Affinage

PAX9

Paired box protein Pax-9 · UniProt P55771

Length
341 aa
Mass
36.3 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAX9 is a paired-domain transcription factor that directs reciprocal mesenchymal-epithelial signaling during the development of teeth, palate, axial skeleton, pharyngeal organs, and taste-bearing epithelia (PMID:9732271, PMID:10556064). Through its paired domain it binds defined recognition sequences (e.g., the e5 site) and transactivates target promoters, with disease-associated missense and frameshift mutations selectively abolishing DNA binding and transactivation of Bmp4 and Msx1 while sparing nuclear localization and protein partner interaction, establishing loss of DNA binding as the predominant pathogenic mechanism in PAX9-associated oligodontia (PMID:7649395, PMID:14607846, PMID:19429910). In tooth and palate mesenchyme PAX9 sustains an inductive program—activating Bmp4, Msx1, Fgf3/Fgf10, and Osr2—and acts in part by physically associating with and synergizing with MSX1 on the Msx1 and Bmp4 promoters (PMID:9732271, PMID:16651263, PMID:20123092, PMID:24173808); Osr2 lies genetically downstream, as Osr2 knocked into the Pax9 locus rescues Pax9-dependent palate morphogenesis (PMID:21420399, PMID:24173808). PAX9 also gates Wnt signaling during palatogenesis, directly binding and repressing the Wnt antagonists Dkk1 and Dkk2 so that reducing Dkk1 or Wise rescues Pax9-null palatal clefts (PMID:28893947, PMID:32390226, PMID:28692808). In the axial skeleton PAX9 functions redundantly with PAX1 to drive sclerotome chondrogenesis through direct activation of the Bapx1 promoter downstream of Shh (PMID:10556064, PMID:12490554), and it is further required in pharyngeal endoderm for cardiovascular outflow morphogenesis via genetic interaction with Tbx1 (PMID:31444215) and for thymic epithelial development (PMID:11932925). Beyond development, PAX9 can act as a context-dependent transcriptional repressor: it recruits the PLU-1/NuRD complex through a conserved VP motif (PMID:12657635) and occupies distal enhancers genome-wide in small-cell lung cancer cells to restrict enhancer activity and suppress differentiation genes (PMID:34341073).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 Medium

    Established that PAX9 is a sequence-specific DNA-binding protein, defining the biochemical basis for its later-discovered transcriptional roles.

    Evidence In vitro EMSA with the Drosophila even-skipped e5 paired-domain recognition site

    PMID:7649395

    Open questions at the time
    • No endogenous mammalian target identified at this stage
    • Activator vs. repressor function not resolved
  2. 1996 Medium

    Resolved that PAX9 transactivation is dose- and isoform-dependent, with the N-terminal/paired region negatively regulating C-terminal activation domains.

    Evidence Zebrafish Pax9a/Pax9b splice isoform reporter assays with paired-domain binding sites

    PMID:8900176

    Open questions at the time
    • Functional relevance of dual isoforms in mammals unknown
    • Switch between activation and repression not mechanistically defined
  3. 1998 High

    Demonstrated that Pax9 is required for the inductive capacity of tooth mesenchyme, placing it at the top of an odontogenic signaling cascade.

    Evidence Pax9 null mouse with in situ analysis of Bmp4, Msx1, Lef1 at the tooth bud stage

    PMID:9732271

    Open questions at the time
    • Whether Bmp4/Msx1/Lef1 are direct vs. indirect targets not shown
    • Cell-autonomous mechanism within mesenchyme not dissected
  4. 1999 High

    Revealed functional redundancy between Pax1 and Pax9 in vertebral column formation, explaining the absence of axial defects in single Pax9 mutants.

    Evidence Pax1/Pax9 compound mutant mice with histology, BrdU, TUNEL, in situ hybridization

    PMID:10556064

    Open questions at the time
    • Shared vs. distinct downstream targets not defined here
    • Molecular basis of Pax9 compensatory upregulation unknown
  5. 2000 Medium

    Positioned Uncx4.1 upstream of Pax9 in the caudolateral sclerotome pathway, beginning to assemble the regulatory hierarchy controlling axial Pax9 expression.

    Evidence Uncx4.1 knockout mouse skeletal phenotype compared with Pax1/Pax9 double mutants

    PMID:10804168

    Open questions at the time
    • Direct vs. indirect regulation of Pax9 not established
    • No biochemical link demonstrated
  6. 2003 High

    Identified Bapx1 as a direct Pax1/Pax9 transcriptional target downstream of Shh, connecting Pax9 to sclerotome chondrogenic differentiation.

    Evidence Promoter transactivation/binding assays plus retroviral Pax1 gain-of-function in chick presomitic mesoderm

    PMID:12490554

    Open questions at the time
    • Direct Pax9 (vs. Pax1) binding to Bapx1 not separately quantified
    • Cofactor requirements at the promoter not defined
  7. 2003 Medium

    Defined PLU-1 as a VP-motif-dependent co-repressor of PAX9, revealing that PAX9 can actively repress transcription.

