MSX1 (Msh homeobox 1, formerly HOX7) is a nuclear homeodomain transcription factor of the Msh/Msx family. It binds TAAT-core DNA elements and acts mainly as a transcriptional repressor of RNA polymerase II genes, both through sequence-specific binding (with cofactors such as PIAS1 that target it to repressed loci at the nuclear periphery) and through contacts with the basal transcription machinery; in some contexts it activates targets (e.g. Stra8 in fetal germ cells). MSX1 is expressed at sites of epithelial-mesenchymal interaction, notably the neural crest-derived mesenchyme of the face, dental papilla, palate, limb bud and nail bed, and it is induced by BMP signalling. In tooth development it is required in the dental mesenchyme for progression beyond the bud stage, sustaining mesenchymal BMP4 expression and later restraining premature odontoblast differentiation by repressing Bmp2, Bmp4 and Lef1. Heterozygous loss-of-function variants cause selective tooth agenesis (oligodontia), sometimes with cleft lip/palate, and Witkop tooth-and-nail syndrome; Msx1-null mice have cleft secondary palate, arrested tooth buds and craniofacial bone defects. Earlier in development, Msx genes are BMP-responsive neural plate border specifiers: in frog embryos Msx1 acts upstream of Pax3 and Zic to initiate neural crest formation, and in mouse Msx1 and Msx2 together are needed for patterning and survival of cranial and cardiac neural crest. Msx expression at the edge of the neural plate is shared with amphioxus, indicating that this border role predates vertebrates.
Definition: The formation of the neural plate border, the region of ectoderm at the boundary between the neural plate and the non-neural ectoderm that is competent to give rise to neural crest, preplacodal ectoderm, dorsal neural tube and epidermis.
Justification: GO has no term for the neural plate border. GO:0014029 neural crest formation is defined as forming this ectodermal region but is placed under epithelial to mesenchymal transition, so border specifiers end up annotated to an EMT term. The border is conserved in chordates without neural crest (amphioxus, tunicates), so it cannot be a part of neural crest formation. See projects/NEURAL_CREST_FORMATION_OBSOLETION.md.
Parent term: ectoderm development
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | ACCEPT | Summary: Logical inference from the repressor MF. MSX1 is a homeodomain transcriptional repressor of Pol II genes. Reason: Mouse Msx1 is a potent repressor in vitro and in cells, and Msx1 and Msx2 repress through the same consensus; the human R31P allele that loses repression causes tooth agenesis. Repression of Pol II targets (Bmp2/Bmp4/Lef1 in dental mesenchyme, MyoD in myoblasts) is the core mechanism. Supporting Evidence: PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. PMID:8861098 both MSX-1 and MSX-2 function as repressors and share the distinct property that they do so independently of their consensus DNA binding sites. PMID:9742121 it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based location for a sequence-specific homeodomain TF; consistent with DNA-bound action. Reason: MSX1 binds TAAT-core elements and target enhancers (e.g. the MyoD CER) in chromatin; chromatin is an appropriate location for a DNA-binding TF. Supporting Evidence: PMID:16600910 PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells |
| GO:0000902 cell morphogenesis | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | MARK AS OVER ANNOTATED | Summary: IDA from the p53/apoptosis overexpression study; any cell shape change reflects apoptosis in cancer cells, not a developmental role. Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. A cell morphogenesis annotation from apoptotic or growth-arrest morphology overstates the biology. Kept as over-annotated rather than removed because the full text was not seen. Supporting Evidence: PMID:15705871 Overexpression of homeobox Msx1 induced apoptosis of cancer cells harboring nonfunctional wild-type p53 and suppressed growth of human tumor xenografts in nude mice. |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of a mouse contributes_to cis-regulatory binding annotation. Reason: Msx1 binds cis-regulatory elements of its targets, with PIAS1 conferring selectivity in vivo; the contributes_to qualifier fits cofactor-dependent binding. Supporting Evidence: PMID:16600910 PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Msx1 (PIAS1/MyoD CER study). Reason: Mouse Msx1 binds the MyoD core enhancer region selectively in myoblasts; the homeodomain is identical in human, and