Affinage

HOXA13

Homeobox protein Hox-A13 · UniProt P31271

Length
388 aa
Mass
39.7 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HOXA13 is a homeodomain transcription factor that patterns the distal limb (autopod), urogenital tract, and placental vasculature by binding AT-rich DNA and directly regulating target genes that govern cell adhesion, chondrogenesis, and signaling (PMID:8898214, PMID:9428414, PMID:17200107). Its homeodomain recognizes a high-affinity AT-rich consensus and binds DNA as a dimer, with N-terminal arm minor-groove contacts and helix-3 major-groove recognition of an ATAA core; dimer-interface and recognition-helix residues are required for DNA binding and transcriptional activation (PMID:17200107, PMID:21829694). Through these promoter and enhancer interactions HOXA13 activates Bmp2 and Bmp7 in the autopod, activates EphA7/EphA6 to control mesenchymal cell adhesion and chondrogenic condensation, activates Aldh1a2 to drive retinoic-acid-dependent interdigital cell death, and represses the BMP antagonist Sostdc1 to license BMP/SMAD signaling in the distal limb (PMID:11684655, PMID:15342482, PMID:16314414, PMID:17200107, PMID:17304517, PMID:23553814). HOXA13 acts partially redundantly with Hoxd13 in autopod and posterior trunk morphogenesis and suppresses Gli3 transcription to enable digit 1 formation (PMID:8898214, PMID:9428414, PMID:31896583). In urogenital development it sustains Fgf8 and Bmp7 in the urethral plate and directs Müllerian duct and ureter remodeling in part through Gata3, while in the placenta it activates Tie2 and Foxf1 to specify labyrinth vasculature (PMID:12783783, PMID:18483557, PMID:30649340). Regulatory specificity is augmented by direct protein interaction with all MEIS family members through the C-terminal domain of MEIS1B (PMID:15617687). Loss-of-function and dominant-negative HOXA13 mutations cause hand-foot-genital syndrome: nonsense and recognition-helix missense mutations abolish DNA binding and transactivation, while N-terminal polyalanine expansions reduce steady-state protein through enhanced degradation and form cytoplasmic aggregates that sequester wild-type HOXA13 and HOXD13 (PMID:9020844, PMID:10839976, PMID:15385446, PMID:17935235, PMID:28947713). A recognition-helix missense allele combined with a promoter deletion underlies Guttmacher syndrome (PMID:11968094).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Established that HOXA13 is genetically required for distal limb (autopod) skeletal patterning and acts partially redundantly with Hoxd13.

    Evidence Targeted Hoxa13 and Hoxd13 knockouts in mice with all allele combinations analyzed

    PMID:8898214

    Open questions at the time
    • Did not identify direct molecular targets
    • Mechanism of redundancy with Hoxd13 unresolved
  2. 1995 High

    Showed HOXA13 confers a distal positional identity and controls homophilic cell-adhesive properties, linking a transcription factor to mesenchymal cell sorting.

    Evidence Retroviral misexpression in chick limb bud plus in vitro cell dissociation/reassociation assays

    PMID:7590231

    Open questions at the time
    • Adhesion molecules mediating sorting not identified
    • Direct transcriptional targets unknown
  3. 1997 High

    Connected HOXA13 loss-of-function mutation to a human Mendelian disease and to urogenital/vascular morphogenesis, defining the homeodomain as the critical functional element.

    Evidence HFGS family sequencing identifying a homeodomain-truncating nonsense mutation; Hoxa13 knockout urogenital/umbilical artery phenotyping

    PMID:9020844 PMID:9428414

    Open questions at the time
    • Biochemical demonstration of lost DNA binding not shown
    • Downstream targets in urogenital tract unidentified at this stage
  4. 2000 Medium

    Defined the spectrum and distinct mechanisms of HFGS-causing mutations (nonsense, polyalanine expansion, recognition-helix missense), revealing that mutation class shapes phenotype severity.

    Evidence Sequencing of multiple HFGS families with genotype-phenotype correlation; comparative vertebrate sequence analysis of the N-terminal polyalanine region; Hypodactyly frameshift protein characterization

    PMID:10625554 PMID:10656931 PMID:10839976

    Open questions at the time
    • Functional mechanism of missense allele inferred not demonstrated
    • How polyalanine expansion impairs function not yet resolved
  5. 2001 High

    Identified the first direct effector pathway: HOXA13 regulates EphA7 to drive chondrogenic condensation, and established dominant Hoxa13 identity in limb and uterus via homeobox swap.

    Evidence Reciprocal genetics with EphA7 antibody-blocking in micromass culture; Hoxa11-to-Hoxa13 homeobox knock-in with expression profiling

    PMID:11684655 PMID:11688568

    Open questions at the time
    • Direct HOXA13 binding to EphA7 not yet shown at this stage
    • Most of the >100 candidate targets uncharacterized
  6. 2002 Medium

    Demonstrated that specific HFGS mutant proteins can act as dominant negatives in vivo and linked a recognition-helix missense allele to Guttmacher syndrome.

    Evidence Retroviral overexpression of HFGa13 in chick caudal endoderm; allele dissection in a Guttmacher syndrome family

    PMID:11830557 PMID:11968094

    Open questions at the time
    • Dominant-negative mechanism inferred from phenotype, not biochemistry
    • Promoter deletion contribution to Guttmacher phenotype unclear
  7. 2003 Medium

    Placed HOXA13 upstream of Fgf8/Bmp7 signaling in genital tubercle morphogenesis and showed it represses MyoD in limb muscle precursors.

