Affinage

FOXP2

Forkhead box protein P2 · UniProt O15409

Length
715 aa
Mass
79.9 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXP2 is a forkhead-domain transcription factor that orchestrates the development and function of cortico-basal ganglia and cerebellar circuits underlying vocal communication and motor learning (PMID:27595386, PMID:30108312). Its forkhead domain is the primary driver of sequence-specific DNA binding, while a leucine-zipper coiled-coil mediates homo- and heterodimerization (with FOXP1 and FOXP4) and additionally contributes to DNA binding, and the C2H2 zinc finger supports dimerization (PMID:30887622); specific FOXP1/2/4 dimer combinations differentially tune target-gene output (PMID:25027557). FOXP2 acts predominantly as a DNA-binding-dependent repressor of proliferation- and synaptic-regulatory genes—most notably directly binding and repressing the Mef2c promoter to control corticostriatal synaptogenesis and spinogenesis (PMID:27595386)—and can also activate maturation programs in cooperation with cofactors NFIA/NFIB without requiring its own DNA binding (PMID:31067457), while β-catenin physically engages its DNA-binding domain to modulate Wnt-pathway target output (PMID:33284517). In the striatum FOXP2 is selectively expressed in D1-receptor projection neurons and shapes dopaminergic D1/D2 signaling, AMPA/GABA balance and GAD67-dependent GABA release, with loss producing aberrant striatal plasticity and motor-skill learning deficits (PMID:30187194, PMID:33976169, PMID:30031127); in the cerebellum it constrains Purkinje-cell intrinsic excitability to support skilled movement (PMID:30108312). FOXP2 is post-translationally SUMOylated at K674 by PIAS1/PIAS3 and deSUMOylated by SENP2, a modification required for cerebellar Purkinje-cell dendritic arborization, motor function and vocalization (PMID:26867680, PMID:26212494, PMID:27009683). Beyond the nervous system, FOXP2 cooperates with FOXP1 to drive lung alveolarization through direct targets such as T1alpha and via inhibition of Nkx2.1 (PMID:17428829, PMID:18239190), and acts as a flow-induced, FOXC2-dependent regulator of collecting lymphatic vessel and valve morphogenesis (PMID:33934370). The two human-lineage amino acid substitutions, products of positive selection, specifically tune corticostriatal dendritic morphology, long-term depression and procedural learning (PMID:12524352, PMID:21111790, PMID:25225386).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 Medium

    Established FOXP2 as a transcription factor and identified the human-specific coding changes that were the entry point to its language relevance, framing it as a target of recent adaptive evolution.

    Evidence Comparative cDNA sequencing across primates with population genetics, plus RACE/RT-PCR domain and isoform characterization

    PMID:12189486 PMID:12524352

    Open questions at the time
    • No functional validation that the human substitutions alter transcriptional activity
    • Suppression domain only broadly defined
    • Roles of the polyglutamine tract and zinc finger not tested
  2. 2007 High

    Resolved a non-neural function by showing FOXP2 cooperates with FOXP1 in lung and esophageal development and acts on direct targets, demonstrating it is a bona fide DNA-binding regulator in vivo.

    Evidence Mouse knockout and compound mutant genetics, in vitro promoter assays, in vivo ChIP on T1alpha; Co-IP/EMSA/reporter showing inhibition of Nkx2.1

    PMID:17428829 PMID:18239190

    Open questions at the time
    • Whether the same target logic applies in neural tissue not addressed
    • Cofactor requirements for repression vs activation unresolved
  3. 2008 Medium

    Linked FOXP2 dynamics to active vocal behavior by showing singing acutely lowers FoxP2 protein in songbird basal ganglia, connecting its level to circuit plasticity.

    Evidence Immunohistochemistry and Western blot in singing vs non-singing zebra finches with corticosterone controls

    PMID:18701760

    Open questions at the time
    • Mechanism of acute protein downregulation unknown
    • Downstream target de-repression not directly demonstrated
  4. 2010 High

    Demonstrated that the two human substitutions have circuit-specific physiological consequences, distinguishing adaptive coding changes from a simple loss-of-function gene.

    Evidence Humanized knock-in mice; dendritic morphology and LTD electrophysiology across multiple brain regions

    PMID:21111790

    Open questions at the time
    • Molecular basis of altered LTD not defined
    • Target genes mediating the dendritic effect unidentified
  5. 2011 High

    Defined FOXP2 target networks and an in vivo striatal phenotype, establishing it as a regulator of neurite outgrowth and striatal circuit activity during learning.

