FOXP2 is a forkhead DNA-binding transcription factor that regulates gene expression in the nucleus. It recognizes regulatory DNA and associates with FOXP-family proteins and transcriptional corepressors. FOXP2 can repress targets such as CNTNAP2, while other targets are activated in particular cellular contexts. Human pathogenic variation links it to speech and language development and altered basal-ganglia anatomy; experimental models establish context-dependent effects on neuronal development and vocal behavior, with additional cooperative roles in foregut muscle development. Alternative splicing produces proteins with different domain content, and the functions and localization of all declared products are not established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | ACCEPT | Summary: Negative regulation of Pol II transcription is a core FOXP2 process. Reason: Human CNTNAP2 expression decreases with FOXP2, and human WT constructs repress SV40/SRPX2 reporters. These corroborate the original GO:0001227-based electronic mapping. Other targets can be activated in distinct conditions; this process is not asserted as the direction of every FOXP2 response. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | KEEP AS NON CORE | Summary: Chromatin association is a supported cellular context for FOXP2. Reason: The TFClass chromatin annotation is consistent with human FOXP2 ChIP at CNTNAP2 and chromatin-associated FOXP-family recovery. Retain this context without interpreting regional occupancy as sequence-specific binding at every locus or a permanent structural chromosome component. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: FOXP2 recognizes Pol II regulatory DNA. Reason: The literal PTN000215041 IBD lies on the verified human FOXP2 lineage. Independent human CNTNAP2 intron-1 ChIP and sequence-controlled EMSA support regulatory DNA recognition; the intronic element is not described as a core promoter. Preserve the original phylogenetic donors and qualifier. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-based DNA-binding transfer agrees with direct human evidence. Reason: Human FOXP2 binds the CNTNAP2 regulatory element in chromatin and nuclear-extract EMSA, with probe and R553H controls. This supports the unrestricted Pol II cis-regulatory recognition term independently of the original P58463 electronic transfer, without assigning it to every natural product. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | TOO GENERAL | Summary: The Pol II transcription-factor class is correct but less specific than the retained repressor activity. Reason: TFClass identifies the appropriate transcription-factor class. GO:0001227 is an is_a subtype and describes the demonstrated human DNA-binding repression activity. Selected targets can instead be activated, so this specificity judgment does not claim that FOXP2 always represses. |
| GO:0001221 transcription coregulator binding | IEA GO_REF:0000107 | MODIFY | Summary: Corepressor binding is a supported refinement of the broad coregulator class. Reason: Human FOXP2 associates with the transcriptional corepressors CTBP1 and CTBP2 in tagged-cell BRET, and independent source-specific Y2H records recover these partners. Their established corepressor class makes GO:0001222 informative for the FOXP2 transcriptional mechanism. The refinement does not assign corepressor activity to FOXP2 or establish isolated binding affinity. Proposed replacements: transcription corepressor binding |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: DNA-binding repression is a central FOXP2 activity. Reason: The PTN000215042 repressor IBD is on the actual human target path. Human CNTNAP2 regulatory DNA binding and RNA reduction, plus human SV40/SRPX2 reporter repression, independently support the inherited activity. Repression is target-dependent rather than an exclusive output in every cell state. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: The electronic repressor transfer is corroborated by human experiments. Reason: Human FOXP2 recognizes regulatory DNA and decreases CNTNAP2 expression; sequence-verified human constructs also repress SV40/SRPX2 reporters. The mouse-based source is retained, while independent human findings establish the gene-level activity and do not define all natural products. |
