Affinage

MSX1

Homeobox protein MSX-1 · UniProt P28360

Length
303 aa
Mass
31.5 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 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

MSX1 is a homeodomain transcription factor that orchestrates epithelial-mesenchymal inductive signaling during tooth, craniofacial bone, neural crest, spinal cord, and reproductive organ development, with loss-of-function in mice causing cleft palate, arrested tooth development, and craniofacial bone defects (PMID:7914451, PMID:9753686). In dental mesenchyme MSX1 sits within a BMP4 signaling circuit: it acts downstream of epithelial BMP4 and is required for BMP4 to drive its own mesenchymal expression, with BMP4 beads rescuing the tooth and digit-regeneration phenotypes of Msx1 mutants (PMID:8898217, PMID:12944425); the BMP-to-Msx1 step proceeds through an atypical Smad4-independent, Smad1/5/8-dependent pathway in which pSmad1/5/8 binds the Msx1 promoter directly (PMID:25274628). In parallel, epithelial FGF8 induces Fgf3 via MSX1, and CDK1 phosphorylation of MSX1 at Ser136 enhances its direct activation of Fgf9 and Fgf18 promoters to drive Erk1/2 proliferative signaling (PMID:9753686, PMID:33080014). MSX1 functions predominantly as a transcriptional repressor that can act independently of its consensus DNA site through multiprotein complexes—autorepressing its own promoter via TBP/Sp1/CBP/p300, repressing the myoD enhancer to block myogenic differentiation, and forming ternary complexes with SRF/myocardin or cardiac T-box proteins to suppress smooth-muscle genes and Connexin43 (PMID:7664340, PMID:8861098, PMID:10215616, PMID:17030628, PMID:18285513). It additionally represses the gonadotrope genes αGSU and GnRHR and the Wnt antagonists Dkk2/Sfrp2/Sostdc1, whose derepression underlies the Msx1-null tooth phenotype, while directly activating Atoh1 and Stra8 in spinal and germ-cell contexts (PMID:22071108, PMID:23371388, PMID:24715462, PMID:27713059, PMID:35114852). MSX1 physically partners with Pax9, Lhx2, and Tbx2 to modulate promoter activity and Bmp4 output, and is regulated by upstream factors FOXE1 and PHOX2B (PMID:9697309, PMID:15721141, PMID:16651263, PMID:23720046, PMID:18201699, PMID:21177256). Beyond development, MSX1 translocates from nucleus to mitochondria upon viral infection to facilitate TBK1-complex assembly in RLR-mediated antiviral signaling (PMID:27194789). In humans, MSX1 homeodomain mutations cause selective tooth agenesis through haploinsufficiency and co-segregate with Witkop (tooth-and-nail) syndrome (PMID:9742121, PMID:11369996).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1992 High

    Established that MSX1 actively blocks terminal differentiation and promotes a proliferative state, defining its core role as a gatekeeper of the undifferentiated progenitor phenotype rather than a passive marker.

    Evidence Forced Hox-7.1 (Msx1) expression in a myogenic cell line with MyoD1 mRNA and differentiation readouts

    PMID:1360150

    Open questions at the time
    • Did not identify the molecular mechanism of MyoD suppression
    • Did not determine whether repression was direct
  2. 1995 High

    Resolved the mechanism of MyoD suppression by showing MSX1 binds the myoD enhancer and represses it directly, defining MSX1 as a direct transcriptional repressor.

    Evidence DNA binding assay, myoD enhancer reporter, chromosome transfer, and antisense rescue in human fibroblasts

    PMID:7664340

    Open questions at the time
    • Did not establish whether repression always requires DNA binding
    • Co-repressor partners not identified
  3. 1996 High

    Showed MSX1 can repress independently of its consensus DNA site and mapped repressor potency to the N-terminus, revealing a non-canonical, DNA-binding-independent repression mode.

    Evidence DNA binding assays, transcriptional reporters, and domain-swap analysis comparing MSX-1 and MSX-2

    PMID:8861098

    Open questions at the time
    • Did not identify the protein partners mediating DNA-independent repression
    • In vitro assays only
  4. 1996 High

    Placed MSX1 within the tooth morphogenesis pathway as a node downstream of epithelial BMP4 that is required for mesenchymal BMP4 autoregulation, defining its role in epithelial-mesenchymal signaling relay.

    Evidence Msx1-/- genetic epistasis with BMP4 bead rescue of tooth germs

    PMID:8898217

    Open questions at the time
    • Mechanism by which Msx1 induces Bmp4 not resolved
    • Did not distinguish direct vs indirect Bmp4 activation
  5. 1998 High

    Distinguished parallel epithelial inductive inputs by showing FGF8 induces Fgf3 via MSX1 independently of the BMP4 pathway, establishing MSX1 as an integrator of distinct signaling cues.

    Evidence Msx1-/- epistasis with FGF and BMP bead assays and marker gene analysis

    PMID:9753686

    Open questions at the time
    • Did not show direct MSX1 binding to Fgf3 regulatory regions
    • Did not resolve crosstalk between FGF and BMP arms
  6. 1998 High

    Defined a homeodomain-mediated MSX1-Lhx2 interaction that mutually blocks DNA binding, introducing protein sequestration as a mechanism of MSX1 action.

