Affinage

HOXA2

Homeobox protein Hox-A2 · UniProt O43364

Length
376 aa
Mass
41.0 kDa
Annotated
2026-06-10
68 papers in source corpus 38 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HOXA2 is a homeodomain transcription factor that functions as a selector gene for second branchial arch identity, with its loss causing homeotic transformation of second-arch neural crest-derived skeletal elements toward first-arch identity and its ectopic expression sufficient to impose hyoid/second-arch fate on first-arch crest (PMID:7903601, PMID:7903600, PMID:11076758, PMID:11076757). It acts within cranial neural crest cells, where the decision to maintain or downregulate HOXA2 is intrinsic to premigratory crest and where postmigratory crest retains plasticity such that temporally controlled HOXA2 inactivation still produces homeotic transformation (PMID:7600967, PMID:16221728). HOXA2 patterns the skeleton largely by repression: it acts upstream of Sox9 and Cbfa1 to inhibit chondrogenesis and intramembranous ossification, and it suppresses BMP-dependent osteoblast differentiation (PMID:9636074, PMID:17359301, PMID:29184513). Genome-wide it binds Hox and Pbx-Hox motifs and directly regulates downstream targets including Six2, Meox1, and Wnt-signaling genes, with cofactor dependency on Pbx/Meis (PMID:18164701, PMID:18321982, PMID:21245383, PMID:22223247). Its own transcription is governed by a modular cis-regulatory network—Krox20-dependent r3/r5 enhancers, a Hoxb1-responsive intronic r4 enhancer, an AP-2-dependent neural crest enhancer, and Sox-site-containing coding-exon r2 enhancers (PMID:7743939, PMID:8625806, PMID:10068641, PMID:17113575, PMID:19104046). In the somatosensory nervous system HOXA2 is necessary and sufficient to specify barrelette neuron identity and topographic whisker-map connectivity (PMID:16902088, PMID:26489473). Beyond transcription, HOXA2 activity is modulated post-translationally: a PPP1CB/KPC2 complex drives its cytoplasmic relocalization while stabilizing it, and HOXA2 promotes ubiquitin-independent proteasomal degradation of the E3 ligase RCHY1 to stabilize p53 (PMID:24244684, PMID:26303204, PMID:31323436). Loss-of-function HOXA2 nonsense mutations cause autosomal dominant bilateral microtia through impaired activation of the HMX1 enhancer (PMID:32649979).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1993 High

    Established the core developmental role of HOXA2 by showing it is required to specify second branchial arch identity, defining it as a Hox selector gene.

    Evidence Homologous recombination knockout in mouse with skeletal and histological analysis

    PMID:7903600 PMID:7903601

    Open questions at the time
    • Did not identify direct transcriptional targets
    • Did not resolve whether the requirement is in neural crest or surrounding tissue
  2. 1994 High

    Resolved whether arch-specific HOXA2 expression is environmentally imposed or prespecified, showing the maintenance/downregulation decision is intrinsic to premigratory crest.

    Evidence Rhombomere transplantation/grafting in chick embryos with in situ hybridization

    PMID:7600967

    Open questions at the time
    • Did not identify the molecular determinant of the intrinsic decision
  3. 1995 High

    Began dissecting the cis-regulatory logic of HOXA2 by defining separate r2 and r4 enhancers and showing cross-species conservation of the r2 element.

    Evidence Transgenic lacZ reporters with point mutagenesis in mouse and Drosophila

    PMID:7743939

    Open questions at the time
    • Did not identify trans-acting factors binding these enhancers
  4. 1996 High

    Identified the first direct upstream regulator of HOXA2, Krox20, acting through r3/r5 enhancer binding sites, and placed Eph receptor MDK1 downstream of HOXA2.

    Evidence In vitro binding, site-directed mutagenesis, transgenic reporters, and Krox20-null analysis; in situ hybridization in Hoxa2-null embryos

    PMID:8625806 PMID:8806819

    Open questions at the time
    • Did not show whether MDK1 regulation is direct
    • Did not define combinatorial inputs beyond Krox20 sites
  5. 1998 High

    Defined the mechanism of HOXA2 skeletal patterning as repression of the chondro-osteogenic program, placing it upstream of Sox9 and Cbfa1.

    Evidence Hoxa2-null analysis with Sox9 misexpression and molecular marker analysis

    PMID:9636074

    Open questions at the time
    • Did not establish whether Sox9/Cbfa1 regulation is direct
    • Did not identify intermediate effectors
  6. 1999 High

    Extended HOXA2 function into hindbrain neuronal patterning and showed cofactor dependency, with neuronal repression in second-arch crest requiring co-expressed Pbx and Meis.

    Evidence Single and compound Hoxa2/Hoxb2 mutant mice; P19 overexpression with Pbx/Meis cofactors; in ovo electroporation

    PMID:10230789 PMID:18164701

    Open questions at the time
    • Did not map direct neuronal target genes
    • Cofactor requirement shown in heterologous cells
  7. 2000 High

    Demonstrated HOXA2 is a sufficient selector of arch fate and that this requires coordinated tissue context, while positioning HOXA2 within the Hoxa1/Hoxb1 cross-regulatory network.