    Evidence Hoxa13(GFP) mutant analysis with in vitro Fgf8 supplementation rescue; gain- and loss-of-function MyoD readout in chick and C2C12

    PMID:12783783 PMID:14706073

    Open questions at the time
    • Direct binding to Fgf8/Bmp7 or MyoD regulatory regions not shown
    • Relationship between muscle and skeletal roles unclear
  8. 2004 High

    Provided the first direct in vivo evidence that HOXA13 binds and activates BMP gene enhancers, and that polyalanine expansion causes loss of function via protein destabilization.

    Evidence Enhancer-binding assays and ChIP from autopod with BMP2/BMP7 rescue; polyalanine-expansion knock-in mouse dissecting RNA vs protein vs translation

    PMID:15342482 PMID:15385446

    Open questions at the time
    • Degradation machinery for expanded protein not identified
    • Quantitative contribution of BMP targets to full phenotype incomplete
  9. 2005 High

    Established the biochemical basis of HOXA13 specificity: direct EphA7 promoter regulation, MEIS cofactor interaction, and preference for AT-rich chromatin.

    Evidence ChIP and transactivation with binding-site mutagenesis on EphA7; yeast two-hybrid and Co-IP MEIS interaction mapping; CsCl-purified chromatin ChIP with AT-content analysis

    PMID:15617687 PMID:16314414 PMID:16321965

    Open questions at the time
    • Functional consequence of MEIS interaction on target selection in vivo not resolved
    • Genome-wide binding landscape not yet mapped
  10. 2007 High

    Defined the high-affinity AT-rich binding consensus, added repression (Sostdc1) and vascular (EphA6/EphA7) targets, and linked polyalanine aggregates to sequestration of wild-type Hox proteins.

    Evidence SELEX binding-site determination with limb ChIP and reporter assays; genital tubercle ChIP for EphA6/EphA7; COS-cell aggregation and geldanamycin co-aggregation assays

    PMID:17200107 PMID:17304517 PMID:17935235

    Open questions at the time
    • Determinants of activation versus repression at AT-rich sites unclear
    • Role of Hsp90 in vivo in HFGS not established
  11. 2008 High

    Extended HOXA13 direct transcriptional control to placental labyrinth vasculature via Tie2 and Foxf1, with quantified high-affinity promoter binding.

    Evidence Hoxa13 mutant placenta microarray, placental ChIP, in vitro affinity measurement (Kd 27-42 nM), and reporter assays

    PMID:18483557

    Open questions at the time
    • Cofactor requirements for vascular target selection unknown
    • Whether placental and limb targets share regulatory logic untested
  12. 2011 High

    Provided atomic-level mechanism of DNA recognition, showing HOXA13 binds as a dimer with defined residues required for binding, dimerization, and transactivation.

    Evidence NMR structure of the homeodomain-DNA complex with site-directed mutagenesis and dual binding/transcription assays

    PMID:21829694

    Open questions at the time
    • Structure of full-length protein with N-terminal region and cofactors absent
    • Generality of dimeric binding across all targets untested
  13. 2013 High

    Linked HOXA13 to retinoic-acid-driven interdigital programmed cell death through direct Aldh1a2 regulation.

    Evidence Limb ChIP and reporter assays plus maternal RA supplementation rescue in Hoxa13 mutants

    PMID:23553814

    Open questions at the time
    • Interaction of RA pathway with BMP-dependent cell death not integrated
    • Partial rescue indicates additional unidentified targets
  14. 2019 High

    Mapped HOXA13 genome-wide binding in limb and revealed it transiently suspends cartilage differentiation by repressing pro-chondrogenic factors while validating enhancers near Bmp2 and Tshz2.

    Evidence ChIP-Seq with KO and double-KO transcriptomics and in vivo enhancer deletions; conditional KO defining Müllerian/ureter roles via Gata3

    PMID:30649340 PMID:30895612

    Open questions at the time
    • Direct versus indirect status of many repressed factors unresolved
    • Temporal control of the differentiation switch mechanism incomplete
  15. 2020 Medium

    Integrated HOXA13 into the digit-1 patterning network by showing it suppresses Gli3 transcription to permit 5'Hoxd expression.

    Evidence Hoxa13 mutant analysis with regulatory-element binding and in situ hybridization epistasis

    PMID:31896583

    Open questions at the time
    • Direct binding to Gli3 regulatory sequences shown indirectly
    • Interplay with Hoxd13 at this locus not fully dissected
  16. 2021 Medium

    Documented HOXA13 as an oncogenic transcription factor in epithelial cancers, directly activating target genes that drive proliferation, metastasis, and chemoresistance.

    Evidence ChIP/luciferase identification of CDH17, FN1, ABCC4 as direct targets; epistatic rescue with ACLY/IGF1R; miRNA-mediated regulation of HOXA13

    PMID:28387908 PMID:34075028 PMID:34094932 PMID:35197128

    Open questions at the time
    • Cofactor and chromatin context for cancer targets versus developmental targets unclear
    • Most cancer findings from single labs without independent replication
  17. 2017 Medium

    Showed that HOXA13 expression itself is controlled by a long-range repressive chromatin element at the HOXA locus, and that an oncogenic NUP98-HOXA13 fusion deregulates MSI2.