    Evidence In vitro pulldown, co-IP, DNA binding competition, and domain deletion

    PMID:9697309

    Open questions at the time
    • Physiological context of Msx1-Lhx2 interaction not defined
    • No in vivo functional consequence demonstrated
  7. 1998 High

    Explained human tooth agenesis mechanistically by showing the R31P homeodomain mutation destabilizes MSX1 and abolishes DNA/protein binding and repression via haploinsufficiency rather than dominant interference.

    Evidence Biochemical binding/repression assays plus ectopic limb expression of MSX1(R31P)

    PMID:9742121

    Open questions at the time
    • Did not identify which target gene dosage is most critical for the phenotype
    • Limited to one mutation
  8. 1999 High

    Identified the co-repressor machinery for DNA-independent autorepression, showing MSX1 assembles with TBP, Sp1, and CBP/p300 to repress its own promoter.

    Evidence Msx1 promoter reporter, co-IP with TBP/Sp1/CBP/p300, and binding-site mutagenesis

    PMID:10215616

    Open questions at the time
    • Did not establish stoichiometry or order of complex assembly
    • Generalizability to other MSX1 targets untested
  9. 2001 High

    Linked MSX1 repression to chromatin modification by showing a related Msx protein recruits HDAC1 and squelches CBP/p300 HAT activity, framing histone deacetylation as a repression route.

    Evidence Msx1 promoter reporter, co-IP, HAT assay, and trichostatin A rescue (Msx3 context)

    PMID:11115394

    Open questions at the time
    • Demonstrated for Msx3, not directly for MSX1 itself
    • In vivo relevance to MSX1 autoregulation not shown
  10. 2001 Medium

    Connected MSX1 to a Mendelian disease beyond isolated agenesis, showing a homeodomain nonsense mutation co-segregates with Witkop syndrome and that nail development requires Msx1.

    Evidence Candidate-gene linkage, sequencing, and Msx1-/- mouse nail histology

    PMID:11369996

    Open questions at the time
    • Single family for co-segregation
    • Molecular basis of nail defect not defined
  11. 2003 High

    Extended the Msx1-BMP4 axis to regeneration and skeletal patterning, showing it is required for digit-tip regeneration, dorsal neural tube Wnt1 expression, and Dlx5/Cbfa1 induction in alveolar bone.

    Evidence Msx1-/- regeneration assay with BMP4 rescue, chick electroporation, and multi-mutant marker analysis

    PMID:12874124 PMID:12944425 PMID:14654219

    Open questions at the time
    • Direct vs indirect target relationships not all resolved
    • Tissue-specific cofactors not identified
  12. 2005 High

    Defined MSX1 as a top-tier regulator of neural crest induction acting upstream of Pax3, and as required for crest cell survival and migration, broadening its developmental scope.

    Evidence Xenopus overexpression/morpholino epistasis and Msx1/Msx2 double-mutant mouse analysis

    PMID:15691759 PMID:16221730

    Open questions at the time
    • Direct MSX1 targets in crest induction not all mapped
    • Redundancy with Msx2 complicates single-gene attribution
  13. 2006 High

    Established physical MSX1-PAX9 cooperativity, showing PAX9 enhances MSX1 transactivation of Bmp4 and that a disease PAX9 mutation uncouples binding from transactivation.

    Evidence Co-IP, GST pulldown, Bmp4 promoter reporter, PAX9 mutagenesis, and siRNA

    PMID:15721141 PMID:16651263

    Open questions at the time
    • Interaction interface not mapped by mutagenesis
    • In vivo requirement of the MSX1-PAX9 complex not directly tested
  14. 2008 High

    Generalized the protein-sequestration repression mode by showing MSX1 forms ternary complexes with SRF/myocardin and with cardiac T-box proteins to repress SMC genes and Connexin43.

    Evidence Co-IP, EMSA, ChIP, Y2H, and promoter reporters with domain analysis

    PMID:17030628 PMID:18285513

    Open questions at the time
    • Physiological consequences in vascular/cardiac tissue not fully resolved by knockout
    • Did not rank repression contribution vs DNA-site binding
  15. 2008 Medium

    Connected MSX1 to cardiac EMT and to Notch pathway control, expanding its repertoire to valve formation and neuroblastoma differentiation signaling.

    Evidence Msx1/Msx2 double-mutant AV cushion analysis and inducible MSX1 expression in neuroblastoma cells

    PMID:18201699 PMID:18667074

    Open questions at the time
    • Direct MSX1 targets in these contexts not defined
    • Single-study findings without independent replication
  16. 2011 Medium

    Identified an activating role in reproduction, showing MSX1 directly binds Stra8 regulatory sequences and is required for meiosis initiation in female germ cells.

    Evidence Msx1/Msx2 double-mutant ovary analysis with Stra8 binding and overexpression in F9 cells

    PMID:22071108

    Open questions at the time
    • Direct vs cooperative binding not fully resolved
    • Single study
  17. 2013 High

    Demonstrated context-dependent direct repression through homeodomain sites at the αGSU and GnRHR promoters, and showed nuclear localization depends on the intact homeodomain.

    Evidence Promoter truncation/mutation reporters, siRNA, Msx1-null mouse expression, and localization of MSX1 truncation mutant

    PMID:23371388 PMID:24329876

    Open questions at the time
    • Localization study was Medium-confidence and lacked functional rescue
    • Co-repressors at gonadotrope promoters not identified
  18. 2013 High

    Resolved an antagonistic MSX1-Tbx2 module controlling mesenchymal Bmp4 dosage, with Tbx2 heterozygosity partially rescuing the Msx1-null tooth arrest.