human MSX1 binds DNA in SELEX. Supporting Evidence: PMID:16600910 PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for Pol II regulatory region sequence-specific DNA binding across the Msx clade. Reason: Phylogenetically sound: Msx homeodomain proteins bind TAAT-core sites; human MSX1 binds DNA in vitro and the DNA-contacting R31 is required. Supporting Evidence: PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. PMID:9742121 it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of the same DNA-binding term from mouse. Reason: Same as IBA row. Supporting Evidence: PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for DNA-binding TF activity, Pol II-specific. Reason: Correct for an Msx homeodomain TF. The more precise repressor term GO:0001227 is also present; the generic term covers context-dependent activation (e.g. Stra8). Supporting Evidence: PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. PMID:22071108 In F9 cells, Msx1 can bind to Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA for DNA-binding TF activity. Reason: Same as IBA row. Supporting Evidence: PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass assignment as a DNA-binding TF. Reason: Same as IBA row. Supporting Evidence: PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer from mouse (IDA) of cis-regulatory region sequence-specific DNA binding. Reason: Consistent with MSX1 binding target enhancer/promoter elements. Supporting Evidence: PMID:16600910 PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer from mouse IDA/IMP (PMID:8861098) of Pol II-specific repressor activity. This is the core molecular function. Reason: Mouse Msx1 is a strong repressor; the human R31P disease allele loses repression and DNA binding and is null. Repression of Bmp2/Bmp4/Lef1 keeps dental mesenchyme undifferentiated. Note that part of Msx1 repression is independent of its own DNA sites (TBP/core-machinery contacts), so the repressor term describes the best-characterised but not the only mechanism. Supporting Evidence: PMID:8861098 both MSX-1 and MSX-2 function as repressors and share the distinct property that they do so independently of their consensus DNA binding sites. PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. PMID:9742121 it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. PMID:29148101 overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer from mouse IDA (Le Bouffant 2011, Stra8 in fetal germ cells). Reason: Msx1 can activate Stra8 in germ cells, so activation occurs in some contexts, but MSX1 is predominantly a repressor; activation is non-core. Supporting Evidence: PMID:22071108 In F9 cells, Msx1 can bind to Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. |
| GO:0001837 epithelial to mesenchymal transition | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer from a mouse IMP sourced to PMID:11023873. Reason: The source paper studies epithelial-mesenchymal interactions in the tooth germ by tissue recombination; it does not report an epithelial to mesenchymal transition. Msx1 acts in dental mesenchyme to signal to epithelium, which is inductive signalling, not EMT. The electronic transfer to human should be removed and the mouse source checked. Supporting Evidence: PMID:11023873 The development of many organs depends on sequential epithelial-mesenchymal interactions PMID:11023873 through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. |
| GO:0002039 p53 binding | IPI PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | KEEP AS NON CORE | Summary: IPI: MSX1 homeodomain binds p53 (Park et al. 2005). Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. p53 binding is an informative MF and the interaction was shown directly, so it is retained, but as non-core. Supporting Evidence: PMID:15705871 Here, we identify homeobox Msx1 as a p53-interacting protein and show its novel function as a p53 regulator. PMID:15705871 The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. |