    Evidence Genome-wide in vivo ChIP-chip with expression profiling and neurite assays; in vivo recordings in KE-mutation knock-in mice during motor learning

    PMID:21765815 PMID:21876543

    Open questions at the time
    • Which direct targets drive each physiological phenotype not pinned
    • Cell-type specificity of the 264 target loci unresolved
  6. 2013 High

    Connected FOXP2 to dopaminergic signaling and neurogenesis, showing it gates D1R-dependent corticostriatal modulation and the radial-glia-to-intermediate-progenitor transition.

    Evidence shRNA knockdown in songbird Area X with electrophysiology and protein quantification; in utero electroporation gain/loss-of-function in mouse cortex

    PMID:23283338 PMID:24268418

    Open questions at the time
    • Direct vs indirect regulation of D1R/DARPP-32 not established
    • Human-specific overexpression effect mechanism unclear
  7. 2014 High

    Showed the human substitutions bias the brain toward enhanced procedural learning and that FOXP1/2/4 dimer combinations diversify target output, refining how FOXP2 shapes behavior and transcription.

    Evidence Humanized knock-in mice with behavior, dopamine, expression and LTD readouts; FOXP1/2/4 stable transfection RT-qPCR in HEK293; progenitor cultures with Shh-pathway and PDGFRa analysis

    PMID:24453072 PMID:25027557 PMID:25225386

    Open questions at the time
    • Dimer-specific target rules tested only in overexpression cells
    • Shh interaction mechanism not biochemically defined
  8. 2016 High

    Identified the central direct effector axis (Mef2c repression) and a conserved regulatory PTM (SUMOylation), establishing the mechanistic core of FOXP2 action in striatum and cerebellum.

    Evidence Foxp2 KO with ChIP on Mef2c and genetic rescue; biochemical SUMO assays mapping K674, PIAS1/PIAS3 writers and SENP2 eraser; in utero electroporation of SUMO mutants in Purkinje cells; VLDLR ChIP in Area X

    PMID:26212494 PMID:26867680 PMID:27009683 PMID:27105823 PMID:27595386

    Open questions at the time
    • How SUMOylation alters transcription mechanistically not resolved (no localization/stability/repression change detected in cells)
    • Whether Mef2c is the sole effector of spinogenesis untested
  9. 2019 High

    Dissected domain contributions to dimerization versus DNA binding and showed region-specific, mechanistically distinct circuit roles, separating cortical, striatal and cerebellar functions.

    Evidence Single-molecule mass photometry and switchable DNA biochips for domain dissection; region-specific conditional knockouts with in vivo Purkinje and striatal electrophysiology; ATAC-seq/RNA-seq with NFIA/NFIB cofactor identification in human neurons

    PMID:30108312 PMID:30887622 PMID:31067457 PMID:31711176

    Open questions at the time
    • Structural basis of LZ contribution to DNA binding not solved
    • How NFI-dependent activation integrates with DNA-binding-dependent repression unclear
  10. 2020 High

    Mapped β-catenin as a structural regulator of FOXP2 transcription, linking it to Wnt signaling at the level of intrinsically disordered region contacts.

    Evidence NMR interaction mapping, Co-IP, reporter assays and RNA-seq of β-catenin-modulated FOXP2 targets

    PMID:33284517

    Open questions at the time
    • In vivo relevance of the β-catenin–FOXP2 interaction not tested
    • Whether this competes with DNA binding functionally unresolved
  11. 2021 High

    Extended FOXP2 function to vocal motor sequencing via dopaminergic control and to a wholly non-neural role in flow-induced lymphatic vessel morphogenesis.

    Evidence shRNA knockdown plus optogenetic dopamine manipulation during birdsong; endothelial/lymphatic conditional knockouts with in vitro shear-stress and NFATc1 assays

    PMID:33934370 PMID:33976169

    Open questions at the time
    • Direct FOXP2 targets in lymphatic endothelium not identified
    • Whether FOXC2 regulates FOXP2 directly or indirectly under flow unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FOXP2 selects between DNA-binding-dependent repression and cofactor-dependent activation across different cell types, and how SUMOylation and dimer composition direct that choice, remains unresolved.
  • No unified model linking PTM state, dimer partner, and target-gene outcome
  • Mechanistic consequence of SUMOylation on chromatin engagement undefined
  • Direct targets driving non-neural phenotypes largely unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CTBP1CTNNB1FOXP1FOXP4NFIANKX2-1PIAS1PIAS3