    Evidence Endogenous co-IP, compound mutant epistasis, and Tbx2 knockdown

    PMID:23720046

    Open questions at the time
    • Molecular basis of antagonism on Bmp4 not fully defined
    • Other T-box partners not tested in dental context
  19. 2014 High

    Established MSX1 as a direct transcriptional activator in spinal cord patterning, binding the Atoh1 3' enhancer to specify dorsal dI1 interneurons.

    Evidence ChIP, in vitro activation assay, Msx1/Msx2 double-mutant phenotype, and lineage analysis

    PMID:24715462

    Open questions at the time
    • Switch determining repressor vs activator behavior not defined
    • Cofactors for activation not identified
  20. 2014 High

    Defined the upstream signaling logic linking BMP to Msx1, showing an atypical Smad4-independent, Smad1/5/8-dependent pathway in which pSmad1/5/8 directly binds the Msx1 promoter.

    Evidence BRE reporter, pSmad IP, Smad2/3 knockdown, Smad4 overexpression, ChIP, and conditional Smad4 KO

    PMID:25274628

    Open questions at the time
    • Generality of Smad4-independent regulation beyond dental mesenchyme unknown
    • Did not address feedback onto BMP4 directly
  21. 2016 High

    Revealed a non-transcriptional, extranuclear function: MSX1 relocates to mitochondria upon infection to scaffold TBK1-complex assembly in antiviral RLR signaling.

    Evidence MSX1 KO/KD, TBK1-complex co-IP, subcellular fractionation, and Sendai virus assay

    PMID:27194789

    Open questions at the time
    • Structural basis of TBK1-complex scaffolding unknown
    • How nuclear-to-mitochondrial trafficking is triggered not defined
  22. 2016 High

    Identified Wnt-antagonist derepression as the proximate cause of the Msx1-null tooth defect, with Dkk2/Sfrp2/Sostdc1 acting downstream and Wnt activation rescuing morphogenesis.

    Evidence RNA-seq, multiple compound mutants, and pharmacological Wnt rescue

    PMID:27713059 PMID:35114852

    Open questions at the time
    • Whether MSX1 represses these Wnt antagonists directly not established
    • Tissue specificity of the rescue not fully resolved
  23. 2020 High

    Defined a phosphorylation-gated activating mechanism in which CDK1 phosphorylates MSX1 at Ser136 to enhance direct Fgf9/Fgf18 promoter activation and drive Erk-dependent proliferation.

    Evidence ChIP, phosphosite mutagenesis, FGF9/18 knockdown/neutralization, and conditional double KO