| GO:0003161 cardiac conduction system development | NAS PMID:26786210 The formation and function of the cardiac conduction system. | MARK AS OVER ANNOTATED | Summary: NAS from a review of cardiac conduction system development. Reason: The primary evidence is that Msx1/Msx2 bind Tbx2/3/5 and, with Tbx3, repress Cx43 in a cardiac cell line. There is no conduction-system loss-of-function phenotype for MSX1 alone; Msx1/2 double mutants show conotruncal (neural crest) defects instead. A developmental process annotation from an author statement in a review overstates the evidence. Supporting Evidence: PMID:26786210 CCS development involves complex regulatory networks that act in stage-, tissue- and dose-dependent manners PMID:18285513 Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro homeodomain mapping to DNA binding. Reason: Correct, though general. Supporting Evidence: PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI yeast two-hybrid interaction with RBPMS isoform 3. Reason: Generic protein binding is uninformative. The high-throughput screen gives no functional context for an MSX1-RBPMS interaction, so no more specific MF can be supported. Removal does not mean the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus. Reason: MSX1 is a nuclear transcription factor. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0005634 nucleus | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | ACCEPT | Summary: IDA nucleus (Park et al. 2005). Reason: Nuclear localisation of MSX1 is consistent across studies. Supporting Evidence: PMID:15705871 The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA nucleus. Reason: As above. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS nucleus from mouse. Reason: As above. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: nucleoplasm. Reason: Consistent with a nuclear TF. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of a mouse IPI (Msx1 with Tbx5). Reason: Msx1 binds T-box factors in pull-downs and co-represses Cx43 with Tbx3; a TF partner complex is plausible but context-specific. Supporting Evidence: PMID:18285513 we demonstrate that muscle segment homeobox genes Msx1 and Msx2 are able to bind the cardiac T-box proteins Tbx2, Tbx3, and Tbx5 PMID:18285513 Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to regulation of DNA-templated transcription. Reason: Correct, general. Supporting Evidence: PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA regulation of transcription by RNA polymerase II. Reason: Correct level for the Msx clade. Supporting Evidence: PMID:7823952 Msx-1 is a potent repressor of transcription and can function through both TATA-containing and TATA-less promoters. PMID:8861098 both MSX-1 and MSX-2 function as repressors and share the distinct property that they do so independently of their consensus DNA binding sites. |
| GO:0009887 animal organ morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA animal organ morphogenesis. Reason: True (tooth, palate) but very general; the specific terms carry the information. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. |
| GO:0010463 mesenchymal cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer from mouse IMP: mesenchymal cell proliferation. Reason: Msx1 knockdown reduces dental mesenchyme proliferation; a real but downstream, tissue-specific role. Supporting Evidence: PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. |
| GO:0010629 negative regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: negative regulation of gene expression (Bmp2/Bmp4). Reason: A consequence of MSX1 repressor activity on Bmp2/Bmp4/Lef1 in dental mesenchyme; better captured by GO:0000122. Supporting Evidence: PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. PMID:29148101 overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. |
| GO:0030308 negative regulation of cell growth | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | MARK AS OVER ANNOTATED | Summary: IDA: overexpression suppressed tumour cell growth. Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. Growth suppression after overexpression is not evidence that endogenous MSX1 negatively regulates cell growth; in dental mesenchyme MSX1 promotes proliferation. Supporting Evidence: PMID:15705871 Overexpression of homeobox Msx1 induced apoptosis of cancer cells harboring nonfunctional wild-type p53 and suppressed growth of human tumor xenografts in nude mice. PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. |
| GO:0034399 nuclear periphery | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer from mouse IDA: nuclear periphery (is_active_in). Reason: In myoblasts PIAS1 retains Msx1 at the nuclear periphery near repressed targets; context-specific subnuclear location. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0034399 nuclear periphery | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: nuclear periphery. Reason: As above. Supporting Evidence: PMID:16600910 We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. |