| GO:0003677 DNA binding | IDA PMID:16407075 Structure of the forkhead domain of FOXP2 bound to DNA. | TOO GENERAL | Summary: The structural DNA-binding result supports a more informative retained binding class. Reason: PMID:16407075 directly assays a recombinant human FOXP2 503–584 forkhead fragment with DNA. This is positive binding evidence, not an assay of all full-length products. Independent human regulatory-element experiments establish retained GO:0000978, an is_a descendant of DNA binding; the broader original term adds no distinct function. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: Unrestricted DNA binding is broader than the established regulatory sequence recognition. Reason: The mouse transfer is biologically compatible with FOXP2. Retained GO:0000978 is an is_a descendant of GO:0003677 and captures its sequence-specific Pol II regulatory DNA binding more precisely. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:18987363 A functional genetic link between distinct developmental lan... | TOO GENERAL | Summary: The original human experiment establishes a more specific regulatory activity. Reason: PMID:18987363 combines human FOXP2 chromatin occupancy and sequence-controlled EMSA with reduced CNTNAP2 RNA. The retained Pol II repressor activity is more informative than the generic transcription-factor term. The intron-1 site is not recast as a core promoter. Supporting Evidence: |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: The general transcription-factor class is less precise than the retained Pol II repressor activity. Reason: The InterPro and mouse evidence agree with FOXP2 biology. GO:0001227 is an is_a descendant of this unrestricted transcription-factor term. Target-dependent activation remains part of the biological synthesis and is not excluded by retaining the experimentally established repressor activity. |
| GO:0005515 protein binding | IPI PMID:19907493 Human-specific transcriptional regulation of CNS development... | MODIFY | Summary: FOXP4 association supports a specific transcription-factor-binding class. Reason: The original PMID:19907493 source-specific FOXP4 assay was not independently resolved in the selected reading. Independently read PMID:25027557 human FOXP2/FOXP4 co-IP supports the same partner association; the original nuclear scope is preserved, without claiming that the later assay verifies the earlier experiment. Official human FOXP4 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0005515 protein binding | IPI PMID:19907493 Human-specific transcriptional regulation of CNS development... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Selected PMID:19907493 Methods/Results recover FOXP1 with FOXP2 in SH-SY5Y nuclear colocalization and co-IP/immunoblot or mass-spectrometry experiments. Human and chimp FOXP2 constructs are distinguished; the association is not a purified binary-affinity measurement. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | MODIFY | Summary: CTBP2 association supports transcription corepressor binding. Reason: The original PMID:21653829 annotation is retained. Its exact FOXP2/CTBP2 supplement record and membership in the 52-pair HEK validation subset remain unverified; current IntAct absence is not refutation. Independent human WT FOXP2–CTBP2 BRET in PMID:27933109 and separate exact Y2H records support the same gene-level association. Official CTBP2 corepressor classification supports GO:0001222, without certifying the earlier assay. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:24722188 Protein interaction network of alternatively spliced isoform... | MODIFY | Summary: The exact CTBP1-2 association supports corepressor binding. Reason: PMID:24722188 has exact Y2H records for FOXP2 and Q13363-2. IntAct describes a FOXP2 93–715 sufficient-binding region and retains a partner-isoform annotation caveat; selected original Methods establish the yeast screening/retest design but do not identify this pair in the sampled MAPPIT validation. CTBP1 is a verified transcriptional corepressor. Preserve the partner isoform and do not equate the recorded region to a proven natural FOXP2 construct. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:24893771 Investigating protein-protein interactions in live cells usi... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: PMID:24893771 contains exact reciprocal tagged BRET pair records in HEK293 and selected nuclear-control observations. BRET supports cellular proximity of the recorded partners; signal magnitude is not affinity or native stoichiometry. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | MODIFY | Summary: FOXP4 association supports a specific transcription-factor-binding class. Reason: Selected PMID:25027557 Methods/Results show tagged human FOXP2/FOXP4 co-IP and nuclear colocalization. Its BC143867 FOXP2 construct is described as 714 residues, so it is not silently mapped to the current 715-residue canonical product. Cotransfection does not isolate one pure native heterodimer. Official human FOXP4 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Selected PMID:25027557 human co-IP supports the FOXP2/FOXP1 association. The described 714-residue BC143867 construct is distinguished from current canonical FOXP2. This original row has no nuclear extension; the separately preserved nuclear-scoped row is not collapsed into it. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Selected PMID:25027557 co-IP and nuclear colocalization support the original FOXP2/FOXP1 nuclear context. The described 714-residue BC143867 construct is not assumed to equal current canonical FOXP2. The nuclear extension is retained separately from the unqualified companion record. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The positive SDCBP/syntenin-1 interaction is retained with bounded functional scope. Reason: Three exact PMID:25416956 Y2H records support the original FOXP2/SDCBP/syntenin-1 pair. The partner is an adaptor with diverse trafficking and signaling roles; this pair does not establish an adaptor function or trafficking mechanism for FOXP2. Fragment coordinates are not specified for this dataset and are not copied from other papers. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The positive CCNC/cyclin C interaction is retained with bounded functional scope. Reason: Three exact PMID:25416956 Y2H records support the original FOXP2/CCNC/cyclin C pair. Cyclin C is a kinase regulator and Mediator component, but the pair alone does not show which function is germane to FOXP2 or establish a specific coregulator mechanism. Fragment coordinates are not specified for this dataset and are not copied from other papers. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: CTBP2 binding can be refined to the transcription corepressor class. Reason: PMID:25416956 supplies three exact curated Y2H records for this FOXP2/CTBP2 pair. The official partner record establishes transcriptional corepressor activity, making GO:0001222 informative in this transcription-factor context. The pair result does not itself prove that the partner mediates FOXP2 repression in vivo. Dataset features do not establish a FOXP2 fragment here; coordinates from other papers are not transferred, and the original partner identifier is unchanged. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: TLE5 binding can be refined to the transcription corepressor class. Reason: PMID:25416956 supplies three exact curated Y2H records for this FOXP2/TLE5 pair. The official partner record establishes transcriptional corepressor activity, making GO:0001222 informative in this transcription-factor context. The pair result does not itself prove that the partner mediates FOXP2 repression in vivo. Dataset features do not establish a FOXP2 fragment here; coordinates from other papers are not transferred, and the original partner identifier is unchanged. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: CTBP1-2 binding can be refined to the transcription corepressor class. Reason: PMID:25416956 supplies three exact curated Y2H records for this FOXP2/CTBP1-2 pair. The official partner record establishes transcriptional corepressor activity, making GO:0001222 informative in this transcription-factor context. The pair result does not itself prove that the partner mediates FOXP2 repression in vivo. Dataset features do not establish a FOXP2 fragment here; coordinates from other papers are not transferred, and the original partner identifier is unchanged. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The positive PIN1 interaction is retained with bounded functional scope. Reason: Three exact PMID:25416956 Y2H records support the original FOXP2/PIN1 pair. PIN1 is a peptidyl-prolyl isomerase, but this interaction does not establish FOXP2 isomerization, a phosphosite requirement, or catalytic regulation. An enzyme-class relabeling adds no demonstrated FOXP2 functional specificity here. Fragment coordinates are not specified for this dataset and are not copied from other papers. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The positive FAM124A interaction is retained with bounded functional scope. Reason: Three exact PMID:25416956 Y2H records support the original FOXP2/FAM124A pair. The retained official partner record does not establish a more informative functional class for this FOXP2 interaction. Fragment coordinates are not specified for this dataset and are not copied from other papers. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The positive TSACC interaction is retained with bounded functional scope. Reason: Three exact PMID:25416956 Y2H records support the original FOXP2/TSACC pair. TSACC has a co-chaperone role in TSSK6 activation, but this interaction does not establish that pathway or chaperone regulation as a FOXP2 function. Fragment coordinates are not specified for this dataset and are not copied from other papers. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: FOXP4 association supports a specific transcription-factor-binding class. Reason: Original PMID:25609649 Table S6 recovers FOXP2 from the FOXP4 chromatin-associated bait preparation, supporting the retained nuclear association. Reciprocal FOXP2-bait soluble-fraction recovery is distinct and is not treated as nuclear-specific. Affinity-purification co-complex evidence does not establish an isolated binary interface. Official human FOXP4 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Original PMID:25609649 Table S6 recovers FOXP2 from the FOXP1 chromatin-associated bait preparation. This supports the nuclear-scoped association; reciprocal soluble-fraction recovery is not substituted for that compartment evidence. The result is complex association, not an isolated affinity measurement. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0005515 protein binding | IPI PMID:25853299 A de novo FOXP1 variant in a patient with autism, intellectu... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Selected PMID:25853299 WT/variant FOXP1 BRET and localization experiments include FOXP2. Patient lymphoblast mutant-RNA degradation and engineered transfection assays are separate contexts; the association is retained without asserting abundant mutant protein in patients or a natural mutant isoform. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26647308 Identification and functional characterization of de novo FO... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: PMID:26647308 exact records and selected original functional experiments distinguish tagged BRET from confocal colocalization and WT from variant outcomes. The unrestricted source row remains separate from its nuclear-scoped companion; variant aggregation is not generalized to normal FOXP2. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26647308 Identification and functional characterization of de novo FO... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: PMID:26647308 provides tagged BRET and localization evidence with WT and disease-variant controls. The original nuclear-scoped association is preserved without treating all variant aggregates as nuclear or assigning the assay to all natural products. This extension-bearing row remains separate from the unqualified companion. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | MODIFY | Summary: The CTBP1-2 Y2H association supports corepressor binding. Reason: Exact PMID:27107012 records retain Q13363-2 and the annotated FOXP2 93–715 sufficient-binding region. Selected original BFG-Y2H Methods describe barcoded yeast constructs and pairwise retests; cohort GPCA validation does not certify this exact pair. CTBP1 corepressor classification supports GO:0001222, with no natural-isoform or native-stoichiometry inference. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: The exact CTBP2-3 association supports the corepressor partner class. Reason: Three exact PMID:32296183 Y2H records retain the original CTBP2-3 isoform identifier and annotate the FOXP2 93–715 sufficient-binding region. Official UniProt product mapping shows that P56545-3 retains canonical CTBP2 residues 20–445; it is distinct from the RIBEYE product P56545-2. GO:0001222 is a corepressor-class inference from established CTBP2 function and the retained shared protein region, not a claim that this interaction assay separately established repression by CTBP2-3. The assay supports the recorded interaction without establishing an endogenous complex, equal activity of every partner product, or a uniquely identified natural FOXP2 product. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The positive CDK3 interaction is retained with bounded functional scope. Reason: Three exact PMID:32296183 Y2H records support the original FOXP2/CDK3 pair. CDK3 is a cyclin-dependent kinase, but the screened interaction does not establish FOXP2 phosphorylation, kinase regulation, or a germane kinase-client mechanism. The source records annotate a FOXP2 93–715 sufficient-binding region; no natural product is assigned from that annotation. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: The exact TLE5-2 association supports the corepressor partner class. Reason: Three exact PMID:32296183 Y2H records retain the original TLE5-2 isoform identifier and annotate the FOXP2 93–715 sufficient-binding region. Official UniProt product mapping shows that Q08117-2 retains canonical residues 10–197, including the annotated CCN domain at canonical residues 166–197. GO:0001222 is a corepressor-class inference from established TLE5 function and its retained shared region, not a claim that this interaction assay separately established repression by TLE5-2. The assay supports the recorded interaction without establishing an endogenous complex, equal activity of every partner product, or a uniquely identified natural FOXP2 product. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The positive PIN1 interaction is retained with bounded functional scope. Reason: Three exact PMID:32296183 Y2H records support the original FOXP2/PIN1 pair. The isomerase class of PIN1 is verified, but this pair does not establish isomerization or phosphosite-dependent regulation of FOXP2; that unmeasured mechanism is not inferred from the class name. The source records annotate a FOXP2 93–715 sufficient-binding region; no natural product is assigned from that annotation. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The positive LNX1 interaction is retained with bounded functional scope. Reason: Three exact PMID:32296183 Y2H records support the original FOXP2/LNX1 pair. LNX1 includes ubiquitin-ligase and scaffold functions. This pair does not establish FOXP2 ubiquitination or identify a relevant ligase-active partner product, so a ligase-binding refinement is not asserted. The source records annotate a FOXP2 93–715 sufficient-binding region; no natural product is assigned from that annotation. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The positive TSACC interaction is retained with bounded functional scope. Reason: Three exact PMID:32296183 Y2H records support the original FOXP2/TSACC pair. The established TSSK6 co-chaperone function of TSACC does not by itself identify the functional consequence of its FOXP2 association. The source records annotate a FOXP2 93–715 sufficient-binding region; no natural product is assigned from that annotation. Retain the supported association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: FOXP4 association supports a specific transcription-factor-binding class. Reason: Three exact PMID:33961781 anti-tag coimmunoprecipitation records recover FOXP2 with FOXP4 in HEK293T/HCT116 contexts. These support complex association, not isolated contact; the assay host alone does not prove a nuclear fraction. The original nuclear extension remains explicit, with independent human nuclear FOXP-family experiments as corroboration. Official human FOXP4 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: FOXP1 association supports a specific transcription-factor-binding class. Reason: Three exact PMID:33961781 anti-tag coimmunoprecipitation records recover FOXP2 with FOXP1 in HEK293T/HCT116 contexts. This is source-specific complex-association evidence, while the original nuclear extension is supported biologically by independent nuclear FOXP-family experiments rather than inferred solely from host cells. Official human FOXP1 annotations establish its Pol II DNA-binding transcription-factor class, supporting GO:0061629 without turning the association assay into a direct-contact or transcriptional-effect claim. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: FOXP2 acts in the nucleus. Reason: The original PTN000215041 nucleus IBD is on the verified human lineage, including legitimate human FOXP2 descendant evidence. Human chromatin occupancy, nuclear microscopy and reporter experiments independently support nuclear transcriptional activity. Preserve is_active_in and the original grouped donors; this does not assign identical localization to all short products or engineered variants. |
| GO:0005634 nucleus | IDA PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | ACCEPT | Summary: The tested human FOXP2 construct is nuclear. Reason: Selected PMID:25027557 nuclear microscopy supports the original location. Its human BC143867 construct is described as 714 residues, not automatically current 715-residue O15409-1; the result is retained at gene level without inventing a natural-product identity. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is corroborated by human experiments. Reason: The mouse and UniProt subcellular-location mappings agree with human WT nuclear microscopy and chromatin-associated transcriptional assays. This supports the unrestricted original location while preserving construct and variant-specific limitations. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasmic localization is consistent with the original HPA evidence and human nuclear assays. Reason: The original GO_REF:0000052 IDA is retained as HPA immunofluorescence evidence. Official target HPA metadata are consulted separately from image pixels, and independent human nuclear microscopy and transcriptional assays support the location. No localization of every natural product is inferred. |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000117 | ACCEPT | Summary: FOXP2 participates in transcription-regulatory protein assemblies. Reason: Human FOXP-family co-IP linked to target-expression changes, CTBP association and regulatory DNA recognition support the original generic transcription-regulator-complex assertion. The evidence does not define a single constitutive complex or universal subunit stoichiometry. |
| GO:0005667 transcription regulator complex | IPI PMID:16407075 Structure of the forkhead domain of FOXP2 bound to DNA. | ACCEPT | Summary: The original structural assembly is compatible with transcription-regulator-complex participation. Reason: PMID:16407075 establishes human forkhead-fragment DNA complexes and dimerization; it does not prove the hypothesized native DNA-looping assembly. Independent human FOXP-family functional association and CTBP-binding experiments support the unrestricted transcription-regulator-complex term while the original fragment scope is retained. |
