially rescues interdigital cell death defects in Hoxa13 mutants. Hoxa13 knockout mouse, ChIP (HOXA13 binding to Aldh1a2 locus), RA reporter, maternal RA rescue Developmental dynamics High 23553814
2015 Foxc1a transcription factor binds the aldh1a2 promoter directly in zebrafish embryos (demonstrated by ChIP) to restrict aldh1a2 expression during early somitogenesis; in foxc1a knockouts, increased aldh1a2/RA levels suppress fgf8a and deltaC expression, reducing myod1; knockdown of aldh1a2 in foxc1a nulls partially rescues myod1 expression. TALEN knockout of foxc1a, ChIP assay on zebrafish embryos, morpholino knockdown, gene expression analysis The Journal of biological chemistry High 25724646
2022 Global deletion of both Aldh1a1 and Aldh1a2 in mice blocks spermatogenesis; cell-type-specific deletion showed that RA synthesis by Sertoli cells (but not germ cells) is required for initial spermatogonial differentiation; Aldh1a3 activity cannot compensate for loss of both Aldh1a1 and Aldh1a2. Global and conditional (Sertoli cell- and germ cell-specific) Cre-loxP knockout mice Frontiers in endocrinology High 35574006
2021 ALDH1A2 biallelic hypomorphic missense variants in humans cause a lethal multiple congenital anomaly syndrome with diaphragmatic, pulmonary, and cardiovascular defects; in vitro studies of patient variants show reduced RA production; in silico modeling predicts structural impairment for three of four substitutions. Exome sequencing, in vitro RA production assay, in silico protein modeling Human mutation Medium 33565183
2020 CD137 signaling in intestinal CD11b-CD103+ DCs activates TAK1, which stimulates the AMPK-PGC-1α axis to enhance Aldh1a2 gene expression and RALDH2 production; RA produced then acts on neighboring CD11b+CD103- DCs inducing SOCS3 to suppress IL-23 production. DC-specific CD137 knockout mouse, pathway inhibitor experiments, RA rescue in vivo Cell reports High 32209473
2023 Aldh1a2+ fibroblastic reticular cells (FRCs) in omental milky spots regulate lymphocyte recruitment by controlling CXCL12 display on high endothelial venules; diphtheria toxin-mediated ablation of Aldh1a2+ FRCs reduces milky spot size and cellularity and alters peritoneal lymphocyte composition. Diphtheria toxin-mediated cell ablation in Aldh1a2-DTR knock-in mice, flow cytometry, immunofluorescence The Journal of experimental medicine High 36880532
2020 Wnt/β-catenin signaling directly represses ALDH1A2 expression in fetal kidney cells; β-catenin is recruited to the ALDH1A2 promoter and an intronic element (intron1G) as shown by ChIP; ectopic Wnt ligands (Wnt1, Wnt3a, Wnt4, Wnt9b) all repress ALDH1A2; luciferase reporter confirms functional repression through these regulatory elements. ChIP, luciferase reporter assay, Wnt ligand overexpression, GSK3 inhibitor CHIR99021, immunohistochemistry Frontiers in cell and developmental biology High 32258025
2024 Noncanonical NF-κB signaling (RelB:p52) in intestinal DCs activates Axin1 transcription, promoting β-catenin destruction and thereby reducing β-catenin-dependent Raldh2 expression and RA synthesis; DC-specific deficiency of RelB:p52 reinforces β-catenin-Raldh2-mediated tolerogenic DC function, with β-catenin haploinsufficiency reversing this protection. DC-specific noncanonical NF-κB knockout mice, β-catenin haploinsufficiency, gene expression and Treg/IgA functional analyses The EMBO journal High 39060515
2026 Cardiomyocyte ALDH1A2 is a central RA-producing enzyme that protects against myocardial ischemia-reperfusion injury; Aldh1a2 ablation aggravates heart dysfunction and fibrosis while overexpression is protective; the cardioprotective mechanism involves RA binding to RA receptors and regulating Bmp7 transcription to inhibit cell death and fibrosis. Cardiomyocyte-specific Aldh1a2 knockout and overexpression in mice, I/R surgery, transcriptome analysis, RA receptor signaling studies Cardiovascular research High 41689430
2026 GM-CSF-IL-4-induced differentiating dendritic cells express ALDH1A2 and produce retinoic acid that inhibits DC maturation as an autocrine brake; genetic knockout of Aldh1a2 in DCs enhances DC function and antigen-specific T cell responses, improving DC vaccine efficacy. Aldh1a2 genetic knockout in DCs, ALDH1A2 inhibitor pharmacological studies, DC vaccine functional assays Nature immunology High 41491403
2020 RALDH2 mRNA is a direct post-transcriptional target of the RNA-binding protein tristetraprolin (TTP/ZFP36); Zfp36-/- mice show increased intestinal vitamin A metabolism by gut DCs due to elevated RALDH2, leading to expanded Tregs. Zfp36-/- mice, RALDH2 as direct TTP target identification, gut immune phenotyping Mucosal immunology Medium 32467605
2012 RALDH2 is the predominant RALDH transcript in the chick choroid (>100-fold over RALDH3) and is responsible for increased all-trans retinoic acid synthesis in response to myopic defocus (visual recovery); choroid conditioned medium from recovering eyes inhibits scleral proteoglycan synthesis in vitro at concentrations equivalent to RA. Quantitative RT-PCR, in situ hybridization, immunohistochemistry, LC-tandem MS quantification of atRA in organ cultures, scleral proteoglycan synthesis assay Investigative ophthalmology & visual science High 22323456
2013 PPARγ activation regulates ALDH1A2 (RALDH2) expression in human monocyte-derived dendritic cells; RDH10, RALDH2, and CRABP2 form a linear PPARγ-regulated pathway required for ATRA production; all three proteins are required for efficient ATRA production and signaling in permissive DC types. Knockdown studies in human DCs, PPARγ activation, RA production assays, protein co-expression analysis Journal of lipid research Medium 23833249