    Evidence Yeast two-hybrid, VP-motif mutagenesis, and repression reporter assays

    PMID:12657635

    Open questions at the time
    • Endogenous PAX9-repressed genes not identified
    • In vivo relevance of PLU-1 interaction untested
  8. 2003 High

    Established that oligodontia-causing PAX9 paired-domain mutations (219InsG, R28P) abolish DNA binding via loss-of-function rather than dominant-negative mechanism.

    Evidence EMSA, reporter assays, immunofluorescence localization, and co-transfection dominant-negative tests of mutant PAX9

    PMID:14607846 PMID:14689302

    Open questions at the time
    • Genotype-phenotype severity correlation not yet mapped
    • Effect on partner protein function not assessed
  9. 2005 High

    Showed that a minimum Pax9 gene dosage is required throughout tooth development, linking quantitative Pax9 levels to graded oligodontia severity.

    Evidence Hypomorphic/null allelic series in mice with staged tooth histology

    PMID:16236760

    Open questions at the time
    • Dosage-sensitive target genes not defined
    • Threshold mechanism at the molecular level unknown
  10. 2005 Medium

    Documented direct physical association of PAX9 with MSX1, providing a protein-interaction basis for combinatorial regulation in tooth development.

    Evidence Reciprocal Co-IP and GST pull-down assays

    PMID:15721141

    Open questions at the time
    • Interaction interface not mapped
    • Functional consequence on transcription not tested in this study
  11. 2006 High

    Demonstrated that PAX9 and MSX1 synergistically transactivate Msx1 and Bmp4 promoters and that PAX9 regulates Bmp4 through its DNA-binding paired domain, separating DNA-binding from protein-interaction functions.

    Evidence Co-IP, EMSA, luciferase reporter assays with wild-type and DNA-binding-deficient mutant PAX9; analysis of the Ile87Phe mutation

    PMID:16479262 PMID:16651263

    Open questions at the time
    • Stoichiometry and structure of the PAX9-MSX1-DNA complex unknown
    • Other partner-dependent target genes not identified
  12. 2009 High

    Correlated paired-domain mutation effects on DNA binding and transactivation with oligodontia severity and identified a rare dominant-negative mutant acting through loss of MSX1 synergy.

    Evidence Structure-based modeling, EMSA, reporter assays, Co-IP and localization across eight missense mutants

    PMID:19429910

    Open questions at the time
    • High-resolution PAX9-DNA structure not solved
    • Mechanism of dominant-negative interference not fully defined
  13. 2010 High

    Established in vivo genetic interaction between Pax9 and Msx1 in incisor and lip development, with BMP4 acting downstream as a partial mediator.

    Evidence Compound Pax9/Msx1 mutant mice with marker in situ, BrdU assays, and BMP4 transgenic rescue

    PMID:20123092

    Open questions at the time
    • Direct vs. indirect control of Fgf3/Fgf10 not resolved
    • Incomplete rescue indicates additional unidentified effectors
  14. 2011 High

    Placed Osr2 downstream of Pax9 in tooth development, with Osr2 knock-in rescuing supernumerary tooth phenotypes.

    Evidence Pax9-conditional knockout with Pax9-locus Osr2 knock-in; Co-IP of Osr2 with MSX1 and PAX9

    PMID:21420399

    Open questions at the time
    • Whether Pax9 directly binds the Osr2 promoter not shown
    • Weak PAX9-Osr2 interaction functional role unclear
  15. 2013 High

    Defined Pax9 as the controller of a Bmp4/Fgf10/Msx1/Osr2/Shh network in palatal mesenchyme, with Osr2 sufficient to rescue posterior palate morphogenesis.

    Evidence Tissue-specific Pax9 conditional knockout and Pax9-locus Osr2 knock-in with downstream marker in situ hybridization

    PMID:24173808

    Open questions at the time
    • Direct PAX9 binding to these promoters in palate not all demonstrated
    • Anterior vs. posterior palate mechanistic differences not fully resolved
  16. 2017 High

    Identified direct PAX9 repression of Wnt antagonists Dkk1/Dkk2 as the mechanism linking Pax9 to canonical Wnt signaling in palatogenesis, validated by genetic and pharmacological rescue.

    Evidence ChIP-qPCR for Pax9 at Dkk1/Dkk2/Wnt loci; genetic Dkk1 reduction/overexpression; in utero Dkk inhibitor; Pax9/Wise double-mutant rescue with β-catenin/Axin2 readouts

    PMID:28692808 PMID:28893947 PMID:32390226

    Open questions at the time
    • Direct vs. indirect contribution of Wnt9b/Wnt3 binding unclear
    • Tissue-specific cofactors for repression not identified
  17. 2017 Medium

    Extended Pax9 function to squamous epithelial differentiation, showing it restrains proliferation and that its silencing (including by ethanol and promoter hypermethylation) promotes squamous carcinogenesis.