| GO:0005667 transcription regulator complex | IPI PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | ACCEPT | Summary: Human FOXP2 is recovered in functional transcription-factor assemblies. Reason: PMID:25027557 shows human FOXP2 association with FOXP1/FOXP4 and combination-dependent target-expression changes. This supports generic transcription-regulator-complex participation, without isolating a pure native heterodimer mechanism. The 714-residue BC143867 construct and caption/Methods tag discrepancy remain documented. Supporting Evidence: |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad transcription-regulation term is entailed by retained Pol II repression. Reason: The InterPro assignment is biologically compatible with FOXP2. GO:0000122 is an is_a descendant of GO:0006355 and captures a directly established process. Target-dependent activation is retained in the synthesis without replacing the verified repressive mechanism. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | TOO GENERAL | Summary: The grounded ancestral transcription-regulation term is broader than a retained specific process. Reason: The original PTN000215041 IBD lies on the exact human lineage, with all donor groupings preserved. Human experiments independently establish retained GO:0000122, an is_a descendant of GO:0006357. The specificity judgment does not reject the ancestry or imply uniformly negative output at every target. |
| GO:0007519 skeletal muscle tissue development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited skeletal-muscle developmental context is supported in a cooperative mouse model. Reason: The PTN002909867 IBD lies on the verified human lineage. Current mouse donor PMID:17428829 uses acts_upstream_of_or_within with an esophageal extension: Foxp2-null/Foxp1-heterozygote esophagi lack the usual MyoD-positive skeletal contribution. Both factors are expressed in the muscle compartment. Retain the established developmental transfer as non-core; the compound perturbation does not isolate a human or FOXP2-alone muscle program. Supporting Evidence: |
| GO:0010467 gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXP2 contributes to gene-expression control in a broad cellular context. Reason: The mouse-based gene-expression annotation is compatible with direct human transcription-factor activity and altered target RNA. Preserve the broad process as non-core; regulation of expression is not an is_a subtype of GO:0010467, so the narrower repression annotation is not used as a formal entailment argument for discarding this context. |
| GO:0021702 cerebellar Purkinje cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Purkinje-cell differentiation is a supported model-dependent neuronal context. Reason: The P58463 transfer is consistent with the authentic PMID:22133810 report of poorly developed Purkinje cells in Foxp2 R552H knock-in mice and altered cerebellar Cntnap2/synaptophysin observations. Full source Methods were not recovered here. Retain the existing developmental inference without claiming a demonstrated human Purkinje-cell requirement or a proven CtBP/CNTNAP2 causal pathway. Supporting Evidence: |
| GO:0021757 caudate nucleus development | IMP PMID:11872605 MRI analysis of an inherited speech and language disorder: s... | KEEP AS NON CORE | Summary: Human caudate anatomy supports a bounded developmental phenotype. Reason: The selected original PMID:11872605 MRI analysis of affected KE-family members reports reduced bilateral caudate-head gray matter, corroborated by caudate volumetry. This supports the existing developmental context as non-core. It is a clinical structural association, not a cell-autonomous developmental assay or a complete mechanism linking FOXP2 to caudate formation. Supporting Evidence: |
| GO:0021758 putamen development | IMP PMID:11872605 MRI analysis of an inherited speech and language disorder: s... | KEEP AS NON CORE | Summary: The original human study directly reports a putamen phenotype. Reason: PMID:11872605 includes increased bilateral putamen gray matter in affected KE-family members, despite the abstract emphasis on caudate reduction. Retain the original developmental annotation as a non-core human phenotype. The regional VBM result uses the stated hypothesis-based threshold and does not establish a direct cellular mechanism. Supporting Evidence: |