    Evidence Hi-C and CRISPR deletion of a 7p15.2 element with RNA-seq; ChIP of NUP98-HOXA13 fusion on the MSI2 promoter

    PMID:24971156 PMID:29117547

    Open questions at the time
    • Mechanism of repressive loop formation undefined
    • NUP98-HOXA13 target repertoire beyond MSI2 unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HOXA13 selects activation versus repression at AT-rich sites, and how MEIS and chromatin context route the same DNA-binding activity to distinct developmental versus oncogenic gene programs, remain unresolved.
  • No structural model of HOXA13-MEIS-DNA ternary complex
  • Determinants distinguishing developmental from cancer target selection unknown
  • Mechanism of polyalanine-driven degradation not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3
Partners
HOXD13MEIS1MEIS2MEIS3

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 A nonsense mutation converting a conserved tryptophan in the HOXA13 homeodomain to a stop codon, truncating 20 amino acids from the C-terminus, causes hand-foot-genital syndrome by likely eliminating DNA-binding capacity of the protein. Mutation identification by sequencing in an HFGS family; functional inference from homeodomain truncation Nature genetics High 9020844
1996 Hoxa13 gene knockout in mice causes loss of the most anterior digit and altered morphogenesis of preaxial carpal/tarsal elements in both forelimb and hindlimb autopods; Hoxa13 and Hoxd13 act in a partially redundant manner, and double homozygous mutants almost completely lack chondrified condensations in the autopod. Targeted gene disruption (knockout), analysis of all allele combinations of Hoxa13 and Hoxd13 Development (Cambridge, England) High 8898214
1997 Hoxa13 homozygous knockout mice display agenesis of the caudal portion of Müllerian ducts, absence of presumptive urinary bladder development, and premature stenosis of umbilical arteries, leading to mid-gestational lethality; Hoxa13 and Hoxd13 act redundantly in early morphogenesis of posterior trunk structures including the cloaca. Targeted gene disruption (knockout); histological and morphological analysis of compound mutants Development (Cambridge, England) High 9428414
1995 Misexpression of Hoxa-13 throughout the chick limb bud caused homeotic transformation of zeugopodal cartilages to a more distal (carpal/tarsal) fate and altered homophilic cell-adhesive properties of limb mesenchymal cells, causing Hoxa13-expressing cells to sort out from non-expressing cells in dissociation culture. Replication-competent retroviral misexpression in chick limb buds; in vitro cell dissociation and reassociation assays Genes & development High 7590231
2001 In Hoxa13 mutant mice, EphA7 expression is markedly reduced in affected digits and in mutant mesenchymal micromass cultures; antibody blocking of EphA7 extracellular domain severely inhibits chondrogenic condensation of Hoxa13-expressing heterozygous cells in vitro, indicating that Hoxa13 regulates EphA7 to control mesenchymal cell adhesion and chondrogenic condensation. FACS isolation of GFP-tagged Hoxa13 mutant mesenchymal cells; in vitro micromass chondrogenic assay; antibody blocking experiments; in situ hybridization Development (Cambridge, England) High 11684655
2003 Hoxa13 is required for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium; loss of Hoxa13 causes hypospadias through combined loss of Fgf8 and Bmp7 expression and ectopic noggin expression; Fgf8 supplementation restores proliferation to wild-type levels in mutant genital tubercle, and reduced Bmp7 explains closure defects through loss of apoptosis; Hoxa13 mutants also show altered androgen receptor expression. Hoxa13(GFP) mutant mouse analysis; in vitro Fgf8 supplementation rescue assay; in situ hybridization; immunohistochemistry Development (Cambridge, England) High 12783783
2004 HOXA13 directly binds novel enhancer regions of Bmp2 and Bmp7 to activate their expression in the developing autopod; endogenous HOXA13-Bmp2 and HOXA13-Bmp7 enhancer complexes were confirmed by immunoprecipitation from autopod tissue; exogenous BMP2 or BMP7 application partially rescues the Hoxa13 mutant limb phenotype. Biochemical enhancer-binding assays; chromatin immunoprecipitation from developing autopod; exogenous BMP2/BMP7 rescue of mutant limb phenotype Development (Cambridge, England) High 15342482
2001 Replacement of the Hoxa11 homeobox with the Hoxa13 homeobox (knock-in) confers dominant Hoxa13 function in the limbs and female reproductive tract, causing homeotic transformation of the uterus towards a cervix/vagina identity; gene chip analysis identified over 100 downstream gene expression changes consistent with Hoxa13 target genes. Homeobox-swap knock-in mouse; gene expression profiling (gene chips); histological analysis Development (Cambridge, England) High 11688568
2000 Polyalanine expansions in the N-terminal region of HOXA13 cause hand-foot-genital syndrome; N-terminal sequence is strongly conserved among vertebrates and harbors multiple conserved domains shared with Drosophila AbdB; three large alanine repeats arose after divergence of reptiles from the mammalian lineage, possibly by replication slippage. PCR amplification and sequencing of HOXA13 N-terminal coding sequences across vertebrate species; comparative sequence analysis Mammalian genome Medium 10656931