    PMID:33080014

    Open questions at the time
    • Other CDK1 substrates contributing to phenotype not excluded
    • Whether Ser136 phosphorylation controls repressor/activator switching unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MSX1 switches between transcriptional repressor, direct activator, and cytoplasmic scaffold—and what cofactors or modifications dictate each mode in a given tissue—remains unresolved.
  • No unified model linking context, cofactor availability, and post-translational state to activator vs repressor output
  • Structural basis of partner sequestration vs DNA-site repression not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 1
Partners
LHX2MYOCDPAX9SP1SRFTBK1TBPTBX2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Msx1 loss-of-function in mice causes cleft secondary palate, failure of tooth development, and craniofacial bone abnormalities, establishing a critical role for Msx1 in mediating epithelial-mesenchymal interactions during craniofacial and tooth development. Knockout mouse (Msx1-/- null mutant), phenotypic analysis Nature genetics High 7914451
1992 Forced expression of Msx1 (Hox-7.1) in determined myogenic cells blocks terminal differentiation and causes a decrease in steady-state MyoD1 levels, and confers a transformed proliferative phenotype; the related Hox-8.1 does not produce these effects, indicating specificity. Transfection of Hox-7.1 cDNA into myogenic cell line, differentiation assay, MyoD1 mRNA measurement Nature High 1360150
1996 Msx1 acts downstream of epithelial BMP4 in dental mesenchyme and is required for BMP4 to induce its own expression (autocrine loop) in dental mesenchyme; BMP4 bead rescue of Msx1-/- tooth germs restores cap-stage development, placing Msx1 upstream of mesenchymal BMP4 and Lef1 in the tooth morphogenesis pathway. FGF-induced syndecan-1 expression in dental mesenchyme also requires Msx1. Genetic epistasis (Msx1-/- mouse), BMP4-soaked bead rescue experiments, gene expression analysis in mutant tooth germs Development (Cambridge, England) High 8898217
1995 MSX1 protein binds to the myoD enhancer and represses myoD transcription directly; MSX1 is expressed on human chromosome 4 in primary fibroblasts and its forced expression represses myoD enhancer activity. Antisense MSX1 relieves this repression, establishing MSX1 as a direct transcriptional repressor of myoD. Cell hybrid epistasis, reporter assay (myoD enhancer/promoter), chromosome transfer, antisense knockdown, DNA binding assay Cell High 7664340
1996 MSX-1 and MSX-2 both bind a common consensus DNA site and function as transcriptional repressors independently of their consensus DNA binding sites; MSX-1 is a more potent repressor than MSX-2. The functional differences between MSX-1 and MSX-2 map to their N-terminal regions, outside the homeodomain. DNA binding assays, transcriptional reporter assays, domain-swap analysis Mechanisms of development High 8861098
1998 FGF8 constitutes an epithelial inductive signal that induces Fgf3 expression in dental mesenchyme via Msx1; the BMP4 and FGF8 signaling pathways are distinct—BMP4 cannot induce Fgf3 nor can FGFs induce Bmp4 in dental mesenchyme, although both require Msx1. Msx1 is also required for Dlx2 maintenance at bud stage. Msx1/Msx2 double mutants show an earlier (lamina stage) tooth arrest similar to Dlx1/Dlx2 mutants. Genetic epistasis (Msx1-/- mouse), bead assays with FGF1/2/8, gene expression analysis in mutant tooth germs Development (Cambridge, England) High 9753686
1998 A missense mutation (R31P) in the homeodomain of MSX1 causes selective tooth agenesis via haploinsufficiency: the mutant Msx1(R31P) protein has perturbed structure, reduced thermostability, and severely impaired ability to interact with DNA or protein factors or function in transcriptional repression. Msx1(R31P) does not antagonize wild-type Msx1 activity. Biochemical assays (DNA binding, protein-protein interaction), in vivo activity assay (ectopic expression in limb), transcriptional repression assay Molecular and cellular biology High 9742121
1999 Msx1-mediated transcriptional autorepression of the Msx1 promoter is independent of Msx1-binding motifs and is mediated through a multiprotein complex containing TBP, Sp1, and CBP/p300; graded exogenous expression of TBP, Sp1, or CBP/p300 counteracts Msx1 autoinhibitory activity. Reporter assay (Msx1 promoter-luciferase), co-immunoprecipitation of Msx1 with TBP/Sp1/CBP/p300, mutagenesis of binding sites The Biochemical journal High 10215616
1998 Msx1 protein interacts with Lhx2 (a LIM-type homeoprotein) in vitro and in cellular extracts; interaction is mediated through homeodomain-containing regions of both proteins (not through LIM domains). Msx1-Lhx2 complex formation is incompatible with DNA binding by either protein. In vitro pulldown, co-immunoprecipitation from cellular extracts, DNA binding competition assay, domain deletion analysis Differentiation; research in biological diversity High 9697309
2001 Msx3 represses the Msx1 promoter by recruiting HDAC1 into a complex and by squelching the histone acetyltransferase activity of CBP/p300; Msx3-mediated repression is relieved by trichostatin A (HDAC inhibitor) and by overexpression of CBP/p300. Msx3 and HDAC1 co-immunoprecipitate in a complex lacking CBP. Reporter assay (Msx1 promoter), co-immunoprecipitation, HAT activity assay, HDAC inhibitor (trichostatin A) treatment The Biochemical journal High 11115394
2003 Msx1 regulates BMP4 production in the digit tip, and this Msx1-BMP4 axis is required for digit tip regeneration; Msx1 (but not Msx2) mutant mice show a regeneration defect, and exogenous BMP4 rescues regeneration in Msx1 mutants in a dose-dependent manner. Msx1-/- knockout mouse, organ culture digit regeneration assay, BMP4 rescue, noggin inhibition Development (Cambridge, England) High 12944425
