Paired box protein Pax-7 is a nuclear transcription factor of the Pax3/7 subgroup. It binds DNA through an N-terminal paired domain and a paired-type homeodomain, as a monomer or as a heterodimer with its paralog PAX3, and mainly activates its targets, acting as a pioneer factor that can open closed enhancers. In the early embryo, PAX7 is a neural plate border specifier. It is expressed in the border region from gastrulation, before neural crest specifier genes. It is required for their expression and, with MSX1/2, directly activates FOXD3 enhancers, together with ETS1 cranially and ZIC1 in the trunk. Pax7-expressing cells contribute mainly to cranial neural crest, and its loss in mouse disrupts crest-derived facial structures. PAX7 is also expressed in dorsal neural tube progenitors, where, redundantly with PAX3, it restricts ventral neuronal identity. In skeletal muscle, PAX7 specifies and maintains satellite (muscle stem) cells. It is required for their formation, self-renewal and expansion, and hence for muscle regeneration, and activates targets such as MYF5 and ID3. Biallelic loss-of-function variants cause a congenital myopathy with satellite cell exhaustion, and the PAX7-FOXO1 fusion from t(1;13) drives alveolar rhabdomyosarcoma. Pax3/7 expression at the neural plate border is conserved in amphioxus, so PAX7's border role belongs to an ancestral chordate layer of the neural crest regulatory network.
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:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based ISA: PAX7 as a sequence-specific DNA-binding transcription factor is located on chromatin. Reason: PAX7 is a chromatin-bound transcription factor; in pituitary and muscle precursors it binds and remodels enhancers in chromatin (pioneer activity). Correct and appropriately general. Supporting Evidence: PMID:29358650 Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the Pax family node: binding to RNA polymerase II cis-regulatory sequences. Reason: Core molecular function, inherited across the paired-box family. PAX7 binds cis-regulatory elements in vivo, e.g. the FoxD3 NC1 enhancer in chick cranial crest (ChIP) and melanotrope enhancers in mouse pituitary. Supporting Evidence: PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. PMID:29358650 Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: Core MF at the PAINT level, consistent with paired domain plus homeodomain DNA binding and target activation. The activator child GO:0001228 is proposed separately as NEW. Supporting Evidence: PMID:23284303 Detailed regulatory analysis shows that initial expression of FoxD3 in both cranial and trunk neural crest requires direct input from neural plate border genes, Pax7 and Msx1/2. PMID:29358650 Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (Ensembl ortholog/InterPro): Pol II-specific DNA-binding TF activity. Reason: Consistent with IBA and experimental evidence. Supporting Evidence: PMID:23284303 Detailed regulatory analysis shows that initial expression of FoxD3 in both cranial and trunk neural crest requires direct input from neural plate border genes, Pax7 and Msx1/2. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass ISA: Pol II-specific DNA-binding TF activity (paired-domain class 3.2.1). Reason: Correct classification of PAX7 as a paired-box DNA-binding transcription factor. Supporting Evidence: PMID:9339373 The PAX7 gene encodes a transcription factor that is a member of the PAX family of developmental control genes. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA: DNA binding (paired domain, homeodomain). Reason: Correct but general; more specific DNA-binding rows exist. 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:31092906 Biallelic variants in the transcription factor PAX7 are a ne... | ACCEPT | Summary: IDA from Feichtinger et al. 2019, the report of biallelic PAX7 variants causing myopathy with satellite cell exhaustion. The cached record is abstract-only. Reason: The abstract frames PAX7 as a key transcriptional regulator of satellite cells; the curator (UniProt) presumably annotated from functional assays of variants in the full text, which we cannot see. DNA-binding TF activity is unquestionably correct for PAX7, so the curator is deferred to. The more specific Pol II terms are also present. Supporting Evidence: PMID:31092906 Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara IEA from mouse Pax7: DNA-binding transcription factor activity. Reason: Correct, general parent of the Pol II-specific term. Supporting Evidence: PMID:9339373 The PAX7 gene encodes a transcription factor that is a member of the PAX family of developmental control genes. |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:9339373 The genomic organization and the full coding region of the h... | ACCEPT | Summary: TAS from the human PAX7 gene structure paper (Vorobyov et al. 1997). Reason: The statement that PAX7 encodes a transcription factor is correct; the paper itself is a cloning and exon/intron structure paper, so this is weak but accurate support. Supporting Evidence: PMID:9339373 The PAX7 gene encodes a transcription factor that is a member of the PAX family of developmental control genes. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: active in nucleus. Reason: Nuclear transcription factor; consistent with in vivo chromatin binding. Supporting Evidence: PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA: nucleus. Reason: Correct. Supporting Evidence: PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Pax7 (P47239): nucleus. Reason: Correct. Supporting Evidence: PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA: regulation of DNA-templated transcription. Reason: Correct but general; the Pol II-specific regulation term (IBA) is the better level. Supporting Evidence: PMID:23284303 Taken together, these results place Pax7 and Msx1/2 as general regulators of FoxD3 expression, while Ets1 and Zic1 seem to specifically regulate NC1 and NC2, respectively. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: regulation of transcription by RNA polymerase II. Reason: Core process for a sequence-specific Pol II transcription factor; PAX7 directly regulates FoxD3 in crest and myogenic/pituitary targets elsewhere. Supporting Evidence: PMID:23284303 Taken together, these results place Pax7 and Msx1/2 as general regulators of FoxD3 expression, while Ets1 and Zic1 seem to specifically regulate NC1 and NC2, respectively. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from a broad Pax node: nervous system development. Reason: Not wrong: PAX7 acts at the neural plate border and in the dorsal neural tube (Pax3/Pax7 restrict ventral neuronal identity in the spinal cord). But this is a generic family-level process; the specific roles are captured by the proposed 'neural plate border formation' term (NTR, replacing GO:0014029) and GO:0021904. Same treatment as frog pax3-a. Supporting Evidence: PMID:9858722 Analysis of Pax3 and Pax7 double mutant mice demonstrates that both genes share redundant functions to restrict ventral neuronal identity in the spinal cord. PMID:16688176 This region expresses the transcription factor Pax7 by stage 4 + and later contributes to neural folds and migrating neural crest. |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA: anatomical structure morphogenesis. Reason: Very generic. Loss of Pax7 in mouse causes malformations of cephalic neural crest-derived facial structures (maxilla, nose), so a morphogenetic role exists, but it is a downstream consequence of the border/crest role rather than a core function. Supporting Evidence: PMID:8631261 Our analysis suggests that the observed phenotype is due to a cephalic neural crest defect. |
| GO:0009653 anatomical structure morphogenesis | TAS PMID:9339373 The genomic organization and the full coding region of the h... | KEEP AS NON CORE | Summary: TAS from the human PAX7 gene structure paper, which describes PAX genes as developmental control genes. Reason: The source only places PAX7 in a family of developmental control genes; the term is generic and non-core. Kept because mouse genetics (craniofacial crest derivatives) supports a morphogenetic contribution. Supporting Evidence: PMID:9339373 The PAX7 gene encodes a transcription factor that is a member of the PAX family of developmental control genes. PMID:8631261 Our analysis suggests that the observed phenotype is due to a cephalic neural crest defect. |
| GO:0014816 skeletal muscle satellite cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara IEA from mouse Pax7: skeletal muscle satellite cell differentiation. Reason: Core mammalian role. Pax7 is required for the satellite cell lineage to form (no satellite cells in Pax7-null muscle), and human biallelic PAX7 loss exhausts the satellite cell pool. Supporting Evidence: PMID:11030621 Cell culture and electron microscopic analysis revealed a complete absence of satellite cells in Pax7(-/-) skeletal muscle. PMID:31092906 A lack of PAX7 expression was associated with satellite cell pool exhaustion file:human/PAX7/PAX7-deep-research-falcon.md In postnatal muscle, PAX7 maintains the identity and regenerative potential of myogenic satellite cells and helps govern their progression between quiescence, proliferation, self-renewal and commitment. |