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Human FOXP2 contains two human-lineage-specific amino acid changes within a broadly defined transcription suppression domain, with evidence of positive selection (>60-fold increased substitution rate in hominids), identifying the protein as a transcription factor whose coding sequence was subject to adaptive evolution. Comparative cDNA sequencing across primates and population genetic analysis of intraspecific variation Genetics Medium 12524352
2002 FOXP2 encodes a transcription factor containing a polyglutamine tract, a C2H2 zinc-finger motif, and a forkhead DNA-binding domain; alternative splicing produces multiple isoforms including a truncated protein (FOXP2-S) from an alternate stop codon in exon 10+. 5' RLM-RACE, RT-PCR, genomic structure analysis Human genetics Medium 12189486
2007 Foxp2 and Foxp1 cooperatively regulate lung alveolarization and esophageal muscle development; T1alpha (a type I alveolar epithelial cell gene) is a direct transcriptional target of Foxp2 and Foxp1, as shown by in vitro and in vivo assays; loss of Foxp2 causes defective postnatal lung alveolarization, and additional loss of one Foxp1 allele exacerbates this phenotype and compromises N-myc and Hop expression. Mouse knockout genetics, in vitro promoter assays, in vivo ChIP, genetic epistasis (compound Foxp2-/-; Foxp1+/- mutants) Development High 17428829
2008 Foxp2 physically interacts with the homeodomain transcription factor Nkx2.1 through the Nkx2.1 homeodomain, and this interaction inhibits Nkx2.1 DNA-binding activity and Nkx2.1-mediated transcriptional activation of the surfactant protein C (SP-C) promoter, providing a mechanism for SP-C downregulation during alveolar epithelial type II to type I cell transition. Co-immunoprecipitation, mammalian two-hybrid assay, electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase reporter assay, recombinant protein competition assay American journal of respiratory cell and molecular biology High 18239190
2008 FoxP2 protein levels in Area X of adult male zebra finches are acutely downregulated when birds sing, independently of corticosterone stress levels, suggesting that singing-induced reduction of FoxP2 protein (not just mRNA) may permit expression of target genes important for circuit modification and vocal variability. Immunohistochemistry and Western blot quantification of FoxP2 protein in singing vs. non-singing birds; corticosterone ELISA Journal of neurophysiology Medium 18701760
2010 Introduction of the two human-specific FOXP2 amino acid substitutions into the mouse endogenous Foxp2 gene (humanized mice) specifically increases dendrite length and long-term depression (LTD) in medium spiny neurons of the striatum, and increases dendrite length in cortex and thalamus, but not in amygdala or cerebellum, demonstrating circuit-specific effects of the human substitutions on cortico-basal ganglia circuits. Knock-in mouse model, dendritic morphology analysis, electrophysiological recordings (LTD measurement) in brain slices from multiple regions Neuroscience High 21111790
2011 Foxp2 regulates gene networks linked to neurite outgrowth in the embryonic brain; genome-wide ChIP-chip identified 264 high-confidence direct neural target loci, and functional experiments showed that Foxp2 loss reduces neurite outgrowth in primary neurons and neuronal cell models. In vivo ChIP-chip (genome-wide), expression profiling, in situ hybridization in wild-type vs. Foxp2 mutant embryos, neurite outgrowth assays in primary neurons and cell lines PLoS genetics High 21765815
2011 Mice carrying the KE-family Foxp2 missense mutation show abnormally high ongoing striatal activity and dramatic alterations in striatal plasticity during motor-skill learning (predominantly negative modulation of firing rate instead of positive modulation seen in controls), and altered temporal coordination of striatal firing; demonstrating that FOXP2 is critical for normal striatal circuit function in vivo. In vivo electrophysiological recordings in awake-behaving mice during motor-skill learning task; knock-in mouse model Molecular psychiatry High 21876543
2013 FoxP2 knockdown in the songbird striatum (Area X) disrupts D1 receptor (D1R)-dependent modulation of activity propagation in the corticostriatal pathway important for song variability, partly attributable to reduced D1R and DARPP-32 protein levels; and prevents social modulation of singing-related activity in this pathway. shRNA-mediated knockdown in zebra finch Area X, electrophysiological recordings in anesthetized and singing birds, protein level quantification Neuron High 24268418
2013 FoxP2 knockdown in embryonic cortical precursors inhibits neurogenesis by blocking the transition from radial glial precursors to neurogenic intermediate progenitors; conversely, overexpression of human (but not mouse) FoxP2 enhances genesis of intermediate progenitors and neurons; a speech-disorder-causing human FoxP2 mutant decreases neurogenesis, acting as a dominant-inhibitory protein in the murine system. In utero electroporation knockdown and overexpression in mouse embryonic cortex, histological quantification of progenitor and neuron populations The Journal of neuroscience Medium 23283338