2003 Msx1 is required for dorsal diencephalon patterning and maintenance of the dorsal midline; Msx1 electroporation in chick induces Wnt1 expression, and in Msx1/Msx2 double mutants Wnt1 is completely abolished at the dorsal midline, suggesting Msx genes regulate Wnt1 expression downstream of BMP signaling at the dorsal neural tube midline. Msx1(nlacZ) mutant mice morphological analysis, chick electroporation overexpression, double Msx1/Msx2 mutant gene expression analysis Development (Cambridge, England) Medium 12874124
2004 MSX1 expression is required for cellularisation of salamander myofibers; fibers expressing Msx1 mRNA and protein undergo cellularisation and fragmentation, while morpholino antisense knockdown of Msx1 specifically inhibits cellularisation and fragmentation without affecting other processes. Morpholino antisense knockdown, microinjection lineage tracing, time-lapse microscopy in isolated myofibers PLoS biology High 15314647
2005 In Xenopus, Msx1 is required for neural crest formation and acts upstream of Pax3; Msx1 induces Pax3 and ZicR1 cell-autonomously, and is sufficient to induce multiple early neural crest genes in neuralized ectoderm. FGF8 induces neural crest through both Msx1 and Pax3 activities in parallel. Overexpression and morpholino knockdown in Xenopus, epistasis analysis Developmental cell High 15691759
2005 Msx1/Msx2 double mutants show defects in cranial neural crest migration and increased apoptosis in neural crest-derived cells of cranial ganglia and first pharyngeal arch; Msx1/2 mutation leads to altered Krox20 and Epha4 expression and increased Bmp4 expression in migratory cranial neural crest. Msx1/Msx2 double-mutant mouse analysis, marker gene expression (neural crest, hindbrain), apoptosis and proliferation assays Development (Cambridge, England) High 16221730
2005 Pax9 physically interacts with Msx1 protein in vitro and in vivo (co-IP and GST pulldown); the interaction requires direct protein-protein contact. This interaction is linked to regulation of tooth development in dental mesenchyme. Co-immunoprecipitation, GST pulldown assay Archives of oral biology Medium 15721141
2006 Pax9 directly regulates Msx1 expression and interacts with Msx1 at the protein level to enhance Msx1's transactivation of the Bmp4 promoter; a disease-associated PAX9 mutation (L21P) can bind Msx1 protein but fails to transactivate Msx1 and Bmp4 promoters due to impaired paired-domain DNA binding. Co-immunoprecipitation, promoter reporter assay, mutagenesis of PAX9 paired domain, siRNA knockdown The Journal of biological chemistry High 16651263
2006 BMP2/4/6-induced Msx1 and Msx2 expression in vascular smooth muscle cells precedes down-regulation of smooth muscle marker genes; Msx1 forms a ternary complex with SRF and myocardin and inhibits binding of SRF/myocardin to the CArG-box motif, repressing SMC marker gene transcription. Co-immunoprecipitation, gel-shift assay, chromatin immunoprecipitation, promoter reporter assay Molecular and cellular biology High 17030628
2007 Msx1 and Msx2 are required for osteogenesis in cranial neural crest-derived frontal bone primordium; in Msx1/Msx2 double null mutants the frontal bone is absent, and Runx2 expression is lost in the frontonasal cranial neural crest cells, placing Msx genes upstream of Runx2 in the osteogenic lineage. Msx1/Msx2 double-null conditional mutant mice, immunohistochemistry, marker gene expression analysis Mechanisms of development High 17693062
2008 Msx1 and Msx2 interact physically with cardiac T-box proteins Tbx2, Tbx3, and Tbx5 via their T-box and homeodomain regions; Msx proteins together with Tbx2/Tbx3 suppress Connexin43 (Cx43) promoter activity. ChIP confirms Msx1 binds the Cx43 promoter at a conserved site near a T-box binding site. Yeast two-hybrid, in vitro pulldown, promoter reporter assay, chromatin immunoprecipitation Cardiovascular research High 18285513
2008 Msx1 and Msx2 are required for endothelial-mesenchymal transformation (EMT) during atrioventricular valve formation; in Msx1/2 double null mutant AV cushions, Bmp2/4 and Notch1 signaling is decreased and EMT is impaired. Msx1/2 also regulate AV myocardial patterning genes (Anf, Tbx2, Hand1, Hand2). Msx1/Msx2 double-null mutant mice, marker gene expression analysis, histological analysis BMC developmental biology Medium 18667074
2008 MSX1 inducible expression in SJNB-8 neuroblastoma cells strongly up-regulates Delta-Notch pathway genes DLK1, NOTCH3, and HEY1, induces NOTCH3 protein cleavage to its activated form, and down-regulates NEUROD1. MSX1 is a downstream target of PHOX2B (inducible PHOX2B down-regulates MSX1). Inducible expression system, Affymetrix microarray, Northern blot, Western blot (NOTCH3 cleavage) Experimental cell research Medium 18201699
2011 Msx1 and Msx2 are required for meiosis initiation in female germ cells; Msx1/Msx2 double mutant ovaries show decreased meiotic cells and impaired Stra8 activation. In F9 cells, Msx1 directly binds Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. Msx1/Msx2 double-mutant embryo analysis, chromatin binding (ChIP-type experiment with Msx1 and Stra8 regulatory sequences), Msx1 overexpression assay in F9 cells Development (Cambridge, England) Medium 22071108
2013 Msx1 represses the αGSU and GnRHR promoters in gonadotrope cell lines through consensus homeodomain binding sites (DARE element in GnRHR; JRE at -114 in αGSU); siRNA knockdown of Msx1 in αT3-1 cells increases endogenous αGSU and GnRHR expression; Msx1-null mice at e18.5 have elevated αGSU and GnRHR expression. Reporter assay with truncation/mutation analysis, siRNA knockdown, Msx1-null mouse gene expression analysis Molecular endocrinology (Baltimore, Md.) High 23371388