2000 Novel HOXA13 mutations causing HFGS include nonsense mutations (N-terminal to or within homeodomain), a polyalanine expansion, and a missense mutation at an invariant homeodomain residue; the missense mutation produces an exceptionally severe limb phenotype, indicating that different mutation types can act by distinct mechanisms (loss of function vs. potentially altered function). Mutation identification by sequencing in six HFGS families; clinical phenotype correlation American journal of human genetics Medium 10839976
2002 A specific HOXA13 mutation (HFGa13) acts as a dominant negative in vivo; overexpression of HFGa13 in chick caudal endoderm causes taillessness and severe gut/genitourinary malformations; HFGa13 negatively regulates Hoxd13 expression and antagonizes functions of endogenous Hoxa13 and Hoxd13. Retroviral overexpression in chick caudal endoderm; in situ hybridization; phenotypic analysis Development (Cambridge, England) Medium 11830557
2004 Polyalanine expansion mutations in HOXA13 (tested in mouse knock-in model, +10 alanines in third polyalanine tract) cause loss of function through reduction of steady-state protein levels in vivo, not through impaired mRNA expression or splicing; in vitro translation efficiency is normal, implicating enhanced protein degradation as the mechanism. Homologous recombination knock-in mouse; quantitative RT-PCR; western blot; in vitro translation assay Human molecular genetics High 15385446
2005 HOXA13 and HOXD13 directly bind multiple conserved sites in the EphA7 promoter in vivo and in vitro, and activate EphA7 transcription; a mutation of the HOXA13/HOXD13 binding site in the EphA7 promoter abolishes transcriptional activation; the HOXD13(147L) brachydactyly-polydactyly mutation fails to bind the EphA7 promoter or transactivate it. Promoter characterization; in vivo ChIP in developing mouse limbs; in vitro transcription activation assays; mutagenesis of binding site The Journal of biological chemistry High 16314414
2005 HOXA13 interacts with all MEIS proteins (MEIS1A, MEIS1B, MEIS2, MEIS3) but not more diverged TALE superclass members; the C-terminal domain of MEIS1B (93 amino acids) is both necessary and sufficient for HOXA13 interaction; multiple HOX peptide domains contribute to MEIS binding; HOXA13 and MEIS1 coexpression occurs in developing male and female reproductive tracts. Yeast two-hybrid assays; Co-immunoprecipitation in mammalian cells; deletion mutagenesis of MEIS domains; expression analysis Developmental biology High 15617687
2005 HOXA13 binds AT-rich chromatin immunoprecipitated fragments (Hox-enriched fragments, HEFs) in NIH 3T3 cells; all HEFs augment transcription of a heterologous promoter when HOXA13 is coexpressed; multiple HOXA13 binding sites in the Enpp2 locus are necessary for full HOXA13-induced Enpp2 expression; HOXA13 upregulates Enpp2 without changing general histone acetylation at its locus. CsCl centrifugation-based chromatin purification and immunoprecipitation (ChIP); transcriptional reporter assays; AT-content analysis Nucleic acids research Medium 16321965
2007 HOXA13 homeodomain binds DNA with a novel high-affinity site (AT-rich); HOXA13 binds and represses the BMP antagonist Sostdc1 through two conserved regulatory sites in vivo (confirmed by limb ChIP); absence of HOXA13 leads to ectopic Sostdc1 expression, reduced BMP-activated gene expression, and decreased SMAD phosphorylation in the distal limb. Empirical SELEX-based DNA binding site determination; limb ChIP; in vitro reporter assays; analysis of Hoxa13 mutant limbs The Journal of biological chemistry High 17200107
2007 HOXA13 directly regulates EphA6 and EphA7 expression in the genital tubercle (GT) vascular endothelia; HOXA13 binds conserved cis-regulatory elements in the EphA6 and EphA7 promoters with high affinity; GT ChIP confirms HOXA13 binding in vivo; HOXA13 activates EphA6 and EphA7 expression through these regulatory elements in vitro; loss of HOXA13 is associated with reduced EphA6/EphA7 and vascular defects in the GT. In vitro DNA-binding assays; chromatin immunoprecipitation from genital tubercle; transcriptional reporter assays in vitro Developmental dynamics High 17304517
2007 HOXA13 polyalanine expansion proteins form cytoplasmic aggregates; distribution between cytoplasm and nucleus is polyalanine tract size-dependent; Hsp90 inhibitor geldanamycin reduces steady-state abundance of expanded HOXA13 proteins; wild-type HOXA13 and HOXD13 are sequestered in polyalanine expansion aggregates, explaining dominant-negative effects. COS cell transfection with polyalanine-expanded HOXA13 constructs; immunocytochemistry; geldanamycin treatment; co-aggregation assays American journal of medical genetics. Part A Medium 17935235
2008 HOXA13 is essential for placental labyrinth vascular formation; loss of HOXA13 alters placental endothelial cell morphology and reduces expression of Tie2 and Foxf1; HOXA13 directly binds the Tie2 and Foxf1 promoters in vivo (placental ChIP) with high affinity (Kd = 27–42 nM); HOXA13 can use bound promoter regions to activate gene expression in vitro. Hoxa13 mutant mouse analysis; microarray; ChIP from placenta; in vitro DNA binding (affinity measurement); reporter assays PLoS genetics High 18483557