    Evidence Inducible gain-of-function in Xenopus; retroviral overexpression in chick; Hoxa1/Hoxa2 single and double mutant analysis

    PMID:10662633 PMID:11076757 PMID:11076758

    Open questions at the time
    • Did not identify the environmental cues required for coordinated transformation
  8. 2001 High

    Refined the r3/r5 enhancer model by showing Krox20 sites require additional combinatorial cis-elements (BoxA, RE1, RE3) for segmental activity.

    Evidence Systematic cis-element mutagenesis in transgenic embryos with Krox20-null validation

    PMID:11336508

    Open questions at the time
    • Did not identify factors binding the non-Krox20 elements
  9. 2005 High

    Showed HOXA2 acts cell-autonomously in postmigratory crest and is continuously required, revealing rapid downstream target responses (Alx4, Bapx1, Six2, Msx1) upon inactivation.

    Evidence Inducible Cre-ERT2 temporal Hoxa2 knockout with skeletal and expression analysis

    PMID:16221728

    Open questions at the time
    • Did not establish directness of the downstream target changes at this stage
  10. 2006 High

    Established HOXA2 as a direct target of Hoxb1 via a conserved intronic r4 enhancer with cooperating Hox/Pbx sites, and extended its role to sensory circuit assembly.

    Evidence Comparative genomics, in vitro binding, transgenic mutagenesis, ectopic HOXB1; conditional knockout with neuroanatomical tracing

    PMID:16902088 PMID:17113575

    Open questions at the time
    • Did not determine how HOXA2 directs topographic connectivity molecularly
  11. 2007 High

    Distinguished a cell-autonomous anti-chondrogenic activity of HOXA2 from its patterning role and linked HOXA2 to rhombomere-specific control of respiratory circuitry.

    Evidence Conditional Hoxa2 misexpression in Col2a1+ chondrocytes; Hoxa2-null respiratory analysis with r2-lineage tracing

    PMID:17359301 PMID:17897445

    Open questions at the time
    • Did not identify direct chondrocyte target genes
    • Respiratory mechanism from single lab
  12. 2008 High

    Identified direct in vivo transcriptional targets (Six2) and elaborated the embedded coding-exon and ultraconserved r4 cis-regulatory elements responsive to Hox/Pbx.

    Evidence ChIP, reporter assays, genetic epistasis (Six2/Meox2 mutants); cell transfection, ChIP, chick electroporation; transgenic coding-exon r2 enhancer mutagenesis

    PMID:18321982 PMID:18417536 PMID:19104046

    Open questions at the time
    • Did not establish the full set of direct targets
    • Sox factors binding the r2 coding-exon enhancer not functionally identified
  13. 2011 High

    Confirmed Meox1 as a direct HOXA2 target through binding-site mutagenesis and genetics, and revealed that Meox1 can occupy the same DNA sequences as HOXA2.

    Evidence ChIP, promoter mutagenesis, Meox1/Meox2 double mutant genetics, expression analysis

    PMID:21245383

    Open questions at the time
    • Did not resolve functional consequences of shared Meox1/HOXA2 site occupancy
  14. 2012 High

    Provided genome-wide binding landscape showing HOXA2 occupies thousands of sites at Hox/Pbx-Hox motifs and activates Wnt-beta-catenin signaling in its expression domain.

    Evidence ChIP-seq in mouse embryos with motif analysis and Wnt signaling assays in Hoxa2 mutants

    PMID:22223247

    Open questions at the time
    • Did not distinguish functional from incidental binding events
  15. 2013 Medium

    Uncovered a non-transcriptional function of HOXA2 in the proteasome pathway, degrading RCHY1 to stabilize p53, and a post-translational regulatory input via the proteasome and ubiquitin machinery.

    Evidence Co-precipitation, proteasome interaction and ubiquitination assays, p53 stabilization assays

    PMID:24244684

    Open questions at the time
    • Single lab
    • Physiological context of p53 stabilization not defined in vivo
  16. 2013 High

    Refined HOXA2 fate-mapping of the auricle and demonstrated it controls pinna morphogenesis partly via BMP signaling and Eya1.

    Evidence Genetic fate mapping, conditional gain- and loss-of-function, molecular pathway analysis

    PMID:24067355

    Open questions at the time
    • Did not establish whether BMP/Eya1 regulation is direct
  17. 2015 Medium

    Defined the molecular and domain requirements for HOXA2 post-translational regulation: RCHY1 degradation needs homeodomain plus C-terminus, and KPC2 induces HOXA2 nuclear exit to dampen transcriptional activity.

    Evidence Domain deletion analysis, proteasome assays, cross-species comparison; co-precipitation, BiFC, transcriptional reporter assays

    PMID:26303204 PMID:26496426

    Open questions at the time
    • Single lab
    • In vivo relevance of nuclear export regulation not established
  18. 2015 High

    Showed HOXA2 is necessary and sufficient to switch sensory neuron identity and that its skeletal selector activity is context-dependent across crest subpopulations.

    Evidence Conditional ectopic expression in dPrV neurons with tracing and morphology analysis; conditional ectopic expression in CNCC subpopulations with Edn1-Dlx5/6 manipulation

    PMID:25889273 PMID:26489473

    Open questions at the time
    • Did not identify the neuronal target genes mediating identity switch
  19. 2017 High

    Established that HOXA2 inhibits palatal osteogenesis by suppressing canonical BMP signaling, demonstrated by pharmacological rescue.