2013 Tbx2 is induced in dental mesenchyme by epithelial BMP4 and physically interacts with Msx1 protein in C3H10T1/2 cells; Tbx2 and Msx1 antagonistically regulate mesenchymal Bmp4 expression—the bud stage tooth arrest in Msx1-/- mice is partially rescued in Msx1-/-;Tbx2+/- compound mutants with restoration of Bmp4 expression and enamel knot formation. Co-immunoprecipitation (endogenous), compound mutant genetic epistasis, Tbx2 knockdown in C3H10T1/2 cells Development (Cambridge, England) High 23720046
2014 Msx1 and Msx2 proteins activate Atoh1 transcription by directly binding to homeodomain binding sites in the Atoh1 3' enhancer; ChIP confirms Msx1 binding to this regulatory sequence in vivo. Msx1/Msx2 double mutants fail to express Atoh1 in the most dorsal spinal progenitor pool, resulting in loss of dI1 interneurons. Msx1/Msx2 double-mutant mouse analysis, in vitro transcriptional activation assay, ChIP, cell lineage analysis Development (Cambridge, England) High 24715462
2014 BMP signaling induces Msx1 expression in dental mesenchyme via an atypical (Smad4-independent, Smad1/5/8-dependent) canonical pathway: pSmad1/5/8-Smad4 complexes are absent in early dental mesenchyme due to Smad4 saturation by pSmad2/3; Smad1/5 (not Smad4) are required for BMP-induced Msx1 expression, and pSmad1/5/8 can translocate to nucleus and bind the Msx1 promoter directly in the absence of Smad4. Transgenic BRE-Gal reporter, pSmad immunoprecipitation, Smad2/3 knockdown, Smad4 overexpression, ChIP (pSmad1/5/8 on Msx1 promoter), conditional Smad4 KO The Journal of biological chemistry High 25274628
2016 MSX1 modulates RLR-mediated innate antiviral signaling: MSX1 knockout/knockdown impairs Sendai virus-triggered TBK1 and IRF3 activation and antiviral gene induction. Upon viral infection, MSX1 translocates from the nucleus to the cytoplasm/mitochondria and is required for assembly of TBK1/IKK-related kinase-associated protein 1/TANK complexes. MSX1 knockout and knockdown, co-immunoprecipitation (TBK1 complex), subcellular fractionation/localization, Sendai virus infection assay Journal of immunology High 27194789
2016 Msx1 and Osr2 have opposing effects on Wnt antagonist expression (Dkk2, Sfrp2) in developing tooth mesenchyme; Msx1 suppresses Dkk2 and Sfrp2, and loss of Msx1 causes their upregulation. Pharmacological Wnt activation or combined genetic inactivation of DKK2/SFRP2/SFRP3 rescues molar morphogenesis in Msx1-/- mice. RNA-seq in mutant embryos, genetic epistasis (Msx1-/- combined with Dkk2-/-, Sfrp2-/-, Sfrp3-/-), pharmacological rescue (LiCl, DKK inhibitor) Developmental biology High 27713059
2020 Phosphorylation of Msx1 at Ser136 by CDK1 is critical for enhancing Fgf9 and Fgf18 expression and cell proliferation; Msx1 directly binds to and upregulates Fgf9 and Fgf18 promoters, and Fgf9/18 knockdown or antibody neutralization inhibits Msx1-activated Erk1/2 phosphorylation. Mesenchymal deletion of Msx1/2 decreases Fgf9/18 expression and Erk1/2 phosphorylation leading to limb defects. ChIP (Msx1 binding to Fgf9/18 promoters), phosphomimetic/phosphoablative mutagenesis of Ser136, FGF9/18 knockdown and antibody neutralization, conditional double KO mouse Nucleic acids research High 33080014
2013 The nuclear localization of MSX1 depends on the intact homeodomain/MH4 region: wild-type MSX1 localizes exclusively at the nuclear periphery in transfected cells, whereas a disease-associated truncation mutant (W139X) lacking the entire homeodomain is stable but localizes diffusely throughout the whole cell. Transfection of wild-type and mutant MSX1 constructs, subcellular localization by immunofluorescence European journal of oral sciences Medium 24329876
2010 FOXE1 directly transactivates MSX1 and TGF-β3 promoters by binding to specific forkhead binding motifs; FOXE1 forkhead-domain mutations (but not polyalanine-stretch polymorphisms) abrogate the ability to bind and transactivate MSX1 and TGF-β3 promoters. In Foxe1-/- mice, Msx1 mRNA is nearly absent from palatal shelves. Promoter reporter assay with FOXE1 binding site mutations, ChIP, Foxe1-/- mouse mRNA analysis Human molecular genetics Medium 21177256
2022 Sostdc1/Wise is a Wnt antagonist involved in the Msx1-dependent odontogenic pathway; genetic inactivation of Sostdc1 rescues maxillary molar morphogenesis in Msx1-/- mice with full penetrance. Combined inactivation of Dkk2 and Sostdc1 rescues both maxillary and mandibular molar morphogenesis in Msx1-/- mice, establishing Dkk2 as the primary Wnt antagonist downstream of Msx1. Genetic compound mutant epistasis (Msx1-/-;Sostdc1-/-, Msx1-/-;Dkk2-/-, Msx1-/-;Dkk2-/-;Sostdc1-/-), gene expression analysis Journal of dental research High 35114852
2001 A heterozygous nonsense mutation in the homeodomain of MSX1 co-segregates with Witkop syndrome (tooth and nail syndrome); Msx1-knockout mice show defective nail plate development in addition to tooth defects, establishing Msx1 as critical for both tooth and nail development. Candidate-gene linkage analysis, direct sequencing, restriction-enzyme analysis, histological analysis of Msx1-/- mice American journal of human genetics Medium 11369996
2003 Msx1/Bmp4 pathway regulates alveolar bone formation by inducing Dlx5 and Cbfa1 in dental mesenchyme; Dlx5 and Cbfa1 expression is reduced in Msx1-/- dental mesenchyme, and ectopic BMP4 restores Dlx5 expression in Msx1 mutants, placing Dlx5 downstream of Bmp4 which is downstream of Msx1 in the alveolar bone pathway. Msx1-/- mouse gene expression analysis, ectopic BMP4 bead rescue, Cbfa1-/- mouse expression analysis, in vitro BMP4 gene induction Mechanisms of development High 14654219