    Evidence Conditional Pax9 knockout in mouse oesophagus, expression profiling, ethanol exposure, bisulfite sequencing, NMBA carcinogen model

    PMID:29055049

    Open questions at the time
    • Direct transcriptional targets in epithelium not defined
    • Mechanism connecting PAX9 loss to carcinogenesis incomplete
  18. 2019 High

    Demonstrated a pharyngeal-endoderm requirement for Pax9 in cardiovascular development through genetic interaction with Tbx1.

    Evidence Pax9 null cardiovascular phenotyping, Tbx1/Pax9 double-heterozygous epistasis, Pax9Cre lineage tracing, transcriptomics

    PMID:31444215

    Open questions at the time
    • Direct biochemical Pax9-Tbx1 relationship not shown
    • Endodermal target genes mediating arch artery defects not identified
  19. 2019 Medium

    Positioned SIX2 as a direct upstream activator of PAX9 in palatogenesis, with a human SIX2 variant reducing PAX9 expression.

    Evidence SIX2 null mouse, ChIP/binding to PAX9 regulatory element, functional analysis of SIX2 p.Gly264Glu

    PMID:31765609

    Open questions at the time
    • Other upstream regulators of PAX9 in palate not mapped
    • Quantitative contribution of SIX2 to PAX9 dosage unclear
  20. 2021 High

    Revealed a genome-wide enhancer-repression mechanism in which PAX9 cofunctions with the NuRD complex to restrict differentiation and tumor-suppressor gene activity in SCLC.

    Evidence CRISPR dropout screen, PAX9 ChIP-seq, enhancer-state profiling, PAX9-NuRD Co-IP, HDAC inhibitor rescue, RNA-seq after depletion