    Evidence Hoxa2-null analysis, primary MEPM culture, dorsomorphin BMP inhibition rescue

    PMID:29184513

    Open questions at the time
    • Did not identify direct HOXA2 targets within the BMP pathway
  20. 2019 Medium

    Defined a PPP1CB/KPC2 complex that paradoxically stabilizes HOXA2 while exporting it from the nucleus, creating a cytoplasmic reservoir that limits transcriptional activity.

    Evidence Co-immunoprecipitation, co-localization, nuclear export, transcriptional reporter, and ubiquitination assays

    PMID:31323436

    Open questions at the time
    • Single lab
    • Physiological trigger for nuclear export not defined
  21. 2020 Medium

    Showed HOXA2 expression is controlled epigenetically and promotes osteogenesis in stem-cell contexts, via HOTAIRM1-mediated promoter hypomethylation.

    Evidence HOTAIRM1 and HOXA2 knockdown/overexpression, DNMT1 ChIP, bisulfite sequencing, osteogenic differentiation assays

    PMID:32324272

    Open questions at the time
    • Single lab
    • Apparent pro-osteogenic role contrasts with anti-osteogenic patterning role; context dependence not reconciled
  22. 2020 Medium

    Linked HOXA2 to a human Mendelian disorder by showing nonsense mutations cause autosomal dominant bilateral microtia through impaired HMX1 enhancer activation.

    Evidence Next-generation sequencing in Chinese families; dual luciferase HMX1 enhancer reporter assays

    PMID:32649979

    Open questions at the time
    • Single functional readout (HMX1 enhancer)
    • Disease mechanism not validated in vivo
  23. 2021 Medium

    Revealed that in vivo HOXA2 binding specificity is not fully explained by intrinsic affinity, and that HOXA2 forms heterodimers with HOXA3.

    Evidence ChIP-seq, in vitro DNA binding, heterodimer co-immunoprecipitation

    PMID:34940502

    Open questions at the time
    • Single lab
    • Functional significance of HOXA2-HOXA3 heterodimers unknown
  24. 2024 Medium

    Identified NSD2/H3K36me2-mediated repression of the HOXA2 locus as a regulator of mesenchymal stem cell osteogenesis relevant to osteoporosis.

    Evidence ChIP, luciferase assays, NSD2 knockdown/overexpression, OVX mouse model with micro-CT

    PMID:38996954

    Open questions at the time
    • Single lab
    • Direct HOXA2 effectors in this context not defined
  25. 2025 Medium

    Extended HOXA2 transcriptional activity to adult disease by showing it activates SIRT1 to reduce ER stress and attenuate renal fibrosis.

    Evidence HOXA2 overexpression in vivo (AAV), ChIP at SIRT1 promoter, DNMT1 methylation analysis, deacetylase and ATF6 acetylation assays