| GO:0034504 protein localization to nucleus | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | MARK AS OVER ANNOTATED | Summary: IDA: Msx1 promotes nuclear accumulation of p53. Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. MSX1 is not a nuclear transport factor; nuclear accumulation of p53 is an indirect effect of binding/stabilisation. Supporting Evidence: PMID:15705871 The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. |
| GO:0035880 embryonic nail plate morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of embryonic nail plate morphogenesis. Reason: Real but pleiotropic: Witkop syndrome and Msx1-null nail plate defects. Supporting Evidence: PMID:11369996 Nail plates in Msx1 -null mice were defective and were thinner than those of their wild-type littermates. |
| GO:0035880 embryonic nail plate morphogenesis | IMP PMID:11369996 A nonsense mutation in MSX1 causes Witkop syndrome. | KEEP AS NON CORE | Summary: IMP: S202X MSX1 causes Witkop tooth-and-nail syndrome; Msx1-null mice have thin nail plates. Reason: Well supported in human and mouse; nail is a secondary site of the same mesenchymal Msx1 function as in tooth, so kept as non-core. Supporting Evidence: PMID:11369996 Msx1 is critical for both tooth and nail development PMID:11369996 Nail plates in Msx1 -null mice were defective and were thinner than those of their wild-type littermates. |
| GO:0042475 odontogenesis of dentin-containing tooth | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of odontogenesis of dentin-containing tooth. Reason: Core mammalian role. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. PMID:11023873 through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. |
| GO:0042475 odontogenesis of dentin-containing tooth | IMP PMID:10742093 MSX1 mutation is associated with orofacial clefting and toot... | ACCEPT | Summary: IMP: human MSX1 truncation causes tooth agenesis with clefting. Reason: Human genetic evidence for the core tooth role; the cache has only the title (no abstract), but the title states the phenotype. Supporting Evidence: PMID:10742093 MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. |
| GO:0042475 odontogenesis of dentin-containing tooth | IMP PMID:11369996 A nonsense mutation in MSX1 causes Witkop syndrome. | ACCEPT | Summary: IMP: Witkop syndrome. Reason: Missing permanent teeth caused by MSX1 S202X. Supporting Evidence: PMID:11369996 Msx1 is critical for both tooth and nail development |
| GO:0042475 odontogenesis of dentin-containing tooth | IMP PMID:8696335 A human MSX1 homeodomain missense mutation causes selective ... | ACCEPT | Summary: IMP: R31P homeodomain missense causes familial selective tooth agenesis. Reason: Strong human genetic evidence; R31P is functionally null. Supporting Evidence: PMID:8696335 We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis. PMID:9742121 it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. |
| GO:0042476 odontogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of odontogenesis. Reason: Parent of the above; correct. Supporting Evidence: PMID:11023873 through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. |
| GO:0042481 regulation of odontogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of regulation of odontogenesis. Reason: MSX1 regulates stage-specific tooth development (bud-to-cap progression; restraint of odontoblast differentiation). Supporting Evidence: PMID:11023873 through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. PMID:24028588 MSX1 may promote proliferation and prevent the differentiation of dental mesenchymal cells by the inhibition of Bmp2 and Bmp4 expression. |
| GO:0042481 regulation of odontogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS regulation of odontogenesis. Reason: As above. Supporting Evidence: PMID:29148101 overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. |
| GO:0042482 positive regulation of odontogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of positive regulation of odontogenesis (mouse IMP, PMID:7914451). Reason: Msx1 is required for tooth development to pass the bud stage. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. PMID:11023873 through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. |
| GO:0042482 positive regulation of odontogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS positive regulation of odontogenesis. Reason: As above. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. |