| GO:0014816 skeletal muscle satellite cell differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Pax7 (P47239): skeletal muscle satellite cell differentiation. Reason: Core. Satellite cells are absent in Pax7-/- mice, Pax3/Pax7 double mutants lose the resident myogenic progenitor population, and PAX7 deficiency in patients is associated with satellite cell pool exhaustion. Supporting Evidence: PMID:11030621 Cell culture and electron microscopic analysis revealed a complete absence of satellite cells in Pax7(-/-) skeletal muscle. PMID:15843801 In the absence of both Pax3 and Pax7, further muscle development is arrested and only the early embryonic muscle of the myotome forms. PMID:31092906 A lack of PAX7 expression was associated with satellite cell pool exhaustion |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:10871843 Transcriptional modulation of the anti-apoptotic protein BCL... | UNDECIDED | Summary: TAS (ProtInc) from Margue et al. 2000, on BCL-XL transcriptional modulation by PAX3 and PAX3/FKHR. Reason: The cached record is abstract-only and the abstract concerns PAX3 and PAX3/FKHR, not PAX7; the full text may discuss PAX7 (the same paper sources a TAS apoptotic-process row on human PAX3). We cannot verify what the statement says about PAX7. Biologically, PAX7 loss is associated with satellite cell loss in humans and mice, but this has not been shown to be an anti-apoptotic transcriptional function of PAX7, so the row is left undecided rather than accepted or removed. Supporting Evidence: PMID:10871843 we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR PMID:31092906 A lack of PAX7 expression was associated with satellite cell pool exhaustion |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara IEA: sequence-specific DNA binding. Reason: Correct; supported by SELEX and ChIP data. 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. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: IDA from the methyl-SELEX survey of human TFs (Yin et al. 2017), which profiled full-length TFs and DNA-binding domains on double-stranded ligands. Reason: Direct biochemical evidence of sequence-specific double-stranded DNA binding by human PAX7 (motif data in the supplement). 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:16688176 Specification of the neural crest occurs during gastrulation... | NEW | Summary: Pax7 is a neural plate border specifier in amniotes. In chick it marks the gastrula epiblast region specified to form crest. It is required for Slug, Sox9, Sox10 and HNK-1, and with Msx1/2 it binds and activates the FoxD3 NC1/NC2 enhancers directly. Pax7-null mice have cephalic crest defects. Reason: Human PAX7 has no neural crest term. The combined evidence places PAX7 in the border layer. It is expressed at the border before crest specifiers and is required for their expression (chick translation-blocking morpholinos). It directly occupies a specifier enhancer (FoxD3 NC1, ChIP), and mouse Pax7-/- shows cephalic crest derivative dysgenesis, with Pax3 redundancy. Lineage tracing shows Pax7 descendants contribute mainly to cranial crest. Term level: 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), following the border-gene convention used for frog pax3-a, zic1, MSX1 and TFAP2A. GO:0014034 commitment was not added. Frog Pax3 earned it from Pax3+Zic1 sufficiency to induce crest, and no equivalent sufficiency is shown for Pax7. Pax7+ border cells are not all crest-fated, and its effects on Sox10 are indirect. GO:0014036 is for the downstream specifiers. Participation: PAX7 does part of the work, as a DNA-binding activator at specifier enhancers. Comparator (QuickGO 2026-10-08): no Pax7 in any species carries an NC-branch term. Chick PAX7 (O42349) has only ISS muscle/neural-tube terms (Basch 2006 is uncurated), mouse Pax7's crest phenotype paper was curated to GO:0048706, and same-layer frog pax3 and zic1 carry GO:0014029 by IMP. This is a coverage gap, not a convention. ISS, because the experiments are in chick and mouse. Supporting Evidence: PMID:16688176 This region expresses the transcription factor Pax7 by stage 4 + and later contributes to neural folds and migrating neural crest. PMID:16688176 In chicken embryos, Pax7 is required for neural crest formation in vivo, because blocking its translation inhibits expression of the neural crest markers Slug, Sox9, Sox10 and HNK-1. PMID:23284303 Detailed regulatory analysis shows that initial expression of FoxD3 in both cranial and trunk neural crest requires direct input from neural plate border genes, Pax7 and Msx1/2. PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. PMID:8631261 Our analysis suggests that the observed phenotype is due to a cephalic neural crest defect. PMID:22848431 we found a higher contribution of Pax7 descendants in the cranial compared to either cardiac or trunk neural crest PMID:18562679 Ectodermal Zic and Pax3/7 expression marks the neural plate border, and amphioxus SoxB1-a expression labels the entire neural plate. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS PMID:23284303 Dynamic and differential regulation of stem cell factor FoxD... | NEW | Summary: Pax7 binds and activates cis-regulatory elements: the FoxD3 NC1 enhancer in chick crest (ChIP, knockdown abolishes enhancer activity) and melanotrope enhancers that it opens as a pioneer in mouse pituitary. Reason: The existing MF rows stop at GO:0000981. In every well-characterised context PAX7 acts as an activator of its direct targets. In chick, Pax7 knockdown abolishes NC1/NC2 enhancer activity and endogenous FoxD3, and Pax7 occupies NC1 in vivo. In mouse pituitary, Pax7 opens and activates a melanotrope enhancer repertoire. This matches the GO:0001228 added to the frog Pax3 paralog (pax3-a, IDA). Comparator: among Pax3/7 proteins none carries GO:0001228 in GOA (they sit at GO:0000981); the pax3-a review added it as NEW. ISS from chick/mouse orthologs. Supporting Evidence: PMID:23284303 Detailed regulatory analysis shows that initial expression of FoxD3 in both cranial and trunk neural crest requires direct input from neural plate border genes, Pax7 and Msx1/2. PMID:23284303 These data demonstrate that Pax7, Msx1 and Ets1 bind in vivo to the NC1 enhancer element in the cranial neural crest. PMID:23284303 Taken together, these results place Pax7 and Msx1/2 as general regulators of FoxD3 expression, while Ets1 and Zic1 seem to specifically regulate NC1 and NC2, respectively. PMID:29358650 Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. |
| GO:0043403 skeletal muscle tissue regeneration | ISS PMID:24065826 Pax7 is critical for the normal function of satellite cells ... | NEW | Summary: Pax7 is required in adult satellite cells for their expansion and for muscle regeneration; human PAX7 deficiency exhausts the satellite cell pool. Reason: Mouse Pax7 (P47239) carries GO:0043403 by IMP (PMID:9608680), but this did not project to human. Adult conditional deletion causes satellite cell cell-cycle arrest and a profound regeneration deficit, and PAX7 myopathy patients show satellite cell exhaustion. PAX7 does the work inside the regenerating stem cells as their identity and expansion transcription factor. The more specific GO:0014834 (satellite cell maintenance in regeneration) was considered, but no Pax7 in any species carries it; its carriers are niche/signalling genes (Wnt7a, Fzd7, Igf1, Ezh2, Selenon). So the mouse convention was followed. Supporting Evidence: PMID:24065826 Here, we demonstrate that Pax7 is an absolute requirement for satellite cell function in adult skeletal muscle. PMID:24065826 Maintenance of Pax7 deletion through continuous tamoxifen administration prevented regrowth of Pax7-expressing satellite cells and a profound muscle regeneration deficit that resembles the phenotype of skeletal muscle following genetically engineered ablation of satellite cells. PMID:31092906 A lack of PAX7 expression was associated with satellite cell pool exhaustion |
| GO:0021904 dorsal/ventral neural tube patterning | ISS PMID:9858722 Pax3 and Pax7 are expressed in commissural neurons and restr... | NEW | Summary: Pax3 and Pax7 are co-expressed in dorsal spinal cord progenitors and redundantly restrict ventral neuronal identity. Reason: Mouse Pax7 carries GO:0021904 (IDA, from an FKBP8 paper where Pax7 serves as a marker), as do rat (ISO) and chick (ISS) Pax7, but human PAX7 does not. The Pax3/Pax7 double mutant gives better grounding: the dorsal identity factors do part of the work of dorsoventral patterning. Non-core relative to the border and satellite cell roles. ISS from mouse. Supporting Evidence: PMID:9858722 Analysis of Pax3 and Pax7 double mutant mice demonstrates that both genes share redundant functions to restrict ventral neuronal identity in the spinal cord. |
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Download this section (compressed HTML)Q: PAX7 directly occupies and is required for the FoxD3 NC1 crest enhancer (chick ChIP), but no gain-of-function sufficiency for crest induction has been shown. Is direct binding at one specifier enhancer enough to annotate GO:0014034 neural crest cell fate commitment, as frog Pax3 carries from Pax3+Zic1 sufficiency data, or should border factors stay at the proposed 'neural plate border formation' term (which replaces GO:0014029)?
Q: Frog uses Pax3 and chick uses Pax7 as the leading border factor, while mouse shows Pax3/Pax7 redundancy. Is the border role of the Pax3/7 pair partitioned differently between lineages after the vertebrate duplication of the single amphioxus Pax3/7, and should GO coverage treat the two paralogs symmetrically?
Q: Basch et al. 2006 and Simoes-Costa et al. 2012 (chick Pax7) are uncurated. Chick PAX7 (O42349, unreviewed) carries only ISS terms. Should these be curated directly (IMP/IDA) on a chick PAX7 entry?
Q: Mouse Pax7-null cephalic crest phenotype (PMID:8631261) is curated to embryonic skeletal system development (GO:0048706) rather than to a neural crest term; is that the intended representation?
Experiment: CUT&RUN for endogenous PAX7 in human pluripotent stem cell-derived neural plate border/crest cultures, to test whether the chick FoxD3 NC1/NC2 inputs are conserved at the human FOXD3 locus and whether PAX7 co-occupies sites with ZIC1, MSX1 and TFAP2A.
Experiment: Gain-of-function test of sufficiency: ectopic PAX7 (with or without ZIC1) in chick non-neural ectoderm or human ectodermal explants, scoring SNAI2, FOXD3 and SOX10, to decide whether PAX7 induces crest fate like frog Pax3+Zic1.
Experiment: Test whether amphioxus Pax3/7 can substitute for Pax7 in the chick NC1 enhancer assay, to separate protein evolution from cis-regulatory evolution of the border-to-crest link.
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