    PMID:41466054

    Open questions at the time
    • Single lab
    • Role of HOXA2 in normal adult kidney not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HOXA2 achieves in vivo target selectivity given that its top ChIP-seq motif is not bound in vitro, and how its cofactor, heterodimer, and post-translational regulatory inputs are integrated to specify distinct skeletal, neuronal, and adult-tissue programs, remains unresolved.
  • No structural model of HOXA2-cofactor-DNA complexes
  • Mechanism reconciling pro- and anti-osteogenic roles unknown
  • Physiological triggers of cytoplasmic relocalization undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 4
Partners
HOXA3KPC2MEISMEOX1PBXPPP1CBRCHY1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Hoxa2 acts as a selector gene for second branchial arch identity: homozygous knockout mice show homeotic transformation of second arch neural crest-derived skeletal elements into first arch identity, establishing Hoxa2 as required for second arch patterning. Homologous recombination knockout in mouse; skeletal staining and histological analysis Cell High 7903600 7903601
1994 Hoxa2 expression in rhombomere 2 neural tube and r4 neural crest is independently regulated: r2-derived neural crest downregulates Hoxa2 while r4-derived neural crest maintains Hoxa2 expression, and this decision is intrinsic (prespecified) to the premigratory neural crest cell population, as shown by rhombomere transplantation experiments. Rhombomere transplantation/grafting experiments in chick embryos; in situ hybridization Development (Cambridge, England) High 7600967
1995 Three independent enhancers control Hoxa2 expression: one drives rhombomere 2-specific expression and one drives rhombomere 4-specific expression; the r2 enhancer is functionally conserved and active in Drosophila head segments paralleling proboscipedia expression domain. Transgenic mouse enhancer analysis with lacZ reporters; point mutation of cis-elements; cross-species (Drosophila) reporter assay Development (Cambridge, England) High 7743939
1996 Krox-20 (Egr2) directly regulates Hoxa2 transcription in rhombomeres 3 and 5: an r3/r5 enhancer in the 5' flanking region of Hoxa2 contains two Krox-20 binding sites whose mutation abolishes r3/r5 activity; ectopic Krox-20 in r4 can transactivate the Hoxa2 reporter, and Hoxa2 r3 expression is lost in Krox-20 null mutants. Transgenic lacZ reporter analysis; deletion mapping; in vitro binding and competition assays with bacterially expressed Krox-20; site-directed mutagenesis; analysis in Krox-20 null mutant embryos Development (Cambridge, England) High 8625806
1996 Hoxa2 is required for MDK1 (Eph receptor RTK) expression in rhombomere 3: MDK1 shows selective loss of expression in r3 and altered expression in other rhombomeres in Hoxa2 null mutant embryos, placing MDK1 downstream of Hoxa2 in the morphogenetic signaling cascade. Analysis of MDK1 expression in Hoxa2 null mutant embryos by in situ hybridization Developmental biology Medium 8806819
1998 Hoxa2 inhibits chondrogenesis and intramembranous ossification in the second branchial arch: it acts upstream of Sox9 (whose expression domain expands into the normal Hoxa2 domain in Hoxa2 mutants), and Cbfa1 is upregulated in second arch of Hoxa2 mutants, suggesting Hoxa2 prevents Cbfa1 induction to inhibit dermal bone formation. Analysis of Hoxa2 null mutant embryos; Sox9 misexpression experiments; expression analysis of Sox9 and Cbfa1 Development (Cambridge, England) High 9636074
1999 AP-2 family transcription factors directly regulate Hoxa2 neural crest-specific expression: an AP-2 binding site in the Hoxa2 neural crest enhancer is required for cranial neural crest expression (but not hindbrain expression); AP-2 family members transactivate the enhancer in cell culture and transgenic embryos. Transgenic enhancer deletion analysis; site-directed mutagenesis; cell culture co-transfection assays; analysis in AP-2α null mutant embryos Development (Cambridge, England) High 10068641
1999 Hoxa2 and Hoxb2 control both anteroposterior and dorsoventral patterning of neuronal subtypes in the rostral hindbrain: they differentially regulate, in a rhombomere-specific manner, gene expression in broad D-V restricted domains and narrow longitudinal columns, and functionally synergize in controlling ventral neuronal subtypes in r3. Analysis of Hoxa2 and Hoxb2 single and compound mutant mice; in situ hybridization for neuronal markers Neuron High 10230789
1999 Hoxa2 normally represses neurogenic potential of second arch cranial neural crest cells, and Hoxa2 overexpression reduces neuronal differentiation frequency only when Pbx and Meis cofactors are co-expressed. Analysis of facial ganglia in Hoxa2 mutant mice; overexpression of Hoxa2 in P19 embryonal carcinoma cells with/without Pbx and Meis cofactors; in ovo electroporation in chick Developmental biology Medium 18164701
2000 Hoxa2 induction at postmigratory stages in Xenopus is sufficient to cause mirror-image homeotic transformation of jaw elements (mandibular to hyoid morphology), demonstrating Hoxa2 is a selector of hyoid fate and that skeletal pattern of mandibular crest is not committed before migration. Inducible Hoxa2 gain-of-function system in Xenopus embryos at defined neural crest migratory stages Development (Cambridge, England) High 11076758
2000 Hoxa2 overexpression in chick first branchial arch neural crest transforms first arch cartilages into second arch elements; however, transformation requires global Hoxa2 overexpression in both crest and surrounding tissue, not neural crest alone, indicating neural crest requires environmental cues to form a coordinated pattern. In ovo overexpression via retroviral vectors in chick first arch; skeletal marker analysis Development (Cambridge, England) High 11076757
2000 Hoxa1 activity is required to set the anterior limit of Hoxb1 expression at the presumptive r3/r4 boundary; failure to do so in Hoxa1 mutants initiates a cascade of gene misexpressions affecting r2-r5 patterning, and Hoxa1 and Hoxa2 function both independently and synergistically in craniofacial development. Generation and analysis of Hoxa1, Hoxa2 single and double mutant mice; gene expression analysis Development (Cambridge, England) High 10662633