2014 Humanized Foxp2 mice (carrying the two human-specific amino acid substitutions) learn stimulus-response associations faster than wild-type littermates when declarative and procedural learning compete; striatal districts show altered dopamine levels, gene expression patterns, and NMDA receptor-dependent long-term depression, demonstrating that the human substitutions tune corticostriatal systems for enhanced procedural learning. Behavioral testing (spatial vs. response learning task), dopamine measurement, gene expression profiling, synaptic plasticity recordings (LTD) in humanized Foxp2 knock-in mice Proceedings of the National Academy of Sciences of the United States of America High 25225386
2014 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 is modulated by homo- and heterodimerization; specific FOXP1/2/4 dimer combinations differentially regulate expression of ten known FOXP2 target genes (including CER1, SFRP4, WISP2, PRICKLE1, NCOR2, SNW1, NEUROD2, PAX3, EFNB3, SLIT1) in HEK293 cells. Stable transfection of FOXP1/2/4 into HEK293 cells, RT-qPCR quantification of target gene expression across dimer combinations Journal of molecular neuroscience Medium 25027557
2014 Foxp2 promotes differentiation of medium spiny neurons from the lateral ganglionic eminence and negatively regulates interneuron formation from the dorsal medial ganglionic eminence by interacting with the Sonic hedgehog pathway; Foxp2 also induces expression of platelet-derived growth factor receptor α (PDGFRα) to mediate its neurogenic effect. Primary neural progenitor culture from embryonic forebrains, overexpression and knockdown assays, cell type quantification, pathway inhibition experiments Developmental neurobiology Medium 24453072
2016 In mouse striatum, Foxp2 directly binds the Mef2c gene promoter and represses Mef2c transcription; this Foxp2-Mef2c axis controls synaptogenesis of corticostriatal inputs and striatal spinogenesis in neonatal mice. Foxp2 deletion de-represses Mef2c, and both intrastriatal and global reduction of Mef2c rescues the vocalization and spinogenesis defects caused by Foxp2 deletion. Mouse Foxp2 knockout, ChIP (direct DNA binding to Mef2c promoter), in vivo Mef2c knockdown rescue experiments, dendritic spine quantification, vocalization assays Nature neuroscience High 27595386
2016 FOXP2 is SUMOylated at a conserved lysine residue (K674 in humans; K673 in mice) by PIAS1/PIAS3 E3 ligases; an aetiological FOXP2 R553H mutation found in speech/language disorder markedly reduces SUMOylation. SENP2 acts as a deSUMOylase for FOXP2. SUMOylation does not detectably alter subcellular localization, stability, dimerization, or transcriptional repression in cellular assays, but the site is conserved across all vertebrate FOXP2 orthologues and in FOXP1 and FOXP4. Co-immunoprecipitation of FOXP2 with PIAS family proteins (pulldown), SUMO modification assays, mutagenesis of SUMOylation site, SENP2 deSUMOylation assay, functional assays (localization, stability, dimerization, transcriptional repression) Scientific reports High 26212494 26867680
2016 FOXP2 sumoylation at K674 (K673 in mice) in neonatal cerebellum is promoted by PIAS3 as the E3 ligase, as demonstrated by in vitro co-immunoprecipitation and in vivo colocalization; this sumoylation modifies FOXP2 transcriptional regulation and is required for cerebellar Purkinje cell dendritic arborization, motor function, and vocal communication. In utero electroporation of sumoylation-site mutants into Purkinje cells, Co-IP, in vivo colocalization, dendritic morphology quantification, vocalization assays, motor behavior tests Biological psychiatry High 27009683
2016 FoxP2 directly binds the VLDLR promoter in zebra finch Area X and activates VLDLR transcription; FoxP2 knockdown in Area X downregulates VLDLR expression and also affects glutamatergic transmission at the corticostriatal synapse onto medium spiny neurons. Lentiviral FoxP2 knockdown in Area X, ChIP demonstrating FoxP2 binding to VLDLR promoter, RT-PCR and protein expression quantification, electrophysiological recordings of glutamatergic transmission Molecular and cellular neurosciences High 27105823
2016 Heterozygous loss of Foxp2 in mice decreases AMPA receptor-mediated excitatory currents and increases GABA receptor-mediated inhibitory currents in D1-receptor-positive striatal medium spiny neurons; this is associated with increased GAD67 expression leading to increased presynaptic GABA content and release. Pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits. Whole-cell patch-clamp recordings in striatal MSNs, GAD67 immunostaining/Western blot, pharmacological rescue in vivo, heterozygous Foxp2 loss-of-function knock-in mice Brain structure & function High 30187194