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature genetics 1048 7914451
1996 Msx1 controls inductive signaling in mammalian tooth morphogenesis. Development (Cambridge, England) 326 8898217
1998 FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development (Cambridge, England) 297 9753686
2005 Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Developmental cell 267 15691759
1998 Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. American journal of human genetics 244 9683588
1992 Expression of Hox-7.1 in myoblasts inhibits terminal differentiation and induces cell transformation. Nature 200 1360150
2003 Digit regeneration is regulated by Msx1 and BMP4 in fetal mice. Development (Cambridge, England) 179 12944425
2001 A nonsense mutation in MSX1 causes Witkop syndrome. American journal of human genetics 172 11369996
2005 Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest. Development (Cambridge, England) 154 16221730
1991 Hox-7 expression during murine craniofacial development. Development (Cambridge, England) 137 1685989
1991 Chicken homeobox gene Msx-1: structure, expression in limb buds and effect of retinoic acid. Development (Cambridge, England) 132 1685987
1995 MSX1 inhibits myoD expression in fibroblast x 10T1/2 cell hybrids. Cell 126 7664340
2004 MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. Journal of dental research 125 15329380
1997 Insertional mutation of the mouse Msx1 homeobox gene by an nlacZ reporter gene. Mechanisms of development 123 9256350
1996 Comparison of MSX-1 and MSX-2 suggests a molecular basis for functional redundancy. Mechanisms of development 117 8861098
2010 Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Developmental biology 115 20123092
2007 Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development. Mechanisms of development 110 17693062
2006 Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. The Journal of biological chemistry 101 16651263
2001 Endogenous Msx1 antisense transcript: in vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals. Proceedings of the National Academy of Sciences of the United States of America 96 11390985
1999 The homeobox gene Msx1 is expressed in a subset of somites, and in muscle progenitor cells migrating into the forelimb. Development (Cambridge, England) 93 10331980
2022 Msx1+ stem cells recruited by bioactive tissue engineering graft for bone regeneration. Nature communications 92 36064711
1995 Ectoderm-mesenchyme and mesenchyme-mesenchyme interactions regulate Msx-1 expression and cellular differentiation in the murine limb bud. Developmental biology 91 7537232
1990 The human homeobox gene HOX7 maps to chromosome 4p16.1 and may be implicated in Wolf-Hirschhorn syndrome. Human genetics 78 1969845
2007 Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract. Developmental biology 77 17601530
2003 Msx1 is required for dorsal diencephalon patterning. Development (Cambridge, England) 77 12874124
2004 A novel MSX1 mutation in hypodontia. American journal of medical genetics. Part A 76 15264286
2006 Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription. Molecular and cellular biology 75 17030628
2004 The regenerative plasticity of isolated urodele myofibers and its dependence on MSX1. PLoS biology 74 15314647
2008 Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium. BMC developmental biology 70 18667074
1998 Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. Molecular and cellular biology 70 9742121
2008 Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43. Cardiovascular research 69 18285513
2014 Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 66 25056439
2008 The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. Experimental cell research 66 18201699
1991 Structure and sequence of the human homeobox gene HOX7. Genomics 65 1685479
2006 MSX1 and orofacial clefting with and without tooth agenesis. Journal of dental research 63 16723652
2011 Msx1 and Msx2 promote meiosis initiation. Development (Cambridge, England) 58 22071108
2000 The expression of the homeobox gene Msx1 reveals two populations of dermal progenitor cells originating from the somites. Development (Cambridge, England) 48 10769239
2014 Msx1 role in craniofacial bone morphogenesis. Bone 47 24929242
2005 Studies on Pax9-Msx1 protein interactions. Archives of oral biology 47 15721141
2010 MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate. European journal of oral sciences 46 20572854
2004 Msx-1 and Msx-2 in mammary gland development. Journal of mammary gland biology and neoplasia 45 15300013
2005 Expression and regulation of the Msx1 natural antisense transcript during development. Nucleic acids research 44 16157866
2010 MSX1 and TGF-beta3 are novel target genes functionally regulated by FOXE1. Human molecular genetics 43 21177256
2016 Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists. Developmental biology 42 27713059
1999 Transcriptional autorepression of Msx1 gene is mediated by interactions of Msx1 protein with a multi-protein transcriptional complex containing TATA-binding protein, Sp1 and cAMP-response-element-binding protein-binding protein (CBP/p300). The Biochemical journal 42 10215616
2008 Identification of a novel missense mutation of MSX1 gene in Chinese family with autosomal-dominant oligodontia. Archives of oral biology 41 18374898
2003 Msx1/Bmp4 genetic pathway regulates mammalian alveolar bone formation via induction of Dlx5 and Cbfa1. Mechanisms of development 41 14654219
1995 Expression and activity of the newt Msx-1 gene in relation to limb regeneration. Proceedings. Biological sciences 41 7732036
2011 Msx1 and Msx2 in limb mesenchyme modulate digit number and identity. Developmental dynamics : an official publication of the American Association of Anatomists 40 21465616
2009 MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer letters 37 19815336
2019 RNA Profiling of the Human and Mouse Spinal Cord Stem Cell Niches Reveals an Embryonic-like Regionalization with MSX1+ Roof-Plate-Derived Cells. Stem cell reports 35 31031189
2006 Tissue response and Msx1 expression after human fetal digit tip amputation in vitro. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 35 16939566
1998 Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity. Differentiation; research in biological diversity 35 9697309