| GO:0043517 positive regulation of DNA damage response, signal transduction by p53 class mediator | IC PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | MARK AS OVER ANNOTATED | Summary: IC from the protein stabilization IDA (p53 study). Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. The study does not, per its abstract, involve a DNA damage response, so a DNA-damage p53 signalling term inferred by curator is a stretch. Supporting Evidence: PMID:15705871 The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of sequence-specific DNA binding. Reason: Correct. Supporting Evidence: PMID:8861098 MSX-1 and MSX-2 interact with a common consensus DNA site, and exhibit similar DNA binding site preferences. |
| GO:0043584 nose development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of nose development (mouse IMP, nasal bone defects). Reason: Real craniofacial phenotype, part of the broader craniofacial role. Supporting Evidence: PMID:7914451 These mice also exhibit abnormalities of the nasal, frontal and parietal bones, and of the malleus in the middle ear. |
| GO:0043584 nose development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS nose development. Reason: As above. Supporting Evidence: PMID:7914451 These mice also exhibit abnormalities of the nasal, frontal and parietal bones, and of the malleus in the middle ear. |
| GO:0045787 positive regulation of cell cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of positive regulation of cell cycle (mouse IMP). Reason: Knockdown prolongs S phase in dental mesenchyme; a downstream, context-specific role. Supporting Evidence: PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. |
| GO:0045787 positive regulation of cell cycle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS positive regulation of cell cycle. Reason: As above. Supporting Evidence: PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Logical inference from the activator MF. Reason: Activation (e.g. Stra8) is context-dependent; MSX1 is mainly a repressor. Supporting Evidence: PMID:22071108 In F9 cells, Msx1 can bind to Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. |
| GO:0048598 embryonic morphogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA embryonic morphogenesis for the Msx clade. Reason: Broad but phylogenetically sound summary of Msx developmental roles (craniofacial, limb, neural crest). Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. PMID:16221730 We show that Msx1/2 mutants exhibit profound deficiencies in the development of structures derived from the cranial and cardiac neural crest. |
| GO:0048839 inner ear development | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl transfer of inner ear development from mouse IMP (PMID:7914451). Reason: The Satokata and Maas abstract reports malleus (middle ear) defects, not inner ear. Mouse Msx1 also carries GO:0042474 middle ear morphogenesis. Without the full text it is unclear whether inner ear defects were reported; GO:0042474 may be the intended term. Supporting Evidence: PMID:7914451 These mice also exhibit abnormalities of the nasal, frontal and parietal bones, and of the malleus in the middle ear. |
| GO:0048839 inner ear development | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS inner ear development. Reason: As above. Supporting Evidence: PMID:7914451 These mice also exhibit abnormalities of the nasal, frontal and parietal bones, and of the malleus in the middle ear. |
| GO:0050821 protein stabilization | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | KEEP AS NON CORE | Summary: IDA: MSX1 stabilises wild-type p53. Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. Supporting Evidence: PMID:15705871 The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. |
| GO:0060021 roof of mouth development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS roof of mouth development (mouse IMP: cleft secondary palate). Reason: Palate development is a core MSX1 role; human MSX1 variants cause clefting. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. PMID:10742093 MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. |
| GO:0060325 face morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of face morphogenesis. Reason: Core craniofacial role. Supporting Evidence: PMID:7914451 All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. |
| GO:0060325 face morphogenesis | IMP PMID:10742093 MSX1 mutation is associated with orofacial clefting and toot... | ACCEPT | Summary: IMP: MSX1 truncating mutation with orofacial clefting. Reason: Human genetic evidence (title only in cache). Supporting Evidence: PMID:10742093 MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. |
| GO:0060325 face morphogenesis | IMP PMID:11332647 Evidence of a sex-dependent association between the MSX1 loc... | ACCEPT | Summary: IMP from a Chilean cleft association study. Reason: Association evidence is weak on its own (a microsatellite allele, sex-dependent), but it agrees with mutation and mouse data, so the face morphogenesis claim is accepted as part of the synthesis. Supporting Evidence: PMID:11332647 genetic variation at the MSX1 locus is a predisposing gene involved in sex-dependent susceptibility to clefting |