2001 Segmental regulation of Hoxa2 in r3/r5 requires five cis-acting regions in addition to conserved Krox20 binding sites: a CTTT (BoxA) motif adjacent to Krox20 sites and two elements sharing TCT motifs (RE1 and RE3) are essential, revealing combinatorial complexity of Krox20-dependent enhancer activity. Functional deletion and mutation analysis of mouse Hoxa2 r3/r5 enhancer in transgenic embryos; analysis in Krox20 mutant background Developmental biology High 11336508
2005 Hoxa2 is selectively required in cranial neural crest cells for hyoid skeletal morphogenesis; temporally controlled Cre-ERT2-mediated Hoxa2 deletion after NCC migration into branchial arches still results in homeotic transformation, showing hyoid NCCs retain plasticity after migration and require Hoxa2 as an integral morphogenetic component; rapid downstream changes in Alx4, Bapx1, Six2, and Msx1 expression follow Hoxa2 inactivation. Conditional Cre-ERT2 temporal Hoxa2 knockout in mouse; skeletal analysis; expression analysis of downstream targets Development (Cambridge, England) High 16221728
2006 Hoxa2 expression in r4 is regulated by a conserved intronic enhancer containing three bipartite Hox/Pbx binding sites (PH1-PH3) and a Pbx-Prep/Meis site; these sites cooperate and are required for enhancer activity; the r4 enhancer mediates response to ectopic HOXB1, establishing Hoxa2 as a direct target of Hoxb1 within a cross-regulatory Hox gene network for r4. Comparative genomic analysis of Hoxa2 locus across 12 vertebrate species; in vitro binding studies; mutational analysis in transgenic mouse and chicken embryos; ectopic HOXB1 expression Developmental biology High 17113575
2006 Hoxa2 expression in the principal sensory nucleus prevents ectopic trigeminal nerve projection to the cerebellum, promotes selective arborization of whisker-related afferents, and is required for topographic connectivity to the thalamus and formation of whisker-related maps in the postnatal somatosensory brain. Hoxa2 conditional knockout; rhombomere lineage tracing; neuroanatomical tracing of sensory maps Science (New York, N.Y.) High 16902088
2007 Persistent Hoxa2 expression in chondrogenic cells (Collagen 2α1-expressing) inhibits chondrocyte differentiation causing chondrodysplasia with delayed cartilage hypertrophy, mineralization, and ossification, demonstrating an anti-chondrogenic activity of Hoxa2 that is distinct from its patterning function. Conditional Cre-mediated misexpression of Hoxa2 in Col2a1-expressing chondrogenic cells in transgenic mice; histological and molecular analysis Differentiation; research in biological diversity High 17359301
2007 Hoxa2 inactivation eliminates a transient control of inspiratory amplitude in the first hours after birth, linked to r2-derived rostral pontine areas; this is distinct from Krox20 function in respiratory frequency, demonstrating rhombomere-specific Hox-dependent control of distinct respiratory circuit components. Hoxa2 knockout mouse analysis of respiratory function; r2-lineage tracing with Hoxa2 enhancer elements Neural development Medium 17897445
2008 A Hox-Pbx responsive cis-regulatory element embedded in the coding sequence of Hoxa2 functions as an r4 regulatory element: it responds to paralog group 1 and 2 Hox proteins and Pbx cofactors (shown by cell transfection and ChIP), cooperates with the intronic r4 enhancer, and is embedded in a 205-bp ultraconserved genomic element (UCE) shared by all vertebrate genomes. Cell transfection assays; chromatin immunoprecipitation (ChIP); chick embryo hindbrain electroporation with reporter constructs; comparative genomics Nucleic acids research High 18417536
2008 Six2 is a direct downstream target of Hoxa2 in vivo: Six2 is ectopically expressed in second arch of Hoxa2 mutants, and Six2/Meox2 double mutants show branchial arch skeletal defects overlapping Hoxa2 targets; ectopic Six2 contributes to the Hoxa2 mutant phenotype and may mediate Hoxa2 control over the IGF pathway. Genetic epistasis analysis in Hoxa2 and Six2/Meox2 mutant mice; chromatin immunoprecipitation for Hoxa2 binding; reporter assays Development (Cambridge, England) High 18321982
2008 A cis-regulatory module embedded in the second coding exon of Hoxa2 directs r2-specific expression via five elements including two Sox binding sites; this coding region-embedded enhancer is highly conserved and functions in concert with other elements for r2 identity. Deletion and mutational analysis of Hoxa2 coding exon enhancer in transgenic mouse embryos; reporter expression analysis Proceedings of the National Academy of Sciences of the United States of America High 19104046
2009 Hoxa2 plays a direct role in palate development independent of tongue effects: Hoxa2 is expressed in the developing palate (E12.5-E15.5); Hoxa2-null palate organ cultures show decreased fusion rates even without tongue; Hoxa2 knockdown decreases fusion; Hoxa2 represses downstream targets Msx1, Bmp4, Barx1, and Ptx1 in the palate. Organ culture of Hoxa2 null palates; antisense retroviral knockdown; expression analysis of downstream targets; cell proliferation assays Developmental dynamics : an official publication of the American Association of Anatomists Medium 19653318
2011 Meox1 is a direct transcriptional target of Hoxa2 in second branchial arch: Meox1 expression is downregulated in Hoxa2 mutant second arch; Hoxa2 binds the Meox1 proximal promoter by ChIP; two conserved Hoxa2 binding sites are required for Hoxa2-dependent Meox1 promoter activation; loss of Meox1 and Meox2 results in malformation of two of three Hoxa2-patterned skeletal elements; Meox1 can bind the same DNA sequences as Hoxa2 on its functional target genes. Chromatin immunoprecipitation (ChIP); promoter mutagenesis; genetic analysis of Meox1/Meox2 double mutants; expression analysis in Hoxa2 null embryos Molecular and cellular biology High 21245383
2012 Genome-wide ChIP-seq mapping of Hoxa2 binding sites reveals large genome coverage potentially regulating thousands of genes; predominant binding motifs correspond to Hox and Pbx-Hox recognition sequences; Hoxa2 targets include Wnt-signaling pathway genes; canonical Wnt-β-catenin signaling is active specifically in the Hoxa2 expression domain and is undetectable in Hoxa2 mutant embryos. ChIP-seq in mouse embryos; sequence motif analysis; in vivo examination of Wnt-β-catenin signaling in Hoxa2 mutant embryos Nucleic acids research High 22223247