2020 ROBO2 binds RALDH2 as a novel binding partner in the common nephric duct; ROBO2 impacts CND migration and fusion with the primitive bladder through RALDH2-dependent signaling; retinoic acid rescues ureter anomalies in Robo2-/- embryos. Robo2-/- mouse, protein interaction (novel binding partner identification), RA rescue experiments Developmental biology Medium 32562756
2025 In T-cell acute lymphoblastic leukemia, ALDH1A2 expression is selectively regulated by the TAL1 oncogene; pharmacological inhibition of ALDH1A2 using Dimate demonstrates anti-leukemic activity, establishing ALDH1A2 as essential for T-ALL cell survival. Transcriptomic and epigenetic analyses, TAL1 regulation studies, pharmacological ALDH1A2 inhibition in T-ALL cell lines and primary patient samples bioRxiv (preprint)preprint Medium
2025 In human Trunk-like Structures (hTLS), neural tube signals induce medially localized ALDH1A2 expression in somites; subsequent RA signaling from somites to the neural tube drives spontaneous neural progenitor patterning and PAX6 expression, establishing a bidirectional signaling loop between neural tube and somites. Human stem cell-based embryo model, single-cell analyses, endogenous signaling manipulation bioRxiv (preprint)preprint Medium
2025 ZBTB12 transcriptionally activates DNMT3B, which then methylates and silences the ALDH1A2 gene in breast cancer; DNMT3B knockdown increases ALDH1A2 protein levels; DNMT1 and DNMT3B are implicated in ALDH1A2 silencing in breast cancer and ovarian cancer cells. Co-immunoprecipitation (ubiquitination), methylation-specific PCR, Western blot, DNMT1/DNMT3B siRNA knockdown, promoter binding analysis Biochemical and biophysical research communications Medium 40543226
2025 The first apo-ALDH1A2 crystal structure was obtained (without ligands/cofactors) using nanolitre sitting-drop crystallization, expanding structural knowledge beyond previously reported NAD-bound or inhibitor-bound forms. X-ray crystallography (apo-enzyme structure from sitting-drop nanolitre crystallization) Biochemical and biophysical research communications Medium 40829477

Source papers

Stage 0 corpus · 96 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) 313 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 194 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 189 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 163 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 161 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 146 10357892
2005 The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer. Cancer research 126 16166285
1999 Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways. Developmental genetics 126 10570467
2014 Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nature genetics 117 24728293
2011 Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2. Development (Cambridge, England) 110 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 74 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 59 29240402
2003 Expression of Raldh2, Cyp26 and Hox-1 in normal and retinoic acid-treated Ciona intestinalis embryos. Gene expression patterns : GEP 56 12799071
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
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 48 26972771
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
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
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 35 36542696
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
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
2008 Expression of the retinoic acid-metabolizing enzymes RALDH2 and CYP26b1 during mouse postnatal testis development. Asian journal of andrology 24 18478160
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 21 11472854
2018 CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features. Blood advances 20 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
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
2003 Patterning of forelimb bud myogenic precursor cells requires retinoic acid signaling initiated by Raldh2. Developmental biology 18 14623241
2023 Aldh1a2 + fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots. The Journal of experimental medicine 17 36880532
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 17 27569851
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
2022 Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis. Frontiers in endocrinology 16 35574006
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
2010 prep1.2 and aldh1a2 participate to a positive loop required for branchial arches development in zebrafish. Developmental biology 9 20423710
2024 The therapeutic potential of Apigenin in amyotrophic lateral sclerosis through ALDH1A2/Nrf2/ARE signaling. Molecular medicine (Cambridge, Mass.) 8 39521994
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 5 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 3 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
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 PTPN2 alleviates Silicotic pulmonary fibrosis by inhibiting senescence of type II alveolar epithelial cells via retinol metabolism regulated by ALDH1A2. International immunopharmacology 0 41558294
2026 Identification of ALDH1A2-mediated cardioprotective benefits in myocardial ischaemia-reperfusion injury. Cardiovascular research 0 41689430
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
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 0 41382115