    PMID:34341073

    Open questions at the time
    • DNA sequence determinants of enhancer occupancy not defined
    • Generalizability beyond SCLC unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how PAX9 switches between activator and repressor modes across tissues and how cofactor choice (MSX1, OSR2, PLU-1/NuRD) is determined at specific loci.
  • No high-resolution structure of PAX9 bound to DNA with cofactors
  • Mechanism selecting activation vs. repression context not resolved
  • Full genome-wide target catalog in developmental tissues lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 7 GO:0140110 transcription regulator activity 7
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 1
Partners
MSX1OSR2PLU-1TBX1
Complex memberships
NuRD complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Pax9-deficient mice arrest tooth development at the bud stage and show loss of mesenchymal expression of Bmp4, Msx1, and Lef1, establishing Pax9 as required for the inductive capacity of the tooth mesenchyme. Targeted gene knockout (null allele) in mice; in situ hybridization for downstream markers Genes & development High 9732271
1995 PAX9 protein binds to the e5 paired-domain recognition sequence from the Drosophila even-skipped promoter, demonstrating DNA-binding activity shared with PAX1. In vitro DNA-binding assay (gel shift / EMSA) with the e5 sequence Developmental biology Medium 7649395
1999 Pax1 and Pax9 act redundantly to control vertebral column development: double homozygous mutant mice completely lack vertebral bodies, intervertebral discs and proximal ribs, with reduced cell proliferation in ventromedial sclerotomes and subsequent increased apoptosis; single Pax9 homozygous mutants show no axial defect, while Pax9 is spatially upregulated to compensate for Pax1 loss. Genetic epistasis using Pax1/Pax9 compound mutant mice; histology, BrdU proliferation assay, TUNEL apoptosis assay, in situ hybridization Development (Cambridge, England) High 10556064
2003 Pax1 and Pax9 directly activate the Bapx1 promoter and physically interact with Bapx1 regulatory sequences; overexpression of Pax1 in chick presomitic mesoderm can substitute for Shh in inducing Bapx1 and initiating chondrogenic differentiation, establishing Bapx1 as a direct transcriptional target of Pax1/Pax9 downstream of Shh in sclerotome development. Pax1/Pax9 double-mutant analysis; retroviral Pax1 overexpression in chick explants; promoter-binding (transactivation assays and direct interaction with Bapx1 promoter region) Development (Cambridge, England) High 12490554
2006 PAX9 directly regulates Msx1 expression; PAX9 and MSX1 proteins physically interact and synergistically transactivate the Msx1 and Bmp4 promoters. A paired-domain missense mutation (L21P/T62C) abolishes DNA binding and promoter transactivation but retains protein-protein interaction with MSX1, indicating PAX9 regulates Bmp4 through its DNA-binding paired domain rather than solely through MSX1 protein interaction. Co-immunoprecipitation; luciferase reporter/transactivation assays with wild-type and mutant PAX9; DNA-binding assays (EMSA) The Journal of biological chemistry High 16651263
2005 Pax9 and MSX1 proteins physically associate in vitro and in vivo (Co-IP and GST pull-down), consistent with a functional protein-protein interaction during tooth development. Co-immunoprecipitation and GST pull-down interaction assays Archives of oral biology Medium 15721141
2003 The 219InsG frameshift mutation in the PAX9 paired domain produces a protein with abolished DNA binding to e5 and CD19-2(A-ins) sequences and no transcriptional activation from paired-domain binding sites; the mutant protein also shows altered nuclear localization. Wild-type PAX9 transactivation is not impaired by co-expression of the mutant, indicating loss-of-function rather than dominant-negative mechanism. EMSA (gel mobility shift), co-transfection reporter assay, immunofluorescence localization, dominant-negative test in co-transfection The Journal of biological chemistry High 14607846
2003 PLU-1 interacts with PAX9 (and BF-1) via a conserved VP motif; PAX9 represses transcription in reporter assays, and co-expression of PLU-1 with PAX9 significantly enhances this repression. Deletion or site-directed mutagenesis of the VP motif in PAX9 abolishes PLU-1 co-repressor activity, identifying PLU-1 as a transcriptional co-repressor of PAX9. Yeast two-hybrid screen; site-directed mutagenesis of VP motif; reporter (transcriptional repression) assay The Journal of biological chemistry Medium 12657635
2003 The R28P missense mutation in the N-terminal subdomain of the PAX9 paired domain dramatically reduces DNA binding to double-stranded paired-domain recognition sequences in vitro, supporting loss of DNA binding as the pathogenic mechanism for oligodontia. Gel mobility shift assay (EMSA) comparing wild-type and R28P mutant PAX9 paired domain binding to dsDNA targets Human genetics Medium 14689302
2006 The Ile87Phe mutation in the C-terminal subdomain of the PAX9 paired domain abolishes DNA binding to e5 and CD19-2(A-ins) sequences but does not alter nuclear localization or protein-protein interaction with MSX1, demonstrating that DNA binding is selectively disrupted independent of partner protein interaction or trafficking. Gel shift assay (EMSA); cell fractionation/immunolocalization; co-immunoprecipitation with MSX1 European journal of human genetics Medium 16479262
2009 Structural and functional analysis of eight paired-domain missense mutations in PAX9 shows that most reduce DNA binding and transactivation of Bmp4 and Msx1 promoters correlating with disease severity; all mutants retain nuclear localization and physical interaction with MSX1; one mutant (retaining DNA binding) shows a dominant-negative effect and loss of synergism with MSX1 rather than loss of DNA binding. Subcellular localization (immunofluorescence), co-immunoprecipitation with MSX1, EMSA, luciferase reporter assays, structure-based modeling Human molecular genetics High 19429910