2011 NMR structure of the HOXA13 homeodomain (A13DBD) bound to an 11-mer DNA duplex reveals: the protein forms a dimer binding DNA with Kd of 7.5 nM; the N-terminal arm contacts the minor groove; helix 3 contacts the ATAA sequence in the major groove; N370 forms hydrogen bonds with adenine; V373 methyl groups contact T5, T6*, T7* for TAA recognition; I366 contacts T3* and T4*; R337, K343, F344 form the dimer interface. Mutants I366A, N370A, V373G reduce DNA binding and transcriptional activity; F344A weakens dimerization and reduces transcriptional activity by 76%. NMR structure determination; site-directed mutagenesis; DNA binding assays; transcriptional activity assays PloS one High 21829694
2013 HOXA13 directly regulates Aldh1a2 (the primary retinoic acid synthesizing enzyme in the limb) by binding a conserved cis-regulatory element in the Aldh1a2 locus; loss of HOXA13 reduces Aldh1a2 expression, RA signaling, and interdigital programmed cell death (IPCD); maternal RA supplementation partially rescues IPCD defects in Hoxa13 mutant hindlimbs. ChIP from limb tissue; reporter assays; RA signaling readout; maternal RA supplementation rescue in Hoxa13 mutants Developmental dynamics High 23553814
2002 Guttmacher syndrome is caused by a HOXA13 missense mutation in the recognition helix of the homeodomain (Q50L) combined with a 2-bp promoter deletion; the promoter deletion alone produces no detectable phenotype; the missense mutation is predicted to perturb DNA-binding properties, potentially resulting in both loss and specific gain of function. Sequencing of HOXA13 in Guttmacher syndrome family; molecular analysis of promoter deletion in isolation Human mutation Medium 11968094
2000 The Hypodactyly (Hoxa13Hd) 50-bp deletion causes a translational frameshift producing a novel stable protein (HOXA13Hd) consisting of the first 25 wild-type amino acids plus 275 arginine/lysine-rich novel residues, lacking the homeodomain; HOXA13Hd localizes to the nucleus in transfected COS-7 cells; transgenic misexpression of HOXA13Hd in developing limbs produces severe proximal and distal limb reduction defects. Transcription start site mapping; immunoprecipitation; cell transfection with immunolocalization; transgenic misexpression in mouse limb Developmental biology High 10625554
2003 Hoxa-13 and Hoxa-11 are expressed in limb muscle precursor cells and represses MyoD expression; forced expression of Hoxa-13 in limb muscle precursors or C2C12 myoblasts causes pronounced repression of MyoD; targeted disruption of Hoxa-13 results in enhanced MyoD expression in the flexor carpi radialis muscle, confirming endogenous regulation. In ovo electroporation; C2C12 cell transfection; gene knockout with in situ hybridization Development, growth & differentiation Medium 14706073
2010 Surviving Hoxa13 homozygous mutant mice display missing phalanges, fused carpal/tarsal elements, and reduced metacarpal/metatarsal length; Gdf5 expression is significantly reduced and diffuse in affected carpal/tarsal anlagen, identifying Gdf5 as a potential direct HOXA13 target gene involved in skeletal element delineation; Bmp2 expression is elevated. Analysis of surviving Hoxa13(GFP) homozygous mutants; quantitative gene expression analysis; in situ hybridization Developmental dynamics Medium 20034107
2015 HOXA13 directly regulates expression of Fgf8 and Bmp7 in the urethral plate, and is also required for the development of the glans penis vasculature; HOXA13 regulates genes required for proper androgen signaling in the genital tubercle. Hoxa13 mutant mouse; expression analysis of downstream targets; in vitro proliferation rescue with Fgf8 Genesis (New York, N.Y. : 2000) Medium 25980463
2015 HoxA13 is more highly expressed in the lower uterine segment (LUS) than the fundal myometrium during pregnancy; HoxA13 upregulates transcription of PTGIS and POSTN in myometrial cells; elevated HoxA13 enhances myometrial cell contractility and cell-cell adhesion; HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy. RNA sequencing of human myometrium; qRT-PCR and immunoblotting; cell contraction/adhesion assays; gene microarray after HoxA13 manipulation The Journal of clinical endocrinology and metabolism Medium 26485220
2016 HoxA13 stimulates myometrial cells to secrete IL-1β, which in turn upregulates IL-6, IL-8, Cox-2 (cyclooxygenase-2), and connexin-43; blocking IL-1β abolishes HoxA13-mediated upregulation of these targets; HoxA13-induced IL-1β promotes recruitment of activated THP-1 monocytes via a mutual feed-forward loop that amplifies cytokine and contraction-associated protein expression. Gene microarray of HoxA13 transcriptome in myometrial cells; IL-1β inhibitor blockade experiment; co-culture of myometrial cells with THP-1 monocytes; qRT-PCR and protein assays Endocrinology Medium 26982635
2017 HOXA13 directly binds the CDH17 promoter via HOXA13-binding sites (confirmed by dual luciferase assay); CDH17 is a downstream transcriptional target of HOXA13 that modulates the Wnt/β-catenin signaling pathway; CDH17 knockdown abrogates HOXA13-induced β-catenin upregulation in gastric cancer cells. Dual luciferase reporter assay; western blotting; siRNA knockdown; CCK-8/transwell assays European review for medical and pharmacological sciences Medium 28387908
2017 HOXA13 promotes gastric cancer progression partly via activation of Erk1/2; RNA-Seq transcriptome analysis identified Erk1/2 pathway as the main downstream mechanism of HOXA13-induced proliferation and metastasis in gastric cancer cells. RNA-Seq transcriptome analysis; western blot; in vitro gain- and loss-of-function; xenograft/metastasis assays OncoTargets and therapy Low 30881033