2017 Foxp2 regulates thalamic nuclear identity and thalamocortical projection patterns during development; in Foxp2(R552H) knock-in mice, posterior thalamic nuclei are shrunken while intermediate-region nuclei expand, and thalamocortical projections are altered, demonstrating a role for Foxp2 in thalamic patterning. Foxp2(R552H) knock-in mouse histology, immunostaining, thalamocortical axon tracing Cerebral cortex Medium 27384060
2018 Selective disruption of Foxp2 in cerebellar Purkinje cells slows lever-pressing speed and impairs skilled locomotion; in vivo recordings reveal increased simple spike firing rate and decreased modulation during limb movements caused by increased intrinsic excitability of Purkinje cells rather than changes in synaptic inputs. Striatal Foxp2 loss affects sequence variability. These effects are region-specific and distinct from each other. Region-specific Cre-mediated Foxp2 conditional knockouts, operant lever-pressing task, skilled locomotion assay, in vivo Purkinje cell electrophysiology, patch-clamp analysis of intrinsic excitability and synaptic inputs Molecular psychiatry High 30108312
2019 FOXP2 represses proliferation-promoting genes in a DNA-binding-dependent manner and activates neuronal maturation genes in cooperation with cofactors NFIA and NFIB without requiring direct DNA binding by FOXP2; these FOXP2/NFI-dependent chromatin alterations drive maturation of excitatory cortical neurons. Genome-wide chromatin accessibility assays (ATAC-seq), transcriptome-wide expression analyses (RNA-seq), FOXP2 knockdown in differentiating human neurons, comparison with developing human brain datasets Cell reports High 31067457
2019 The FOXP2 leucine zipper (LZ) mediates dimerization via coiled-coil formation and also contributes to DNA binding; the C2H2 zinc finger (ZF) contributes to protein dimerization when the LZ coiled-coil is intact but is not involved in DNA binding; the forkhead domain (FHD) is the key driver of DNA binding. Electrically switchable DNA biochips, single-molecule mass photometry, combined biochemical and biophysical domain dissection Angewandte Chemie (International ed. in English) High 30887622
2015 The pH of the FOXP2 forkhead domain affects its tertiary structure and DNA binding affinity; His554 forms a direct hydrogen bond with DNA, and protonation/deprotonation at pH ~6.5 alters this bond and thus DNA binding affinity, suggesting pH as a regulatory mechanism for FOXP2 transcriptional activity. Size exclusion chromatography, far-UV circular dichroism, intrinsic and extrinsic fluorescence spectroscopy, fluorescence anisotropy DNA binding assays across pH 5–9 Biochemistry Medium 26055196
2019 Cortex-specific Foxp2 conditional knockout mice show a major deficit in reversal learning (behavioral flexibility) without effects on general activity or anxiety; this is accompanied by decreased cortical dopamine D1 receptor expression at neonatal and adult stages; single-cell transcriptomics revealed non-cell-autonomous changes in upper-layer neurons and interneurons upon cortical Foxp2 deletion. Cortex-specific conditional Foxp2 knockout (Cre-lox), reversal learning behavioral assay, D1R immunostaining and expression quantification, single-cell RNA sequencing Cerebral cortex High 31711176
2020 β-catenin regulates FOXP2 transcriptional activity by physically interacting with FOXP2 at multiple sites: the β-catenin armadillo domain contacts a disordered FOXP2 region with α-helical propensity, while the intrinsically disordered β-catenin N- and C-termini bind the FOXP2 DNA-binding domain; the FOXP2 α-helical motif acts as a key regulatory element; RNA-seq confirmed that β-catenin regulates FOXP2-dependent transcription including Wnt pathway targets. NMR spectroscopy (interaction mapping), cell-based reporter assays, RNA sequencing, co-immunoprecipitation The FEBS journal High 33284517
2016 FOXP1 co-immunoprecipitates FOXP2 from ABC-DLBCL cells, indicating these two transcription factors can co-localize in a multi-protein complex in lymphoma cells. Co-immunoprecipitation from ABC-DLBCL cell lines Oncotarget Low 27224915
2021 FoxP2 expression in basal ganglia (Area X) is vital for fluent initiation and termination of birdsong and maintenance of song syllable sequencing in adulthood; FoxP2 knockdown imbalances dopamine D1 and D2 receptor expression across striatal direct-like and indirect-like pathways; phasic dopamine activation (not inhibition) during singing drives repetition of song syllables, demonstrating that FoxP2 regulates vocal motor sequencing through dopaminergic signaling. shRNA knockdown of FoxP2 in Area X, dopamine receptor expression quantification, optogenetic phasic dopamine activation/inhibition during singing, vocal behavior analysis Nature communications High 33976169