| GO:0021987 cerebral cortex development | IEP PMID:18987363 A functional genetic link between distinct developmental lan... | KEEP AS NON CORE | Summary: Cortical development is retained as a context-dependent neuronal role. Reason: The original PMID:18987363 IEP maps complementary FOXP2/CNTNAP2 expression in human fetal cortex, not a perturbation endpoint. Independent PMID:23283338 mouse mosaic knockdown and human-protein rescue support effects on cortical precursors and neuronal production; PMID:31067457 shows target-dependent transcription/chromatin responses to exogenous FOXP2 in human neuronal cultures. Conversely, PMID:31099752 conditional deletion leaves measured mouse somatosensory lamination, cell counts and gross projections largely intact. Together these support a non-core developmental context, not universal cortical necessity or a resolved explanation for the different models. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: Identical-protein binding is broader than the retained homodimerization activity. Reason: The mouse-based transfer is compatible with human FOXP2 self-association. GO:0042803 is an is_a descendant of GO:0042802 and is independently supported by the human forkhead-fragment monomer/dimer measurements. This does not assert that every cellular self-associated assembly is a dimer. |
| GO:0042802 identical protein binding | IPI PMID:16407075 Structure of the forkhead domain of FOXP2 bound to DNA. | TOO GENERAL | Summary: The original homomer result is captured more specifically by homodimerization. Reason: PMID:16407075 assays the human 503–584 forkhead fragment: crystallography and MALS support monomer/dimer states and an A539P-sensitive domain-swapping mechanism. Retained GO:0042803 entails identical-protein binding. Domain swapping is not assumed to be the obligatory full-length in-vivo mechanism. Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:24893771 Investigating protein-protein interactions in live cells usi... | TOO GENERAL | Summary: Human tagged self-association supports the retained, more specific dimerization capability. Reason: Exact PMID:24893771 BRET records and selected Results show FOXP2 self-association with interaction-disrupting controls. BRET alone does not count subunits; the independent human fragment MALS/structure establishes retained GO:0042803, which entails the broader original identical-binding term. |
| GO:0042802 identical protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | TOO GENERAL | Summary: Gene-level self-association is supported, while this source’s homomer-specific assay remains unresolved. Reason: The PMID:25609649 Table S6 self row is labelled Bait and does not independently establish homomer recovery. Other human BRET and fragment MALS/structural experiments establish FOXP2 self-association and retained GO:0042803, an is_a descendant of identical-protein binding. Preserve this source object without claiming that its bait-detection row measures homodimerization. |
| GO:0042803 protein homodimerization activity | IDA PMID:16407075 Structure of the forkhead domain of FOXP2 bound to DNA. | KEEP AS NON CORE | Summary: FOXP2 can homodimerize in the experimentally tested biochemical context. Reason: Human FOXP2 residues 503–584 form monomer/dimer populations by MALS and a domain-swapped crystallographic dimer; A539P changes that behavior. This supports the existing homodimerization activity as a molecular assembly property. It does not establish obligatory native stoichiometry, a uniquely mapped natural isoform, or the hypothetical DNA-looping model. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IDA PMID:18987363 A functional genetic link between distinct developmental lan... | TOO GENERAL | Summary: The original human binding result supports the retained regulatory-region-specific term. Reason: PMID:18987363 uses human FOXP2 chromatin occupancy and nuclear-extract EMSA at a CNTNAP2 intron-1 element, with sequence and R553H controls. Retained GO:0000978 entails the broader sequence-specific binding claim. The intronic regulatory site is not described as a core promoter. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Sequence-specific DNA binding is correctly assigned but less informative than regulatory-region recognition. Reason: The forkhead-domain InterPro mapping agrees with human sequence-controlled binding experiments. Retained GO:0000978 is an is_a descendant of GO:0043565 and specifies the Pol II cis-regulatory DNA context. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:18987363 A functional genetic link between distinct developmental lan... | TOO GENERAL | Summary: Broad negative transcription regulation is entailed by retained Pol II repression. Reason: Human CNTNAP2 regulatory binding and reduced target RNA directly support repression. GO:0000122 is an is_a descendant of GO:0045892 and provides the retained, more informative process. This does not claim that every target or FOXP-family combination is repressed. Supporting Evidence: |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | TOO GENERAL | Summary: Broad negative transcription regulation is entailed by retained Pol II repression. Reason: The selected human HEK293 expression study reports repression of some targets and activation of others; the described FOXP2 BC143867 construct is 714 residues. GO:0000122 is an is_a descendant of GO:0045892 and provides the retained, more informative process. This does not claim that every target or FOXP-family combination is repressed. |