1996 Zebrafish Pax9 produces two splice isoforms (Pax9a and Pax9b) with distinct C-terminal transactivating domains of different potency; both activate transcription from a paired-domain binding site at low expression levels but show dose-dependent repression at higher amounts. The N-terminal region (including the paired domain) negatively regulates the C-terminal transactivation domains. Alternative splicing characterization; transactivation reporter assays with Pax9a and Pax9b expression vectors; paired-domain binding-site specificity assay The Journal of biological chemistry Medium 8900176
2000 Genetic epistasis in Uncx4.1 mutant mice shows loss of pedicles and proximal ribs resembling the Pax1/Pax9 double-mutant phenotype, placing Uncx4.1 upstream of Pax9 in the caudolateral sclerotome developmental pathway. Targeted Uncx4.1 knockout mouse; comparison of skeletal phenotype with Pax1/Pax9 double mutants; histological and marker analysis Development (Cambridge, England) Medium 10804168
2005 Reduction of Pax9 gene dosage (hypomorphic and null allelic series in mice) causes oligodontia: homozygous hypomorphic mice show missing lower incisors and third molars, while compound hypomorphic/null mice develop severe oligodontia with dental arrest at different stages. Continuously growing incisors also exhibit enamel defects, establishing that a minimum Pax9 dosage is required throughout tooth development. Hypomorphic allele (Pax9neo) generation; compound allele analysis; histology of teeth at different developmental stages Human molecular genetics High 16236760
2010 Pax9 and Msx1 interact genetically in vivo: double homozygous mutants exhibit cleft lip; double heterozygous mutants consistently lack lower incisors with reduced Shh/Bmp2 expression defining a smaller incisor field, drastically reduced Fgf3/Fgf10 mesenchymal expression, reduced cell proliferation, and abnormal ameloblast differentiation. Transgenic BMP4 partially rescues the double-heterozygous incisor phenotype. Compound Pax9/Msx1 mutant mice; in situ hybridization for Shh, Bmp2, Fgf3, Fgf10, Notch1; BrdU proliferation assay; BMP4 transgenic rescue Developmental biology High 20123092
2011 Osr2 acts downstream of Pax9 during tooth development: Osr2 mRNA is downregulated in Pax9-deficient tooth mesenchyme; Osr2 expression from the Pax9 locus (knock-in) rescues supernumerary tooth formation in Osr2-/- mutants; Osr2 forms a stable protein complex with MSX1 and interacts weakly with PAX9 in co-transfected cells. Pax9-conditional knockout with Osr2 knock-in (Pax9Osr2KI); co-immunoprecipitation of Osr2 with MSX1 and PAX9; in situ hybridization for Osr2, Bmp4, Msx1 Developmental biology High 21420399
2013 Pax9 regulates palate development by controlling a molecular network: conditional deletion of Pax9 in palatal mesenchyme reduces Bmp4, Fgf10, Msx1, and Osr2 expression and disrupts Shh in palatal epithelium. Restoration of Osr2 expression from the Pax9 locus (Pax9Osr2KI knock-in) rescues posterior palate morphogenesis in the absence of Pax9 function, placing Osr2 downstream of Pax9 in this pathway. Tissue-specific Pax9 conditional knockout; Pax9Osr2KI knock-in rescue; in situ hybridization for Bmp4, Fgf10, Msx1, Osr2, Shh Development (Cambridge, England) High 24173808
2017 Pax9 regulates Wnt signaling during palatogenesis by suppressing expression of Dkk1 and Dkk2 (Wnt antagonists); ChIP-qPCR shows Pax9 directly binds to regions near the transcription start sites of Dkk1 and Dkk2 and to the intergenic region of Wnt9b/Wnt3. Genetic reduction of Dkk1 (or pharmacological Dkk inhibition) rescues secondary palate clefts in Pax9-/- mice, and genetic overexpression of Dkk1 phenocopies Pax9-/- palate and tooth defects. Genetic Dkk1 reduction/overexpression; small-molecule Dkk inhibitor delivery in utero; ChIP-qPCR for Pax9 binding to Dkk1, Dkk2, Wnt9b/Wnt3 loci Development (Cambridge, England) / Developmental dynamics High 28893947 32390226
2017 Pax9-deficient mice show reduced canonical Wnt signaling in developing palatal mesenchyme (reduced Axin2, reduced active β-catenin, increased Dkk2); genetic inactivation of Wise (a secreted Wnt antagonist expressed in palatal shelves) in Pax9-deficient embryos rescues palatal shelf elevation/reorientation and restores hyaluronic acid accumulation, placing canonical Wnt signaling downstream of Pax9 in palate elevation. Pax9/Wise double-mutant genetic epistasis; immunohistochemistry for active β-catenin, Axin2, hyaluronic acid; in situ hybridization for Dkk2 Journal of dental research High 28692808
2017 Pax9 is required for normal squamous cell differentiation in the oro-oesophageal epithelium: Pax9 deficiency in mouse oesophagus promotes cell proliferation and delays differentiation; ethanol exposure downregulates PAX9 in human oesophageal epithelial cells and mouse forestomach/tongue. PAX9 promoter hypermethylation is associated with silencing in human oro-oesophageal squamous cell carcinoma. PAX9 deficiency or ethanol promotes carcinogen-induced squamous cell carcinogenesis in mice. Conditional Pax9 knockout in mouse oesophagus; global gene expression profiling; ethanol exposure in vitro and in vivo; bisulfite sequencing for promoter methylation; carcinogen (NMBA) challenge model The Journal of pathology Medium 29055049
2002 Pax9 is required in thymic epithelial cells for normal thymopoiesis: in Pax9 null mice, the thymic anlage forms as an ectopic polyp-like structure in the larynx expressing Foxn1/Whn, fails to migrate to the upper mediastinum, and is severely reduced in size by E14.5; TCRβ expression is detectable but TCRγ is absent. Pax9 null mouse analysis; immunohistochemistry and marker expression (Whn/Foxn1, TCRβ, TCRγ) European journal of immunology Medium 11932925