2021 HOXA13 facilitates colorectal cancer metastasis by transactivating ACLY and IGF1R as direct downstream targets; knockdown of ACLY and IGF1R inhibits HOXA13-mediated metastasis; IGF1 upregulates HOXA13 expression through the PI3K/AKT/HIF1α pathway, forming a positive feedback loop (IGF1-HOXA13-IGF1R). Gain- and loss-of-function in CRC cells; rescue experiments with ACLY/IGF1R knockdown/overexpression; pathway inhibitor experiments; in vivo xenograft Cell death & disease Medium 34075028
2018 HOXA13 directly binds the FN1 promoter region to enhance FAK/Src axis activation in gastric cancer, promoting proliferation and metastasis; this was confirmed by ChIP assay and dual luciferase reporter assay; HOXA13 is directly targeted by miR-449a (confirmed by luciferase assay); ITGA5 and ITGB1 interact with FN1 (confirmed by Co-immunoprecipitation). ChIP assay; dual luciferase reporter assay; Co-immunoprecipitation; in vitro and in vivo rescue experiments Experimental hematology & oncology Medium 35197128
2020 Hoxa13 directly modulates Gli3 transcriptional regulation in developing limbs; in Hoxa13 mutants, Hoxd13 expression is lost from the presumptive digit 1 territory, resulting in increased Gli3 repressor activity due to elevated Gli3 transcription; Hox13 paralogs normally bind Gli3 regulatory sequences to suppress Gli3 transcription, thereby enabling 5'Hoxd gene expression and digit 1 formation. Hoxa13 mutant mouse analysis; ChIP-like regulatory element analysis; in situ hybridization; protein expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 31896583
2017 A prostate cancer risk element at 7p15.2 has long-range chromatin interactions with the HOXA locus (confirmed by Hi-C); CRISPR/Cas9 deletion of this element reveals it specifically represses HOXA13 and HOTTIP expression (but not other HOXA genes), via a repressive chromatin loop; HOXA13 forced expression was used to characterize downstream effects. Hi-C analysis; CRISPR/Cas9 deletion; RNA-seq Cell reports Medium 29117547
2019 Hoxa13 plays a critical role in Müllerian duct fusion and in ureter remodeling by regulating elimination of the caudal common nephric duct; Hoxa13 function in the urogenital sinus is partly mediated by Gata3; Hoxa13 is required for proper organization of the ureter and provides positional and temporal cues in the lower urogenital system. Conditional inactivation strategy (Hoxa13 tissue-specific knockout); histological and molecular analysis of urogenital development Human molecular genetics Medium 30649340
2019 ChIP-Seq in developing mouse limbs identifies common target genes of HOXA11 and HOXA13; HOXA13-bound regions contain evolutionarily conserved sequences and multiple HOX binding sites; deletion of target regions neighboring Bmp2 or Tshz2 reduces their expression in the autopod confirming limb-specific enhancer function; HOXA13 transiently suspends cartilage differentiation in the autopod via repression of cartilage-promoting transcription factors (Aff3, Bnc2, Nfib, Runx1t1) and upregulation of Bcl11a. ChIP-Seq; Genechip transcriptome analysis of Hoxa13 KO and Hox13 double KO autopods; in situ hybridization; deletion of enhancer regions Development, growth & differentiation High 30895612
2014 NUP98-HOXA13 fusion protein (arising from chromosomal translocation t(7;11)(p15;p15)) binds the MSI2 promoter and deregulates MSI2 gene expression in blast crisis CML, as confirmed by chromatin immunoprecipitation. Chromatin immunoprecipitation; RT-PCR; cytogenetics Molecular cytogenetics Medium 24971156
2018 HOXA13 directly binds the DHRS2 promoter in gastric cancer cells to down-regulate DHRS2 expression, thereby increasing MDM2 levels; HOXA13 also confers 5-FU resistance through MRP1 via a p53-dependent pathway. ChIP and reporter assays (inferred from description of 'directly down-regulating DHRS2'); in vitro and in vivo functional assays; western blot Molecular carcinogenesis Low 29436749
2019 Hoxa13 binds the FAM3A promoter to enhance its promoter activity in ischemic neuronal cells (HT22); overexpression of Hoxa13 inhibits chronic cerebral ischemia-induced neuronal apoptosis; the Snhg8/miR-384/Hoxa13/FAM3A axis regulates neuronal apoptosis, with miR-384 targeting the Hoxa13 3'UTR. Promoter-binding assay (luciferase); RNA immunoprecipitation; overexpression/knockdown in HT22 cells; in vivo mouse model Cell death & disease Medium 31165722
2022 HOXA13 promotes liver regeneration by upregulating BMP-7 mRNA; overexpression of HOXA13 accelerates hepatocyte proliferation and liver function recovery in a mouse liver regeneration model. In vivo mouse liver regeneration model; HOXA13 overexpression in vivo and in vitro; gene expression analysis Biochemical and biophysical research communications Low 35868069
2021 HOXA13 upregulates ABCC4 expression to confer 5-FU resistance in gastric cancer; HOXA13 directly binds the ABCC4 promoter (confirmed by ChIP); HOXA13 is directly targeted by miR-139-5p (confirmed by luciferase reporter assay). ChIP assay; luciferase reporter assay; RNA-Seq; in vitro and in vivo functional assays Frontiers in oncology Medium 34094932
2017 A missense mutation in the HOXA13 homeodomain (V375F) impairs the ability of HOXA13 to activate transcription of the EPHA7 promoter, as demonstrated by luciferase reporter assay in a Chinese HFGS family. Sanger sequencing; luciferase reporter assay; molecular modelling Journal of genetics Medium 28947713