| GO:0060325 face morphogenesis | IMP PMID:12651933 MSX1 and TGFB3 contribute to clefting in South America. | ACCEPT | Summary: IMP from a South American TDT association study. Reason: As above; supports the established MSX1 role in lip/palate. Supporting Evidence: PMID:12651933 These results suggest that MSX1 and TGFB3 mutations make a contribution to clefts in South American populations. |
| GO:1901330 negative regulation of odontoblast differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of negative regulation of odontoblast differentiation. Reason: Msx1 represses Bmp2/Bmp4/Lef1 and thereby restrains odontoblast differentiation in the bell-stage dental mesenchyme. MSX1 is itself BMP-induced in dental mesenchyme (a BMP target, not a transducer), which closes a feedback loop. Supporting Evidence: PMID:24028588 Knockdown of Msx1 expression was associated with decreased cell proliferation, prolonged time in the S phase of the cell cycle, enhanced odontoblast differentiation, and elevated Bmp2 and Bmp4 expression. PMID:29148101 overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. file:human/MSX1/MSX1-deep-research-falcon.md Thus MSX1 is a BMP-responsive transcriptional factor, not a BMP receptor or a BMP ligand. |
| GO:1901330 negative regulation of odontoblast differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS negative regulation of odontoblast differentiation. Reason: As above. Supporting Evidence: PMID:29148101 overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. |
| GO:1902255 positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator | IDA PMID:15705871 Homeobox Msx1 interacts with p53 tumor suppressor and inhibi... | KEEP AS NON CORE | Summary: IDA: MSX1 overexpression promotes p53-dependent apoptosis. Reason: Single study (Park et al. 2005) in which Msx1 was overexpressed in cancer cell lines and xenografts; the cached record is abstract-only. No developmental or loss-of-function evidence ties endogenous MSX1 to p53 signalling, and MSX1 mutations cause tooth/craniofacial phenotypes, not p53-related ones. Supporting Evidence: PMID:15705871 Overexpression of homeobox Msx1 induced apoptosis of cancer cells harboring nonfunctional wild-type p53 and suppressed growth of human tumor xenografts in nude mice. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: IDA: human MSX1 binds DNA in methylation-sensitive SELEX (Yin 2017). Reason: Direct biochemical evidence for sequence-specific double-stranded DNA binding by the human protein. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. |
| NTR neural plate border formation | ISS PMID:15691759 Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals duri... | NEW | Summary: Msx1 is a BMP-responsive neural plate border specifier: induced at the border by intermediate BMP levels, it activates pax3 and zic, and through them the crest specifiers, and it is required for neural crest formation (Xenopus). Reason: Synthesis across lines of evidence (all in Xenopus or mouse; human is the project proxy). (1) Expression: msx1 is a direct BMP target expressed in the neural folds at an intermediate BMP level (Tribulo 2003). (2) Gain of function: inducible msx1 induces snail, slug and foxd3; in neuralized ectoderm Msx1 is sufficient for multiple early crest genes and induces Pax3 and Zic cell-autonomously (Monsoro-Burq 2005). (3) Loss of function: dominant-negative Msx and msx1/msx2 morpholinos abolish crest markers, with Msx1/Msx2 compensating each other (Tribulo 2003; Khadka 2006). (4) Epistasis: Pax3 acts downstream of Msx1; snail/slug rescue the Msx dominant negative; Gbx2 is upstream of Msx1. (5) Conservation: amphioxus Msx is expressed at the neural plate edge and is BMP-responsive (Yu 2008), so the border role is ancestral. Network layer: border specifier, upstream of Pax3/Zic1. This role is captured by the proposed term 'neural plate border formation' (NTR), which replaces GO:0014029 (proposed for obsoletion: its text describes the border region but it is placed under epithelial to mesenchymal transition), as for pax3-a, zic1 and gbx2. GO:0014036 would overstate it, and GO:0014034 is not added because, unlike Pax3/Zic1, Msx1 has not been shown to bind crest specifier enhancers. Participation: Msx1 is a transcription factor acting inside the border cells, not a signal or substrate. Comparator