1998 Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency. American journal of medical genetics 34 9482651
2014 A miRNA-binding-site SNP of MSX1 is Associated with NSOC Susceptibility. Journal of dental research 33 24603642
2005 Ventral abdominal wall dysmorphogenesis of Msx1/Msx2 double-mutant mice. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 33 15803476
2004 Msx1 disruption leads to diencephalon defects and hydrocephalus. Developmental dynamics : an official publication of the American Association of Anatomists 33 15188430
2011 Sequence analysis of PAX9, MSX1 and AXIN2 genes in a Chinese oligodontia family. Archives of oral biology 32 21530942
2014 Repressed BMP signaling reactivates NKL homeobox gene MSX1 in a T-ALL subset. Leukemia & lymphoma 31 24844359
2001 Postnatal Msx1 expression pattern in craniofacial, axial, and appendicular skeleton of transgenic mice from the first week until the second year. Developmental dynamics : an official publication of the American Association of Anatomists 31 11357189
2021 Novel MSX1 variants identified in families with nonsyndromic oligodontia. International journal of oral science 30 33419968
2009 HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells. Molecular cancer therapeutics 30 19671765
2022 MSX1 Drives Tooth Morphogenesis Through Controlling Wnt Signaling Activity. Journal of dental research 29 35114852
2018 MSX1 induces G0/G1 arrest and apoptosis by suppressing Notch signaling and is frequently methylated in cervical cancer. OncoTargets and therapy 29 30127625
2013 Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development (Cambridge, England) 29 23720046
2010 Msx1 and Dlx5 function synergistically to regulate frontal bone development. Genesis (New York, N.Y. : 2000) 29 20824629
2013 Msx1 regulates proliferation and differentiation of mouse dental mesenchymal cells in culture. European journal of oral sciences 28 24028588
2016 MSX1 Modulates RLR-Mediated Innate Antiviral Signaling by Facilitating Assembly of TBK1-Associated Complexes. Journal of immunology (Baltimore, Md. : 1950) 27 27194789
2014 An atypical canonical bone morphogenetic protein (BMP) signaling pathway regulates Msh homeobox 1 (Msx1) expression during odontogenesis. The Journal of biological chemistry 27 25274628
2016 Msx1 and Msx2 function together in the regulation of primordial germ cell migration in the mouse. Developmental biology 25 27435625
2013 Novel nonsense mutation in MSX1 in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4. European journal of oral sciences 25 24329876
2004 Cloning and characterization of a gene coding for a hydrophobin, Fv-hyd1, specifically expressed during fruiting body development in the basidiomycete Flammulina velutipes. Applied microbiology and biotechnology 25 15834718
2001 Msx1 gene overexpression induces G1 phase cell arrest in human ovarian cancer cell line OVCAR3. Biochemical and biophysical research communications 25 11243867
2019 Elicitor hydrophobin Hyd1 interacts with Ubiquilin1-like to induce maize systemic resistance. Journal of integrative plant biology 24 30803127
2011 Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype. Molecular cancer therapeutics 24 21980133
2006 Msx1 and Msx2 have shared essential functions in neural crest but may be dispensable in epidermis and axis formation in Xenopus. The International journal of developmental biology 24 16586351
2001 Msx3 protein recruits histone deacetylase to down-regulate the Msx1 promoter. The Biochemical journal 24 11115394
2018 Homeobox protein MSX1 inhibits the growth and metastasis of breast cancer cells and is frequently silenced by promoter methylation. International journal of molecular medicine 23 29436596
2014 Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord. Development (Cambridge, England) 23 24715462
2012 Wnt/β-catenin signaling and Msx1 promote outgrowth of the maxillary prominences. Frontiers in physiology 23 23055979
2011 Expression profiling reveals MSX1 and EphB2 expression correlates with the invasion capacity of Wilms tumors. Pediatric blood & cancer 23 21387540
2007 Conditional alleles of Msx1 and Msx2. Genesis (New York, N.Y. : 2000) 23 17654563
2020 Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during mouse lip development. Development (Cambridge, England) 22 32467233
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 Msx1 homeodomain protein represses the αGSU and GnRH receptor genes during gonadotrope development. Molecular endocrinology (Baltimore, Md.) 22 23371388
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
2003 Selection on coding regions determined Hox7 genes evolution. Molecular biology and evolution 22 12949154
2017 Msh homeobox 1 (Msx1)- and Msx2-overexpressing bone marrow-derived mesenchymal stem cells resemble blastema cells and enhance regeneration in mice. The Journal of biological chemistry 20 28461333
2015 MSX1 gene in the etiology orofacial deformities. Postepy higieny i medycyny doswiadczalnej (Online) 20 27259221
2014 Oncogenic deregulation of NKL homeobox gene MSX1 in mantle cell lymphoma. Leukemia & lymphoma 20 24237447
2013 MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma. Molecular cancer therapeutics 20 24048737
2020 Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development. Nucleic acids research 19 33080014
2018 Next generation sequencing reveals a novel nonsense mutation in MSX1 gene related to oligodontia. PloS one 19 30192788
2008 Msx1 expression regulation by its own antisense RNA: consequence on tooth development and bone regeneration. Cells, tissues, organs 19 18728357
2016 Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. Human reproduction (Oxford, England) 18 27312535
2012 MSX1 gene polymorphisms in non-syndromic cleft lip and/or palate. Oral diseases 18 23130753
2008 Differential impact of MSX1 and MSX2 homeogenes on mouse maxillofacial skeleton. Cells, tissues, organs 18 18769023
2018 Growth factors FGF8 and FGF2 and their receptor FGFR1, transcriptional factors Msx-1 and MSX-2, and apoptotic factors p19 and RIP5 participate in the early human limb development. Acta histochemica 17 29409666
2002 Msx1 homeogene antisense mRNA in mouse dental and bone cells. Connective tissue research 17 12489151
2017 NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia. Oncotarget 16 28977998

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