2004 Pax9 regulates region-specific differentiation of the tongue epithelium: in Pax9-deficient mice, filiform papillae lack anterior-posterior polarity (associated with altered Hoxc13 expression), barrier formation is disturbed, 'hard' keratins (Krt1-5, Krt1-24, Krt2-16) are not expressed, and 'soft' skin-specific keratins are upregulated, indicating partial trans-differentiation of tongue epithelium toward skin. Pax9 null mouse; genome-wide expression profiling; in situ hybridization for keratins and Hoxc13 Mechanisms of development High 15454262
2005 Pax9 expression in the anterior limb mesenchyme is dependent on Gli3 (repressor function) and is regulated by Shh-mediated Gli3 processing in a context-dependent manner: in Gli3Xt/Xt polydactylous mice, Pax9 is downregulated in anterior limb; Shh bead implantation in chick shows context-dependent Pax9 regulation differing between limb and somite. Gli3 null (Extra-toes) mouse transcriptional analysis; Shh/Gli3 compound mutant; Shh bead implantation in chick limb and somite Mechanisms of development Medium 16169709
2014 Pax9 acts upstream of Pax1 and Sox9 in the expanding taste progenitor field of the circumvallate papilla; Pax9-deficient mice completely fail to develop circumvallate papilla (arrest vs. partial reduction in Pax1 mutants). Pax9 is also required for Pax9-dependent induction of taste placodes in the soft palate but is dispensable for fungiform papilla taste bud development. Loss of Pax9 causes circumvallate taste progenitor cells to lack K8 and Prox1 expression and to differentiate into epidermal-like epithelium. Pax9 and Pax1 null mouse phenotypic comparison; genetic epistasis; immunofluorescence for K8, Prox1; in situ hybridization PLoS genetics High 25299669
2014 A G-quadruplex structure in PAX9 intron 1 (near exon 1) enhances splicing efficiency of PAX9 intron 1: mutation abolishing quadruplex formation dramatically decreases splicing efficiency in a reporter assay, and stabilization with the G-quadruplex ligand 360A further increases splicing efficiency. Circular dichroism (CD) spectroscopy; double-reporter splicing assay; qPCR; pharmacological G-quadruplex stabilization Human genetics Medium 25204874
2019 Pax9 is required in the pharyngeal endoderm for cardiovascular development; Pax9-deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries. Pax9 and Tbx1 genetically interact in the pharyngeal endoderm: double Tbx1+/-;Pax9+/- heterozygotes have significantly increased interrupted aortic arch incidence compared with Tbx1+/- alone. A Pax9Cre allele localizes the Tbx1-Pax9 interaction site to pharyngeal endoderm. Pax9 null mouse cardiovascular phenotyping; Tbx1/Pax9 double heterozygous mouse; Pax9Cre lineage tracing; transcriptome analysis Development (Cambridge, England) High 31444215
2008 Pbx1/Pbx2 control Pax1/Pax9 expression in the sclerotome; in Pbx1/Pbx2 compound mutant mice, Pax1/Pax9 expression is downregulated in the sclerotome, and axial skeletal development is severely disrupted, placing Pbx1/Pbx2 genetically upstream of Pax1/Pax9 in the sclerotomal pathway. Pbx1/Pbx2 compound mutant mouse; marker analysis by in situ hybridization for Pax1, Pax9; skeletal phenotyping Developmental biology Medium 18691704
2017 PAX9 overexpression in dental pulp cells upregulates LEF1 and AXIN2 expression, indicating a positive regulatory role for PAX9 in canonical Wnt signaling; PAX9 missense mutations show differential loss of transcriptional activity and all overexpressed mutants except Pro118Ser show proper nuclear localization. PAX9 overexpression in dental pulp cells; RT-qPCR for LEF1 and AXIN2; immunofluorescence for subcellular localization; luciferase reporter assay Annals of the New York Academy of Sciences Medium 37005710
2021 PAX9 occupies distal enhancer elements genome-wide in SCLC cells and represses nearby gene expression by restricting enhancer activity; PAX9 physically interacts and cofunctions with the NuRD (nucleosome remodeling and deacetylase) complex at enhancers. Genetic depletion of PAX9 induces a primed-to-active enhancer transition and upregulates neural differentiation and tumor-suppressive genes; pharmacological HDAC inhibition reverses PAX9/NuRD-mediated repression. Genome-wide CRISPR-Cas9 dropout screen; ChIP-seq for PAX9 occupancy; genome-wide enhancer state analysis (H3K4me1, H3K27ac); co-immunoprecipitation of PAX9 with NuRD complex; HDAC inhibitor treatment; RNA-seq after PAX9 depletion Cancer research High 34341073
2019 SIX2 directly binds a PAX9 5' upstream regulatory element and activates PAX9 expression; a human SIX2 coding variant (p.Gly264Glu) found in a cleft palate patient destabilizes SIX2 protein and reduces PAX9 expression, placing SIX2 upstream of PAX9 in the palatogenesis regulatory network. SIX2 null mouse (22% cleft palate penetrance); ChIP/binding to PAX9 regulatory element; functional analysis of SIX2 p.Gly264Glu variant on PAX9 expression Developmental biology Medium 31765609
2008 Pax9 and c-myb function in the same pathway in oral squamous carcinoma cells: Pax9 knockdown induces apoptosis (caspase-3/PARP cleavage, increased Bax, decreased Bcl-2); c-myb overexpression upregulates Pax9; dominant-negative c-myb downregulates Pax9 without Pax9 affecting c-myb levels, placing c-myb upstream of Pax9 in cell survival regulation. Both Pax9 knockdown and dominant-negative c-myb arrest the cell cycle at G0. Pax9 siRNA knockdown; adenoviral c-myb overexpression and dominant-negative c-myb; flow cytometry (cell cycle); Western blot for caspase-3, PARP, Bax, Bcl-2 Cell biochemistry and function Medium 18979497