| GO:0045892 negative regulation of DNA-templated transcription | NAS PMID:25027557 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimeri... | TOO GENERAL | Summary: Broad negative transcription regulation is entailed by retained Pol II repression. Reason: The original NAS attribution is preserved; selected human coexpression experiments and independent reporter studies substantiate gene-level repression without turning the NAS row into an independently curated IDA. GO:0000122 is an is_a descendant of GO:0045892 and provides the retained, more informative process. This does not claim that every target or FOXP-family combination is repressed. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Organ development is retained as informative developmental context. Reason: The ARBA assertion is compatible with human caudate/putamen phenotypes and independent cortical developmental evidence. The more specific brain-region processes contribute through typed part_of relationships; they do not make this organ-level context a redundant is_a class. Retain it as non-core without adding an unmeasured organ phenotype. |
| GO:0048731 system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: System development is retained as a broad but supported biological context. Reason: FOXP2-dependent transcription is linked to nervous-system development by human clinical findings and model-specific neuronal perturbations. Preserve the ARBA process as non-core. The nested developmental part_of relations are not treated as proof that all system-level scope is dispensable, nor does this term imply that FOXP2 acts in every organ system. |
| GO:0048745 smooth muscle tissue development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The smooth-muscle transfer is grounded in a cooperative esophageal developmental phenotype. Reason: The literal PTN002909867 IBD is on the human lineage. In PMID:17428829, Foxp2-null/Foxp1-heterozygote embryos have abnormal esophageal smooth-muscle layers; examined Ki67/TUNEL staining did not show altered proliferation/apoptosis. The original mouse IGI uses acts_upstream_of_or_within and an esophageal extension. Retain the human inherited context as non-core without claiming a human direct smooth-muscle mechanism or a FOXP2-only perturbation. Supporting Evidence: |
| GO:0071625 vocalization behavior | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited vocalization phenotype is compatible with FOXP2’s neuronal regulatory role. Reason: The PTN008698253 IBD lies on the actual human target lineage and preserves both mouse and rat donor identifiers. Current mouse GO:0071625 IMP cites PMID:22133810; current rat records are ISO/IBA, not an independently recovered rat experiment. The authentic source describes impaired ultrasonic vocalization in Foxp2 R552H mice. Retain this behavioral context as non-core without identifying it with human language or claiming that CtBP/CNTNAP2 mediation has been demonstrated. |
| GO:0071625 vocalization behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-based vocalization transfer is biologically supported within its behavioral scope. Reason: The mouse R552H model described in PMID:22133810 has impaired ultrasonic vocalization, and human FOXP2-associated speech phenotypes provide complementary context. Retain the existing electronic behavior annotation as non-core; ultrasonic vocalization is not equivalent to human linguistic processing, and the source’s proposed cerebellar mechanism remains an inference. |
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Download this section (compressed HTML)Q: Which endogenous FOXP2 targets and partner combinations distinguish repression from activation in defined human neuronal states?
Q: How do mosaic FOXP2 reduction, uniform genetic loss and pathogenic variants produce different neuronal-development outcomes?
Q: Which naturally expressed FOXP2 products retain DNA recognition, nuclear localization and FOXP-family or CTBP association in the same human cell state?
Q: Which transcriptional changes connect FOXP2 activity to vocal motor behavior, and which are separable from broader neuronal development?
Experiment: Compare endogenous FOXP2 perturbation and sequence-verified rescue in matched human neuronal states using nascent transcription, occupancy and chromatin accessibility; distinguish direct regulated loci from downstream expression changes.
Experiment: Compare mosaic and uniform loss with matched dosage, timing and cell identity, measuring lineage trajectories and circuit physiology in addition to gross cortical anatomy.
Experiment: Measure endogenous product expression and localization, then test sequence-verified products and partner perturbations with matched transcriptional and interaction readouts.
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