2021 FOXP2 is expressed in collecting lymphatic endothelial cells and is induced by lymph flow (shear stress) in a FOXC2-dependent manner; genetic deletion of Foxp2 in endothelial or lymphatic endothelial cells results in enlarged collecting vessels and defective valves with loss of NFATc1 activity, identifying FOXP2 as a flow-induced transcriptional regulator of collecting lymphatic vessel morphogenesis. Conditional endothelial knockout (Tie2-Cre and Prox1-CreERT2), in vitro shear stress experiments on primary LECs, transcriptional analysis, valve morphology and NFATc1 activity assays The EMBO journal High 33934370
2011 Foxp2 is expressed in FoxP2+ brainstem neurons of the pre-locus coeruleus (pre-LC) and parabrachial nucleus external lateral-inner subdivision (PBel-inner), which project to sodium appetite regulatory forebrain sites including the ventral pallidum, hypothalamic nuclei, VTA, and PAG; these neurons are activated (c-Fos+) specifically by sodium deprivation. Anterograde axonal tracing (PHAL), retrograde tracing (CTb), double immunohistochemistry for FoxP2 and c-Fos Journal of chemical neuroanatomy Medium 21605659
2016 Functional analyses of rare FOXP2 variants identified a CTBP (C-terminal binding protein) co-repressor-binding region in the N-terminal portion of FOXP2. The two human-lineage amino acid substitutions in this region did not affect CTBP binding or other core aspects of FOXP2 function in cellular assays. Polyglutamine tract variants with reduced tract length did not show altered behavior in cellular assays, indicating the tract is non-essential for core FOXP2 function. Co-immunoprecipitation, subcellular localization assays, luciferase reporter (transcriptional repression), dimerization assays, protein interaction assays for multiple FOXP2 variants Journal of neurodevelopmental disorders Medium 27933109
2011 Foxp2 is expressed in FoxP2+ brainstem neurons of the pre-locus coeruleus (pre-LC) and parabrachial nucleus external lateral-inner subdivision (PBel-inner); virtually all c-Fos-activated neurons in both regions after sodium deprivation also express FoxP2, suggesting these are developmentally-related subsets; FoxP2 expression in these neurons is constitutive (independent of sodium deprivation). Double immunohistochemistry for FoxP2 and c-Fos in sodium-deprived vs. control rats Brain research Medium 21108936
2018 Cortical Foxp2 deletion in mice causes abnormalities in social approach behavior and ultrasonic vocalizations, with cell-type-specific downregulation of Mint2 (Apba2), a gene involved in social behavior, in cortical pyramidal neurons; non-cell-autonomous changes in gene expression were also detected. Homozygous cortical Foxp2 conditional KO (Cre-lox), behavioral profiling, acoustical parameter analysis of USVs, cell type-specific gene expression profiling (single-cell or population RNA-seq of cortical pyramidal neurons) Human molecular genetics Medium 30357341
2015 FoxP2 protein expression level regulates cell morphology transitions (multipolar to bipolar) and radial migration patterns in the developing striatum and cortex; in utero electroporation to elevate FoxP2 in striatal subventricular zone promotes bipolar morphology and impairs multipolar radial migration. In utero electroporation overexpression, immunohistochemistry, morphological analysis of migrating cells in mouse and chicken striatum and mouse cortex Brain structure & function Medium 26163006
2018 Foxp2 is specifically expressed in D1 receptor-expressing striatal projection neurons (SPNs) but not in interneurons; 65–77% of Foxp2-positive neurons co-express D1R mRNA and 21–26% co-express D2R mRNA in adult mouse striatum, providing a cellular framework for understanding Foxp2 function in direct vs. indirect striatal pathways. Double immunostaining and double fluorescent in situ hybridization in adult mouse striatum with cell-type markers Neuroscience Medium 30031127
2016 Cntnap2 mRNA levels significantly increase in the cerebellum of Foxp2(R552H) knock-in mice (which have reduced DNA-binding activity), and Cntnap2 immunofluorescence does not decrease in poorly developed Purkinje cells of these mice; Foxp2 co-localizes with CtBP (co-repressor) only in Purkinje cells, suggesting that Foxp2 regulates Cntnap2 in cerebellum through association with CtBP, and that Cntnap2 is a direct in vivo target. RT-PCR and immunofluorescence in Foxp2(R552H) knock-in mouse cerebellum, CtBP co-localization immunostaining Neuroscience letters Medium 22133810
2018 Mapping of the FOXP2 locus by chromatin conformation capture (3C) identified putative enhancer regions engaging in long-range interactions with the FOXP2 promoter; these enhancer regions drive gene expression in reporter assays; FOXP family transcription factors and TBR1 regulate the FOXP2 promoter and enhancer regions, identifying upstream transcriptional regulators of FOXP2. Chromatin conformation capture (3C), luciferase reporter assays for enhancer activity, transcription factor overexpression assays Frontiers in molecular neuroscience Medium 29515369