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Mutation of HOXA13 in hand-foot-genital syndrome. Nature genetics 386 9020844
1996 Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development (Cambridge, England) 373 8898214
2014 Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology (Baltimore, Md.) 366 24114970
1997 Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development (Cambridge, England) 293 9428414
2015 The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. Journal of translational medicine 208 25889214
2000 Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. American journal of human genetics 182 10839976
1995 Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds. Genes & development 180 7590231
2003 Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development (Cambridge, England) 145 12783783
2001 Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Development (Cambridge, England) 136 11684655
2017 Transcriptional and posttranscriptional regulation of HOXA13 by lncRNA HOTTIP facilitates tumorigenesis and metastasis in esophageal squamous carcinoma cells. Oncogene 120 28534516
2015 HOXA13 is a potential GBM diagnostic marker and promotes glioma invasion by activating the Wnt and TGF-β pathways. Oncotarget 91 26356815
2004 HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis. Development (Cambridge, England) 84 15342482
2001 Functional specificity of the Hoxa13 homeobox. Development (Cambridge, England) 83 11688568
2008 HOXA13 Is essential for placental vascular patterning and labyrinth endothelial specification. PLoS genetics 71 18483557
2002 Tail gut endoderm and gut/genitourinary/tail development: a new tissue-specific role for Hoxa13. Development (Cambridge, England) 66 11830557
2002 A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length? Human genetics 64 12073020
2002 Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Blood 63 11830496
2016 HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression. Oncology reports 62 27108607
2018 Long noncoding RNA LUCAT1 promotes malignancy of ovarian cancer through regulation of miR-612/HOXA13 pathway. Biochemical and biophysical research communications 61 30107913
2005 Range of HOX/TALE superclass associations and protein domain requirements for HOXA13:MEIS interaction. Developmental biology 59 15617687
2006 Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). Journal of negative results in biomedicine 57 16556301
2021 IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell death & disease 56 34075028
1999 Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development. The Journal of urology 53 10210434
2005 Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs. The Journal of biological chemistry 52 16314414
2016 Up-regulation of long non-coding HOTTIP functions as an oncogene by regulating HOXA13 in non-small cell lung cancer. American journal of translational research 51 27347311
2002 A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. Human mutation 51 11968094
2017 A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13. Cell reports 50 29117547
2005 Expression of Hoxa-11 and Hoxa-13 in the pectoral fin of a basal ray-finned fish, Polyodon spathula: implications for the origin of tetrapod limbs. Evolution & development 50 15876191
2013 HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina. Gene 47 23376215
1998 Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning. Development (Cambridge, England) 46 9477331
2017 High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models. Laboratory investigation; a journal of technical methods and pathology 45 29035381
2018 Long Non-coding RNA DLEU1 Promotes Proliferation and Invasion by Interacting With miR-381 and Enhancing HOXA13 Expression in Cervical Cancer. Frontiers in genetics 44 30581456
2002 The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes, chromosomes & cancer 44 12112533
2021 3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia. Nature communications 43 34140506
2009 Analysis of hoxa11 and hoxa13 expression during patternless limb regeneration in Xenopus. Developmental biology 42 19958756
2018 HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway. Molecular carcinogenesis 41 29436749
2000 Evolution of N-terminal sequences of the vertebrate HOXA13 protein. Mammalian genome : official journal of the International Mammalian Genome Society 41 10656931
2017 Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells. Stem cells (Dayton, Ohio) 40 28782268
2004 Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model. Human molecular genetics 40 15385446
2003 Hoxa-11 and Hoxa-13 are involved in repression of MyoD during limb muscle development. Development, growth & differentiation 39 14706073
2000 Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein. Developmental biology 38 10625554
1999 Altered Hox expression and increased cell death distinguish Hypodactyly from Hoxa13 null mice. The International journal of developmental biology 35 10470645
2015 A Hoxa13:Cre mouse strain for conditional gene manipulation in developing limb, hindgut, and urogenital system. Genesis (New York, N.Y. : 2000) 32 25980463
2017 HOXA13 upregulation in gastric cancer is associated with enhanced cancer cell invasion and epithelial-to-mesenchymal transition. European review for medical and pharmacological sciences 31 28165563
1999 Distinct signaling molecules control Hoxa-11 and Hoxa-13 expression in the muscle precursor and mesenchyme of the chick limb bud. Development (Cambridge, England) 31 10331987
2016 Long noncoding RNA HOTTIP contributes to the progression of prostate cancer by regulating HOXA13. Cellular and molecular biology (Noisy-le-Grand, France) 30 27064878
2006 Transforming potential of the T-cell acute lymphoblastic leukemia-associated homeobox genes HOXA13, TLX1, and TLX3. Genes, chromosomes & cancer 29 16804919
2020 Comprehensive analysis of the HOXA gene family identifies HOXA13 as a novel oncogenic gene in kidney renal clear cell carcinoma. Journal of cancer research and clinical oncology 28 32444962
2018 The expression of HOXA13 in lung adenocarcinoma and its clinical significance: A study based on The Cancer Genome Atlas, Oncomine and reverse transcription-quantitative polymerase chain reaction. Oncology letters 28 29805592
2017 HOXA13 is associated with unfavorable survival and acts as a novel oncogene in prostate carcinoma. Future oncology (London, England) 28 28766961
2017 CDH17 is a downstream effector of HOXA13 in modulating the Wnt/β-catenin signaling pathway in gastric cancer. European review for medical and pharmacological sciences 27 28387908
2015 Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease. Biochemical and biophysical research communications 27 26043692
2010 Survival of Hoxa13 homozygous mutants reveals a novel role in digit patterning and appendicular skeletal development. Developmental dynamics : an official publication of the American Association of Anatomists 27 20034107
2020 HOXA13 promotes colon cancer progression through β-catenin-dependent WNT pathway. Experimental cell research 26 32822724