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes & development 638 9732271
1995 Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Developmental biology 233 7649395
1999 Pax1 and Pax9 synergistically regulate vertebral column development. Development (Cambridge, England) 205 10556064
1993 Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nature genetics 200 7981748
2001 Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. European journal of human genetics : EJHG 134 11781684
2002 A novel mutation in human PAX9 causes molar oligodontia. Journal of dental research 126 11827258
2004 MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. Journal of dental research 125 15329380
2002 Embryonic submandibular gland morphogenesis: stage-specific protein localization of FGFs, BMPs, Pax6 and Pax9 in normal mice and abnormal SMG phenotypes in FgfR2-IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice. Cells, tissues, organs 118 11731698
2011 Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. American journal of medical genetics. Part A 117 21626677
2010 Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Developmental biology 115 20123092
2002 Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Human genetics 115 11941488
2003 Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Development (Cambridge, England) 110 12490554
2006 Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. The Journal of biological chemistry 101 16651263
2003 Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. American journal of medical genetics. Part A 97 12605438
1996 Expression of avian Pax1 and Pax9 is intrinsically regulated in the pharyngeal endoderm, but depends on environmental influences in the paraxial mesoderm. Developmental biology 93 8812138
2000 Uncx4.1 is required for the formation of the pedicles and proximal ribs and acts upstream of Pax9. Development (Cambridge, England) 91 10804168
2003 A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. European journal of human genetics : EJHG 87 14571272
2005 Novel mutation of the initiation codon of PAX9 causes oligodontia. Journal of dental research 85 15615874
2013 Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis. Development (Cambridge, England) 84 24173808
2005 Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development. Mechanisms of development 81 16169709
2003 Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. The Journal of biological chemistry 80 12657635
2005 Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. Human molecular genetics 72 16236760
1998 Pax genes and organogenesis: Pax9 meets tooth development. European journal of oral sciences 71 9541201
2003 A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia. Human genetics 66 14689302
1996 Zebrafish Pax9 encodes two proteins with distinct C-terminal transactivating domains of different potency negatively regulated by adjacent N-terminal sequences. The Journal of biological chemistry 63 8900176
2006 Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis. European journal of human genetics : EJHG 61 16479262
2017 Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero. Development (Cambridge, England) 60 28893947
2003 Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. European journal of oral sciences 60 12786960
2002 Thymopoiesis requires Pax9 function in thymic epithelial cells. European journal of immunology 58 11932925
2017 Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice. Journal of dental research 56 28692808
2006 New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Movement disorders : official journal of the Movement Disorder Society 56 17044090
2002 Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus. The Journal of pathology 55 12115874
2000 Pax1/Pax9-Related genes in an agnathan vertebrate, Lampetra japonica: expression pattern of LjPax9 implies sequential evolutionary events toward the gnathostome body plan. Developmental biology 55 10882524
2017 A developmental transcriptomic analysis of Pax1 and Pax9 in embryonic intervertebral disc development. Biology open 54 28011632
1995 Differential expression of the chicken Pax-1 and Pax-9 gene: in situ hybridization and immunohistochemical analysis. Developmental dynamics : an official publication of the American Association of Anatomists 51 7647370
2005 PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses. Journal of human genetics 50 16247549
2017 PAX9 gene mutations and tooth agenesis: A review. Clinical genetics 49 28155232
2014 G-quadruplex formation enhances splicing efficiency of PAX9 intron 1. Human genetics 47 25204874
2005 Studies on Pax9-Msx1 protein interactions. Archives of oral biology 47 15721141
2003 Identification of Cis-regulatory elements in the mouse Pax9/Nkx2-9 genomic region: implication for evolutionary conserved synteny. Genetics 46 14504231
2003 Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans. The Journal of biological chemistry 46 14607846
1993 A new Pax gene, Pax-9, maps to mouse chromosome 12. Mammalian genome : official journal of the International Mammalian Genome Society 46 8358169
2009 Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer. Proceedings of the National Academy of Sciences of the United States of America 45 19279207
2006 A novel mutation in PAX9 causes familial form of molar oligodontia. European journal of human genetics : EJHG 45 16333316
2004 Pax9 is required for filiform papilla development and suppresses skin-specific differentiation of the mammalian tongue epithelium. Mechanisms of development 45 15454262
2009 Pathogenic mechanisms of tooth agenesis linked to paired domain mutations in human PAX9. Human molecular genetics 43 19429910
1999 De novo deletion (14)(q11.2q13) including PAX9: clinical and molecular findings. Journal of medical genetics 43 10204852
2017 Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype. Journal of dental research 41 28910570
2010 PAX9 and MSX1 transcription factor genes in non-syndromic dental agenesis. Archives of oral biology 41 21111400
2008 Pbx1/Pbx2 govern axial skeletal development by controlling Polycomb and Hox in mesoderm and Pax1/Pax9 in sclerotome. Developmental biology 38 18691704
2011 Osr2 acts downstream of Pax9 and interacts with both Msx1 and Pax9 to pattern the tooth developmental field. Developmental biology 37 21420399
2017 A review on non-syndromic tooth agenesis associated with PAX9 mutations. The Japanese dental science review 36 29628999