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Molecular evolution of FOXP2, a gene involved in speech and language. Nature 721 12192408
2003 Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. The Journal of comparative neurology 409 12687690
2009 FOXP2 as a molecular window into speech and language. Trends in genetics : TIG 338 19304338
2005 FOXP2 and the neuroanatomy of speech and language. Nature reviews. Neuroscience 266 15685218
2004 FoxP2 expression in avian vocal learners and non-learners. The Journal of neuroscience : the official journal of the Society for Neuroscience 250 15056696
2003 FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain : a journal of neurology 250 12876151
2007 Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development (Cambridge, England) 239 17428829
2004 Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. The Journal of neuroscience : the official journal of the Society for Neuroscience 239 15056695
2011 Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain. PLoS genetics 213 21765815
2003 Language fMRI abnormalities associated with FOXP2 gene mutation. Nature neuroscience 202 14555953
2002 Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics 156 12524352
2002 FOXP2 is not a major susceptibility gene for autism or specific language impairment. American journal of human genetics 150 11894222
2003 Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. Journal of neuroscience research 129 12815709
2013 FoxP2 regulates neurogenesis during embryonic cortical development. The Journal of neuroscience : the official journal of the Society for Neuroscience 127 23283338
2000 The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. American journal of human genetics 116 10880297
2012 The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders. Human genetics 110 22736078
2011 FOXP2 and the role of cortico-basal ganglia circuits in speech and language evolution. Current opinion in neurobiology 104 21592779
2013 Diminished FoxP2 levels affect dopaminergic modulation of corticostriatal signaling important to song variability. Neuron 103 24268418
2014 Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance. Proceedings of the National Academy of Sciences of the United States of America 96 25225386
2016 Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c. Nature neuroscience 94 27595386
2011 An aetiological Foxp2 mutation causes aberrant striatal activity and alters plasticity during skill learning. Molecular psychiatry 89 21876543
2010 Humanized Foxp2 specifically affects cortico-basal ganglia circuits. Neuroscience 87 21111790
2009 Conservation and diversity of Foxp2 expression in muroid rodents: functional implications. The Journal of comparative neurology 87 18972576
2007 Generation of mice with a conditional Foxp2 null allele. Genesis (New York, N.Y. : 2000) 78 17619227
2010 FOXP2 gene and language impairment in schizophrenia: association and epigenetic studies. BMC medical genetics 77 20649982
2008 Birdsong decreases protein levels of FoxP2, a molecule required for human speech. Journal of neurophysiology 72 18701760
2011 Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 70 21690130
2007 Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review. American journal of medical genetics. Part A 68 17330859
2002 FOXP2: novel exons, splice variants, and CAG repeat length stability. Human genetics 63 12189486
2016 FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum. Journal of medical genetics 60 27572252
2008 Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2. The Journal of comparative neurology 59 18461604
2003 FOXP2 in focus: what can genes tell us about speech and language? Trends in cognitive sciences 58 12804692
2005 An evolutionary perspective on FoxP2: strictly for the birds? Current opinion in neurobiology 57 16266802
2014 Transcriptional regulation by FOXP1, FOXP2, and FOXP4 dimerization. Journal of molecular neuroscience : MN 55 25027557
2019 Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes. Cell reports 54 31067457
2004 Association between the FOXP2 gene and autistic disorder in Chinese population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 54 15108192
2014 Foxp2 regulates neuronal differentiation and neuronal subtype specification. Developmental neurobiology 53 24453072
2012 Foxp2 mutations impair auditory-motor association learning. PloS one 53 22412993
2016 Knockout of Foxp2 disrupts vocal development in mice. Scientific reports 51 26980647
2005 Molecular cloning and developmental expression of foxP2 in zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 51 16028276
2006 Singing mice, songbirds, and more: models for FOXP2 function and dysfunction in human speech and language. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 17035521
2015 The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia 48 26021489
2014 What can mice tell us about Foxp2 function? Current opinion in neurobiology 48 25048596
2016 MicroRNA-190 regulates FOXP2 genes in human gastric cancer. OncoTargets and therapy 47 27382302
2011 FoxP2 brainstem neurons project to sodium appetite regulatory sites. Journal of chemical neuroanatomy 47 21605659
2010 FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation. Brain research 47 21108936
2016 Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development. Biological psychiatry 43 27009683