2022 HOXA13 promotes gastric cancer progression partially via the FN1-mediated FAK/Src axis. Experimental hematology & oncology 25 35197128
2007 Elucidation, quantitative refinement, and in vivo utilization of the HOXA13 DNA binding site. The Journal of biological chemistry 25 17200107
2007 HOXA13 directly regulates EphA6 and EphA7 expression in the genital tubercle vascular endothelia. Developmental dynamics : an official publication of the American Association of Anatomists 25 17304517
2019 Mechanism of Snhg8/miR-384/Hoxa13/FAM3A axis regulating neuronal apoptosis in ischemic mice model. Cell death & disease 24 31165722
2011 Structural basis for sequence specific DNA binding and protein dimerization of HOXA13. PloS one 24 21829694
2019 Long noncoding RNA NEAT1 regulates the development of osteosarcoma through sponging miR-34a-5p to mediate HOXA13 expression as a competitive endogenous RNA. Molecular genetics & genomic medicine 22 31044561
2007 Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome. American journal of medical genetics. Part A 21 17935235
2017 Aberrant Expression of lncRNA ( HOXA11-AS1) and Homeobox A ( HOXA9, HOXA10, HOXA11, and HOXA13) Genes in Infertile Women With Endometriosis. Reproductive sciences (Thousand Oaks, Calif.) 20 29017417
2012 HOXA13 and HOXD13 expression during development of the syndactylous digits in the marsupial Macropus eugenii. BMC developmental biology 20 22235805
2009 A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies. Fertility and sterility 20 19591980
2020 The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13. Proceedings of the National Academy of Sciences of the United States of America 19 31896583
2019 Elevated HOXA13 expression promotes the proliferation and metastasis of gastric cancer partly via activating Erk1/2. OncoTargets and therapy 18 30881033
2018 Downregulation of HOXA13 sensitizes human esophageal squamous cell carcinoma to chemotherapy. Thoracic cancer 18 29757528
2005 A genomic approach to the identification and characterization of HOXA13 functional binding elements. Nucleic acids research 18 16321965
2020 Downregulated long noncoding RNA LUCAT1 inhibited proliferation and promoted apoptosis of cardiomyocyte via miR-612/HOXA13 pathway in chronic heart failure. European review for medical and pharmacological sciences 17 31957853
2022 Newt Hoxa13 has an essential and predominant role in digit formation during development and regeneration. Development (Cambridge, England) 16 35274676
2012 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway. Laboratory investigation; a journal of technical methods and pathology 16 22525429
2015 HoxA13 Regulates Phenotype Regionalization of Human Pregnant Myometrium. The Journal of clinical endocrinology and metabolism 15 26485220
2016 HoxA13 Stimulates Myometrial Cells to Secrete IL-1β and Enhance the Expression of Contraction-Associated Proteins. Endocrinology 14 26982635
2014 Severe manifestations of hand-foot-genital syndrome associated with a novel HOXA13 mutation. American journal of medical genetics. Part A 14 24934387
2008 A molecular footprint of limb loss: sequence variation of the autopodial identity gene Hoxa-13. Journal of molecular evolution 14 18855040
2001 Expression of the Hoxa-13 gene correlates to hepatitis B and C virus associated HCC. Biochemical and biophysical research communications 14 11237769
2019 Hoxa13 regulates expression of common Hox target genes involved in cartilage development to coordinate the expansion of the autopodal anlage. Development, growth & differentiation 13 30895612
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
2011 Hallux valgus interphalangeus and a novel mutation in HOXA13. Part of the broadening spectrum of Hand-Foot-Genital syndrome. Foot and ankle surgery : official journal of the European Society of Foot and Ankle Surgeons 13 21549968
2015 Dual genetic diagnoses: Atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1. American journal of medical genetics. Part A 12 26590955
2017 The role of HoxA11 and HoxA13 in the evolution of novel fin morphologies in a representative batoid (Leucoraja erinacea). EvoDevo 11 29214009
2011 Exploration of target genes of HOXA13 in esophageal squamous cell carcinoma cell line. Cancer letters 11 21893383
2009 Diminished vaginal HOXA13 expression in women with pelvic organ prolapse. Menopause (New York, N.Y.) 11 19423998
2003 Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias. Scandinavian journal of urology and nephrology 11 14675924
2023 Long non-coding RNA HOTTIP exerts an oncogenic function by regulating HOXA13 in nasopharyngeal carcinoma. Molecular biology reports 9 37392284
2021 HOXA13 in etiology and oncogenic potential of Barrett's esophagus. Nature communications 9 34099670
2020 Forced expression of HOXA13 confers oncogenic hallmarks to esophageal keratinocytes. Biochimica et biophysica acta. Molecular basis of disease 9 32222541
2019 Multifaceted Hoxa13 function in urogenital development underlies the Hand-Foot-Genital Syndrome. Human molecular genetics 9 30649340
2013 Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation. American journal of medical genetics. Part A 9 23532960
2021 Hoxa11 and Hoxa13 facilitate slow-twitch muscle formation in C2C12 cells and indirectly affect the lipid deposition of 3T3-L1 cells. Animal science journal = Nihon chikusan Gakkaiho 8 33738916
2017 A missense mutation of HOXA13 underlies hand-foot-genital syndrome in a Chinese family. Journal of genetics 8 28947713
2016 HOXA13 exerts a beneficial effect in albumin-induced epithelial-mesenchymal transition via the glucocorticoid receptor signaling pathway in human renal tubular epithelial cells. Molecular medicine reports 8 27176855
2014 Blast crisis Ph+ chronic myeloid leukemia with NUP98/HOXA13 up-regulating MSI2. Molecular cytogenetics 8 24971156
2022 Circ_0008726 promotes malignant progression of ESCC cells through miR-206/HOXA13 pathway. General thoracic and cardiovascular surgery 7 36190650
2021 HOXA13, Negatively Regulated by miR-139-5p, Decreases the Sensitivity of Gastric Cancer to 5-Fluorouracil Possibly by Targeting ABCC4. Frontiers in oncology 7 34094932
2022 HOXA13 promotes liver regeneration through regulation of BMP-7. Biochemical and biophysical research communications 6 35868069
2021 ETS Proto-Oncogene 1 Suppresses MicroRNA-128 Transcription to Promote Osteogenic Differentiation Through the HOXA13/β-Catenin Axis. Frontiers in physiology 6 33746773
2017 Upregulation of HOXA13 as a potential tumorigenesis and progression promoter of LUSC based on qRT-PCR and bioinformatics. International journal of clinical and experimental pathology 6 31966409
2012 The spatio-temporal patterning of Hoxa9 and Hoxa13 in the developing zebrafish enteric nervous system. Pediatric surgery international 6 21971947
2002 Mutational analysis of HOXD13 and HOXA13 genes in the triphalangeal thumb-brachyectrodactyly syndrome. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 6 12382951

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