2006 Exclusion of coding region mutations in MSX1, PAX9 and AXIN2 in eight patients with severe oligodontia phenotype. Orthodontics & craniofacial research 36 16918677
2017 PAX9 regulates squamous cell differentiation and carcinogenesis in the oro-oesophageal epithelium. The Journal of pathology 35 29055049
2006 Natural selection and molecular evolution in primate PAX9 gene, a major determinant of tooth development. Proceedings of the National Academy of Sciences of the United States of America 35 16585527
2005 Association between PAX-9 promoter polymorphisms and hypodontia in humans. Archives of oral biology 33 16137495
2003 Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. American journal of medical genetics. Part A 33 12833407
1999 Expression of the paired-box genes Pax-1 and Pax-9 in limb skeleton development. Developmental dynamics : an official publication of the American Association of Anatomists 33 10030590
2019 Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis. Development (Cambridge, England) 32 31444215
2015 Differentiation of Odontoblast-Like Cells From Mouse Induced Pluripotent Stem Cells by Pax9 and Bmp4 Transfection. Stem cells translational medicine 32 26136503
2014 Novel PAX9 mutations cause non-syndromic tooth agenesis. Journal of dental research 32 24436340
2011 Sequence analysis of PAX9, MSX1 and AXIN2 genes in a Chinese oligodontia family. Archives of oral biology 32 21530942
2010 Non-syndromic oligodontia with a novel mutation of PAX9. Journal of dental research 32 21098475
2007 A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teeth. European journal of oral sciences 32 17697174
2007 Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies. European journal of oral sciences 32 18028048
2008 Tooth dimensions in hypodontia with a known PAX9 mutation. Archives of oral biology 31 18653171
2008 Identification and functional analysis of two novel PAX9 mutations. Cells, tissues, organs 30 18701815
2007 A novel missense mutation in the paired domain of human PAX9 causes oligodontia. American journal of medical genetics. Part A 30 17910065
2018 The Function and Regulatory Network of Pax9 Gene in Palate Development. Journal of dental research 29 30583699
2014 The formation of endoderm-derived taste sensory organs requires a Pax9-dependent expansion of embryonic taste bud progenitor cells. PLoS genetics 29 25299669
2006 Temporal and spatial expression of Pax9 and Sonic hedgehog during development of normal mouse palates and cleft palates in TGF-beta3 null embryos. Archives of oral biology 27 17097601
2023 Tooth agenesis patterns and variants in PAX9: A systematic review. The Japanese dental science review 25 37159578
2013 Characterization of pax1, pax9, and uncx sclerotomal genes during Xenopus laevis embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 24 23401059
2012 Novel PAX9 and COL1A2 missense mutations causing tooth agenesis and OI/DGI without skeletal abnormalities. PloS one 24 23227268
2008 Function of Pax1 and Pax9 in the sclerotome of medaka fish. Genesis (New York, N.Y. : 2000) 24 18395830
2010 Mutations in the PAX9 gene in sporadic oligodontia. Orthodontics & craniofacial research 23 20618716
2008 PAX9 polymorphisms and susceptibility to sporadic tooth agenesis: a case-control study in southeast China. European journal of oral sciences 23 18353002
2008 Pax9 mediated cell survival in oral squamous carcinoma cell enhanced by c-myb. Cell biochemistry and function 23 18979497
2016 Effects of PAX9 and MSX1 gene variants to hypodontia, tooth size and the type of congenitally missing teeth. Cellular and molecular biology (Noisy-le-Grand, France) 22 28040065
2013 SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with non‑syndromic cleft lip with or without palate. Molecular medicine reports 22 23921572
2021 PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer. Cancer research 21 34341073
2015 A novel initiation codon mutation of PAX9 in a family with oligodontia. Archives of oral biology 21 26571067
2012 Novel missense mutations in PAX9 causing oligodontia. Archives of oral biology 21 22277187
2017 Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice. Journal of dental research 20 28813171
2012 Novel missense mutation in PAX9 gene associated with familial tooth agenesis. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 20 22747565
2022 PAX9 reactivation by inhibiting DNA methyltransferase triggers antitumor effect in oral squamous cell carcinoma. Biochimica et biophysica acta. Molecular basis of disease 19 35533906
2010 Mutational analysis of MSX1 and PAX9 genes in Portuguese families with maxillary lateral incisor agenesis. European journal of orthodontics 18 20660504
2005 [Novel mutations of PAX9 gene in Chinese patients with oligodontia]. Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology 18 16191360
2020 Functional study of novel PAX9 variants: The paired domain and non-syndromic oligodontia. Oral diseases 17 33078491
2019 Familial oligodontia and regional odontodysplasia associated with a PAX9 initiation codon mutation. Clinical oral investigations 17 30809714
2019 Genotyping analysis of the Pax9 Gene in patients with maxillary canine impaction. F1000Research 17 31069070
2013 Novel PAX9 mutation associated with syndromic tooth agenesis. European journal of oral sciences 17 24028587
2022 PAX9 in Cancer Development. International journal of molecular sciences 16 35628401
2013 Mutational analysis of AXIN2, MSX1, and PAX9 in two Mexican oligodontia families. Genetics and molecular research : GMR 16 24222224
2012 Association between PAX9 single-nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate. The Journal of craniofacial surgery 16 22976623
2011 A novel nonsense mutation in PAX9 is associated with sporadic hypodontia. Mutagenesis 16 22058014
2020 Pax9's dual roles in modulating Wnt signaling during murine palatogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 15 32390226
2001 Comparative analysis of the genomic organization of Pax9 and its conserved physical association with Nkx2-9 in the human, mouse, and pufferfish genomes. Mammalian genome : official journal of the International Mammalian Genome Society 15 11252173
2023 PAX9 mutations and genetic synergism in familial tooth agenesis. Annals of the New York Academy of Sciences 14 37005710
2019 Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation. Developmental biology 14 31765609

Missed literature

Know a paper Affinage missed for PAX9? Flag it for the maintainers and the community.

No submissions yet.