check (QuickGO 2026-10-05): no Msx protein in any species (human, mouse, chicken, zebrafish, X. laevis, X. tropicalis) carries any neural crest branch term under any evidence; the frog msx entries are TrEMBL with only IBA rows. Same-layer peers pax3-a and zic1 carry GO:0014029 by IMP, so the absence is an uncurated literature gap, not a convention. Evidence is ISS from Xenopus; in mammals Msx1/Msx2 double mutants form crest but show cranial/cardiac crest patterning and survival defects. Flagged for curator sign-off: because no Msx in any species carries a crest-branch term and the mammalian phenotype is patterning rather than border formation, this NEW should not be submitted until the border term exists and a curator confirms that the frog border role transfers to human MSX1 (see suggested_questions). Supporting Evidence: PMID:14627721 Our results indicate that an intermediate level of Bmp activity specifies the expression of Msx genes in the neural fold region. PMID:14627721 msx1 expression is able to induce all other early neural crest markers tested (snail, slug, foxd3) at the time of neural crest specification. PMID:14627721 Furthermore, the expression of a dominant negative of Msx genes leads to the inhibition of all the neural crest markers analyzed. PMID:15691759 In neuralized ectoderm, Msx1 is sufficient to induce multiple early neural crest genes. PMID:15691759 Msx1 induces Pax3 and ZicR1 cell autonomously, in turn, Pax3 combined with ZicR1 activates Slug in a WNT-dependent manner. PMID:15691759 Msx1 and Pax3 are both required for neural crest formation, display overlapping but nonidentical activities, and that Pax3 acts downstream of Msx1. PMID:16586351 These results indicate that Msx1 and Msx2 are both essential for neural crest development, but that the two genes have the same function in this tissue. PMID:19736322 demonstrate that Gbx2 is upstream of the neural fold specifiers Pax3 and Msx1. PMID:18562679 whereas Msx is expressed not only in the epidermal ectoderm, but extends more medially into the neural ectoderm at the edges of the neural plate. PMID:18562679 In Bmp4-treated embryos, the expression of the epidermal marker AP2 was expanded medially; the epidermal domains of Dlx and Msx also were expanded |
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Download this section (compressed HTML)Q: GO has no neural plate border formation/specification term; GO:0014029 neural crest formation is currently used for border specifiers (Msx1, Pax3, Zic1, Gbx2) and is proposed for obsoletion in favour of a new 'neural plate border formation' term. Should that term's scope explicitly include the epidermal and non-crest border derivatives to which Msx genes also contribute?
Q: No Msx protein in any species carries a neural crest process term, although frog loss- and gain-of-function data (Tribulo 2003, Monsoro-Burq 2005, Khadka 2006) are strong. Should the X. laevis msx1.L/msx1.S TrEMBL entries receive the IMP rows directly, rather than relying on ISS to human?
Q: In mouse, Msx1/Msx2 double mutants form crest but show cranial/cardiac crest mispatterning, migration delay and apoptosis (PMID:16221730). Do mammals use Msx genes at the border at all, or has the requirement shifted to later crest development (e.g. GO:0014032 or GO:0001755 by IGI)?
Q: The human inner ear development rows derive from a mouse IMP to Satokata and Maas 1994, whose abstract reports middle ear (malleus) defects. Is GO:0048839 a mis-mapping for GO:0042474 middle ear morphogenesis?
Q: Mouse Msx1 GO:0001837 epithelial to mesenchymal transition is sourced to PMID:11023873, a tissue-recombination study of epithelial-mesenchymal interactions. Should the mouse source annotation be reviewed?
Q: Is MSX1 acting as a repressor at the neural plate border (as in tooth), and what are its direct targets there (pax3, zic1)? Is the border activity DNA-binding dependent?
Experiment: CUT&RUN for endogenous Msx1 in gastrula/neurula Xenopus border explants to test whether Msx1 directly occupies pax3 and zic1 regulatory elements, and whether it binds crest specifier enhancers (which would justify GO:0014034).
Experiment: Replace Xenopus msx1 with amphioxus Msx in the msx1 morphant rescue and animal-cap induction assays to separate protein evolution from cis-regulatory evolution of the border-to-crest link.
Experiment: Conditional Msx1/Msx2 deletion in mouse neural plate border ectoderm (before crest specification) to test whether mammals require Msx genes for crest induction, scoring Pax3, Snai2, Sox10 and Foxd3.
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