2013 Hoxa2 interacts with 20S proteasome subunits and RCHY1 (PIRH2, an E3 ubiquitin ligase targeting p53), promotes proteasomal degradation of RCHY1 in an ubiquitin-independent manner, and thereby alters RCHY1-mediated ubiquitination of p53 and promotes p53 stabilization. Co-precipitation; proteasome interaction assays; ubiquitination assays; p53 stabilization assays PloS one Medium 24244684
2013 The mouse auricle (pinna) derives from Hoxa2-expressing neural crest mesenchyme of the second pharyngeal arch (not from a first/second arch composite as previously proposed); ectopic Hoxa2 expression in first arch neural crest is sufficient to induce complete pinna duplication and loss of external auditory canal; Hoxa2 partly controls pinna morphogenesis through BMP signaling and Eya1 expression. Genetic fate mapping; conditional gain-of-function of Hoxa2 in first arch neural crest; skeletal and molecular analysis; Hoxa2 null and late conditional knockout Development (Cambridge, England) High 24067355
2015 Hoxa2 is necessary and sufficient to specify barrelette neuron identity in the ventral principal sensory nucleus (vPrV): ectopic Hoxa2 expression in dorsal PrV neurons is sufficient to attract whisker-related afferents, induce asymmetric dendrite arbors, allow ectopic barrelette map formation, and redirect dPrV axonal targeting into a whisker-related barreloid map. Conditional ectopic Hoxa2 expression in dPrV neurons; neuroanatomical tracing; dendritic morphology analysis; axonal projection analysis Cell reports High 26489473
2015 Hoxa2 degradation of RCHY1 involves both 19S and 20S proteasome complexes, requires both the Hoxa2 homeodomain and C-terminal moiety; the homeodomain alone mediates RCHY1 binding (shared with other Hox proteins) but is not sufficient for degradation induction; this RCHY1 degradation activity is evolutionarily conserved among vertebrates. Domain deletion analysis; proteasome complex interaction assays; cross-species Hox protein comparison PloS one Medium 26496426
2015 KPC2, an adapter protein of the KPC ubiquitin ligase complex, directly interacts with Hoxa2 and induces its nuclear exit, reducing Hoxa2 transcriptional activity; Kpc2 is expressed in areas overlapping Hoxa2 expression domain in mouse embryos. Co-precipitation; bimolecular fluorescence complementation assays; gene expression analysis; transcriptional reporter assays Biochimica et biophysica acta Medium 26303204
2015 Ectopic Hoxa2 expression in Hox-negative cranial neural crest causes distinct context-dependent phenotypes: transformation of proximal first pharyngeal arch (PA1) derivatives into PA2-like structures (supernumerary styloid process), but impairs rather than transforms other CNCC subpopulations; the hyomandibular-ceratohyal dorsoventral boundary of PA2 passes through the middle of the styloid process. Conditional ectopic Hoxa2 expression in different CNCC subpopulations; Edn1-Dlx5/6 pathway manipulation; skeletal and molecular analysis Developmental biology High 25889273
2017 Hoxa2 inhibits osteogenic differentiation of palatal mesenchyme by suppressing BMP signaling: Hoxa2 null palatal shelves show increased expression of osteoblast markers (Runx2, Sp7, AlpI), increased canonical BMP signaling, and increased osteoprogenitor proliferation; blocking BMP signaling in Hoxa2-null primary MEPM cells with dorsomorphin restores wild-type proliferation and differentiation levels. Analysis of Hoxa2 null embryos; primary MEPM cell culture; BMP signaling inhibition with dorsomorphin; bone matrix deposition assays Frontiers in physiology High 29184513
2019 HOXA2 activity is regulated by a molecularly interacting complex comprising PPP1CB (PP1 phosphatase catalytic subunit) and KPC2 (KPC E3 ubiquitin ligase adapter): PPP1CB interacts with HOXA2 and co-localizes with KPC2 in the cytoplasm; together PPP1CB and KPC2 inhibit HOXA2 transcriptional activity by promoting nuclear export while paradoxically stabilizing HOXA2 via de-ubiquitination, creating a cytoplasmic HOXA2 store. Co-immunoprecipitation; co-localization studies; nuclear export assays; transcriptional reporter assays; ubiquitination assays Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31323436
2020 HOTAIRM1 lncRNA promotes osteogenesis of human dental follicle stem cells by epigenetically upregulating HOXA2: HOTAIRM1 binds to CpG islands of the HOXA2 promoter, inhibits DNMT1 enrichment at the promoter causing hypomethylation, and induces HOXA2 expression; knockdown of HOXA2 inhibits osteogenic differentiation. HOTAIRM1 knockdown/overexpression; HOXA2 knockdown; DNMT1 ChIP assays; bisulfite sequencing of HOXA2 promoter; osteogenic differentiation assays Journal of cellular physiology Medium 32324272
2020 Two HOXA2 nonsense mutations found in Chinese families with autosomal dominant bilateral microtia (c.637A>T, p.Lys213*; c.703C>T, p.Gln235*) impair HOXA2-mediated activation of the long-range enhancer of HMX1, a transcription factor required for ear development, as shown by dual luciferase reporter assay. Next-generation sequencing; dual luciferase reporter assays for HMX1 enhancer activation Gene Medium 32649979
2021 HOXA2 and HOXA3 can form heterodimers, and the highest-enriched DNA binding motif in HOXA2 ChIP-seq peaks is not recognized by HOXA2 in vitro, highlighting that HOX binding specificity in vivo is not fully explained by in vitro affinity. ChIP-seq; in vitro DNA binding assays; heterodimer co-immunoprecipitation Journal of developmental biology Medium 34940502
2024 NSD2-mediated H3K36me2 dimethylation at the HOXA2 locus represses HOXA2 transcription in bone marrow mesenchymal stem cells (BMSCs), inhibiting osteogenic differentiation; ChIP confirmed NSD2 and H3K36me2 occupancy at HOXA2; NSD2 inhibition increases RUNX2 and BSP expression and alleviates OVX-induced osteoporosis in mice. ChIP assays; luciferase reporter assay; NSD2 shRNA knockdown and lentiviral overexpression; in vivo OVX mouse model with micro-CT Cellular signalling Medium 38996954
2025 HOXA2 binds the SIRT1 promoter and enhances SIRT1 transcription and deacetylase activity; increased SIRT1 leads to ATF6 deacetylation and downregulation, reducing ER stress; DNMT1-mediated promoter methylation suppresses HOXA2 in renal fibrosis; HOXA2 overexpression attenuates renal dysfunction and fibrosis in UUO mice. HOXA2 overexpression plasmid transfection and AAV delivery in vivo; ChIP for HOXA2 at SIRT1 promoter; DNMT1 promoter methylation analysis; deacetylase activity assays; ATF6 acetylation analysis Communications biology Medium 41466054

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell 538 7903601
1993 Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 477 7903600
1994 Hoxa-2 expression in normal and transposed rhombomeres: independent regulation in the neural tube and neural crest. Development (Cambridge, England) 215 7600967
1995 Evolutionary-conserved enhancers direct region-specific expression of the murine Hoxa-1 and Hoxa-2 loci in both mice and Drosophila. Development (Cambridge, England) 185 7743939
1998 Hoxa-2 restricts the chondrogenic domain and inhibits bone formation during development of the branchial area. Development (Cambridge, England) 179 9636074
2000 Ectopic Hoxa2 induction after neural crest migration results in homeosis of jaw elements in Xenopus. Development (Cambridge, England) 165 11076758
1996 Segmental expression of Hoxa-2 in the hindbrain is directly regulated by Krox-20. Development (Cambridge, England) 163 8625806
1999 Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron 158 10230789
2000 Homeotic transformation of branchial arch identity after Hoxa2 overexpression. Development (Cambridge, England) 151 11076757
2000 Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse. Development (Cambridge, England) 141 10662633
2006 Hoxa2- and rhombomere-dependent development of the mouse facial somatosensory map. Science (New York, N.Y.) 107 16902088
2005 Temporal requirement of Hoxa2 in cranial neural crest skeletal morphogenesis. Development (Cambridge, England) 102 16221728
1999 Regulation of Hoxa2 in cranial neural crest cells involves members of the AP-2 family. Development (Cambridge, England) 98 10068641
1996 The expression pattern of the mouse receptor tyrosine kinase gene MDK1 is conserved through evolution and requires Hoxa-2 for rhombomere-specific expression in mouse embryos. Developmental biology 79 8806819
2013 Mouse Hoxa2 mutations provide a model for microtia and auricle duplication. Development (Cambridge, England) 76 24067355
2008 A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family. American journal of human genetics 76 18394579
1999 Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants. Development (Cambridge, England) 68 10529419
2006 Expression of Hoxa2 in rhombomere 4 is regulated by a conserved cross-regulatory mechanism dependent upon Hoxb1. Developmental biology 66 17113575
2012 Genome-wide occupancy links Hoxa2 to Wnt-β-catenin signaling in mouse embryonic development. Nucleic acids research 61 22223247
2008 An ultraconserved Hox-Pbx responsive element resides in the coding sequence of Hoxa2 and is active in rhombomere 4. Nucleic acids research 56 18417536
2008 A regulatory module embedded in the coding region of Hoxa2 controls expression in rhombomere 2. Proceedings of the National Academy of Sciences of the United States of America 54 19104046
2007 Fate-mapping the mammalian hindbrain: segmental origins of vestibular projection neurons assessed using rhombomere-specific Hoxa2 enhancer elements in the mouse embryo. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 17804628
2005 Hoxa2 knockdown in Xenopus results in hyoid to mandibular homeosis. Developmental dynamics : an official publication of the American Association of Anatomists 48 16222714
2008 Six2 functions redundantly immediately downstream of Hoxa2. Development (Cambridge, England) 41 18321982
2002 Conservation and diversity in the cis-regulatory networks that integrate information controlling expression of Hoxa2 in hindbrain and cranial neural crest cells in vertebrates. Developmental biology 41 12027433
2006 Evolution of cis elements in the differential expression of two Hoxa2 coparalogous genes in pufferfish (Takifugu rubripes). Proceedings of the National Academy of Sciences of the United States of America 40 16569696
2013 HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss. Human mutation 38 23775976
2020 lncRNA HOTAIRM1 promotes osteogenesis of hDFSCs by epigenetically regulating HOXA2 via DNMT1 in vitro. Journal of cellular physiology 37 32324272
2019 Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and Its Clinicopathological Characteristics in Colorectal Cancer. Frontiers in oncology 35 31165042
2009 Ascorbic acid reverses valproic acid-induced inhibition of hoxa2 and maintains glutathione homeostasis in mouse embryos in culture. Cellular and molecular neurobiology 35 19655241
2015 Distinct effects of Hoxa2 overexpression in cranial neural crest populations reveal that the mammalian hyomandibular-ceratohyal boundary maps within the styloid process. Developmental biology 31 25889273
2001 Differences in Krox20-dependent regulation of Hoxa2 and Hoxb2 during hindbrain development. Developmental biology 31 11336508
2002 Targeted insertion results in a rhombomere 2-specific Hoxa2 knockdown and ectopic activation of Hoxa1 expression. Developmental dynamics : an official publication of the American Association of Anatomists 30 12412013
2015 Hoxa2 Selects Barrelette Neuron Identity and Connectivity in the Mouse Somatosensory Brainstem. Cell reports 29 26489473
2017 Hoxa2 Inhibits Bone Morphogenetic Protein Signaling during Osteogenic Differentiation of the Palatal Mesenchyme. Frontiers in physiology 27 29184513
2007 Distinct roles of Hoxa2 and Krox20 in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening. Neural development 27 17897445
2007 Expression of Hoxa2 in cells entering chondrogenesis impairs overall cartilage development. Differentiation; research in biological diversity 25 17359301
2011 Transient activation of meox1 is an early component of the gene regulatory network downstream of hoxa2. Molecular and cellular biology 22 21245383
2016 Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non-syndromic microtia and distinctive ear morphology. Clinical genetics 21 27503514
2010 Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia. International journal of pediatric otorhinolaryngology 21 20542577
2020 Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia. Gene 17 32649979
2013 The homeodomain transcription factor Hoxa2 interacts with and promotes the proteasomal degradation of the E3 ubiquitin protein ligase RCHY1. PloS one 17 24244684
2001 Coordinated expression of Hoxa2, Hoxd1 and Pax6 in the developing diencephalon. Neuroreport 15 11209945
2009 Hoxa2 plays a direct role in murine palate development. Developmental dynamics : an official publication of the American Association of Anatomists 14 19653318
1999 Differential expression of Hoxa-2 protein along the dorsal-ventral axis of the developing and adult mouse spinal cord. Developmental dynamics : an official publication of the American Association of Anatomists 14 10536059
2004 The Hoxa2 enhancer 2 contains a critical Hoxa2 responsive regulatory element. Biochemical and biophysical research communications 12 15033486
2000 Temporal and spatial expression of Hoxa-2 during murine palatogenesis. Cellular and molecular neurobiology 12 10789828
2007 Altered neuronal lineages in the facial ganglia of Hoxa2 mutant mice. Developmental biology 11 18164701
2015 KPC2 relocalizes HOXA2 to the cytoplasm and decreases its transcriptional activity. Biochimica et biophysica acta 10 26303204
2010 Expressing Hoxa2 across the entire endochondral skeleton alters the shape of the skeletal template in a spatially restricted fashion. Differentiation; research in biological diversity 10 20034726
2015 Analyses of fugu hoxa2 genes provide evidence for subfunctionalization of neural crest cell and rhombomere cis-regulatory modules during vertebrate evolution. Developmental biology 9 26632170
2025 Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival. Cell death and differentiation 7 39833374
2016 Mutational analysis of GSC, HOXA2 and PRKRA in 106 Chinese patients with microtia. International journal of pediatric otorhinolaryngology 7 28109504
2015 Molecular Analysis of the HOXA2-Dependent Degradation of RCHY1. PloS one 7 26496426
2019 HOXA2 activity regulation by cytoplasmic relocation, protein stabilization and post-translational modification. Biochimica et biophysica acta. Gene regulatory mechanisms 6 31323436
2013 Molecular study of a Hoxa2 gain-of-function in chondrogenesis: a model of idiopathic proportionate short stature. International journal of molecular sciences 6 24129174
2004 Early stages of oligodendrocyte development in the embryonic murine spinal cord proceed normally in the absence of Hoxa2. Glia 6 15326611
2024 NSD2-mediated H3K36me2 exacerbates osteoporosis via activation of hoxa2 in bone marrow mesenchymal stem cells. Cellular signalling 5 38996954
1999 Analysis of murine HOXA-2 activity in Drosophila melanogaster. Developmental genetics 5 10322642
2021 Silencing Hoxa2 reverses dexamethasone-induced dysfunction of MC3T3-E1 osteoblasts and osteoporosis in rats. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 4 33984197
2011 Conditional Tet-regulated over-expression of Hoxa2 in CG4 cells increases their proliferation and delays their differentiation into oligodendrocyte-like cells expressing myelin basic protein. Cellular and molecular neurobiology 4 21479584
2021 Molecular Characterization of HOXA2 and HOXA3 Binding Properties. Journal of developmental biology 3 34940502
2016 Mutational Analysis of TCOF1, GSC, and HOXA2 in Patients With Treacher Collins Syndrome. The Journal of craniofacial surgery 2 27526242
2013 Differential distribution of the Ca (2+) regulator Pcp4 in the branchial arches is regulated by Hoxa2. PloS one 2 23671666
2024 Association between mandibular prognathism and Matrilin-1, bone morphogenic protein, Tyr67Asn, homeobox protein hox-A2, Rho-GTPase activating protein, and Myosin 1H genes in the Indian population. Folia medica 1 39257274
2016 Functional and Comparative Genomics of Hoxa2 Gene cis-Regulatory Elements: Evidence for Evolutionary Modification of Ancestral Core Element Activity. Journal of developmental biology 1 29615583
2011 Postnatal growth defect in mice upon persistent Hoxa2 expression in the chondrogenic cell lineage. Differentiation; research in biological diversity 1 22093256
2025 HOXA2 exerts anti-renal fibrosis effects through reducing endoplasmic reticulum stress via the upregulation of SIRT1. Communications biology 0 41466054

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