2012 FoxP2 expression in the cerebellum and inferior olive: development of the transverse stripe-shaped expression pattern in the mouse cerebellar cortex. The Journal of comparative neurology 41 21935935
2003 Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. American journal of medical genetics. Part A 40 12655497
2015 Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 38 26142732
2017 The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration. Frontiers in cellular neuroscience 37 28798667
2016 The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers. Scientific reports 37 26867680
2008 Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain. American journal of respiratory cell and molecular biology 37 18239190
2019 FOXP2 exhibits projection neuron class specific expression, but is not required for multiple aspects of cortical histogenesis. eLife 36 31099752
2019 Altered social behavior in mice carrying a cortical Foxp2 deletion. Human molecular genetics 35 30357341
2018 Differential effects of Foxp2 disruption in distinct motor circuits. Molecular psychiatry 35 30108312
2014 Monoallelic expression of the human FOXP2 speech gene. Proceedings of the National Academy of Sciences of the United States of America 33 25422445
2020 Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression. Cerebral cortex (New York, N.Y. : 1991) 32 31711176
2004 FOXP2 and the mirror system. Trends in cognitive sciences 32 15301747
2004 FoxP2 in song-learning birds and vocal-learning mammals. The Journal of heredity 32 15618302
2017 miR-618 Inhibits Prostate Cancer Migration and Invasion by Targeting FOXP2. Journal of Cancer 31 28900488
2010 Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells. British journal of haematology 31 20096010
2015 Differential coexpression of FoxP1, FoxP2, and FoxP4 in the Zebra Finch (Taeniopygia guttata) song system. The Journal of comparative neurology 30 25556631
2010 The speech and language FOXP2 gene modulates the phenotype of frontotemporal lobar degeneration. Journal of Alzheimer's disease : JAD 30 20858950
2009 Characterization of Foxp2-expressing cells in the developing spinal cord. Neuroscience 30 19463901
2009 Language features in a mother and daughter of a chromosome 7;13 translocation involving FOXP2. Journal of speech, language, and hearing research : JSLHR 30 19797137
2018 Downregulation of FOXP2 promotes breast cancer migration and invasion through TGFβ/SMAD signaling pathway. Oncology letters 28 29805593
2017 Foxp2 Regulates Identities and Projection Patterns of Thalamic Nuclei During Development. Cerebral cortex (New York, N.Y. : 1991) 28 27384060
2021 Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels. The EMBO journal 27 33934370
2019 lncRNA XIST attenuates hypoxia-induced H9c2 cardiomyocyte injury by targeting the miR-122-5p/FOXP2 axis. Molecular and cellular probes 27 31887421
2016 The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation. Journal of cellular biochemistry 27 26212494
2009 FOXP2 and Human Cognition. Cell 27 19490887
2021 Expression of FoxP2 in the basal ganglia regulates vocal motor sequences in the adult songbird. Nature communications 26 33976169
2016 Early neuroimaging markers of FOXP2 intragenic deletion. Scientific reports 26 27734906
2006 Expression of FoxP2 during zebrafish development and in the adult brain. The International journal of developmental biology 26 16525940
2020 The MicroRNA-23b/27b/24 Cluster Facilitates Colon Cancer Cell Migration by Targeting FOXP2. Cancers 25 31936744
2019 Dissecting FOXP2 Oligomerization and DNA Binding. Angewandte Chemie (International ed. in English) 24 30887622
2018 Differential and Overlapping Pattern of Foxp1 and Foxp2 Expression in the Striatum of Adult Mouse Brain. Neuroscience 24 30031127
2017 microRNA‑196b promotes cell migration and invasion by targeting FOXP2 in hepatocellular carcinoma. Oncology reports 24 29207173
2018 The untold stories of the speech gene, the FOXP2 cancer gene. Genes & cancer 23 29725501
2016 Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development. Gene expression patterns : GEP 23 26969076
2014 Specific expression of FOXP2 in cerebellum improves ultrasonic vocalization in heterozygous but not in homozygous Foxp2 (R552H) knock-in pups. Neuroscience letters 23 24607928
2013 FOXP2. Wiley interdisciplinary reviews. Cognitive science 23 24765219
2016 Functional characterization of rare FOXP2 variants in neurodevelopmental disorder. Journal of neurodevelopmental disorders 22 27933109
2010 Association between FOXP2 gene and speech sound disorder in Chinese population. Psychiatry and clinical neurosciences 22 20923434
2018 Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. Frontiers in molecular neuroscience 21 29515369
2008 Multiple transcription start sites for FOXP2 with varying cellular specificities. Gene 21 18316164
2019 LncRNA TSLNC8 inhibits proliferation of breast cancer cell through the miR-214-3p/FOXP2 axis. European review for medical and pharmacological sciences 20 31646574
2018 Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release. Brain structure & function 20 30187194
2022 miR-134-5p promotes inflammation and apoptosis of trophoblast cells via regulating FOXP2 transcription in gestational diabetes mellitus. Bioengineered 19 34969354
2019 Beyond Critical Period Learning: Striatal FoxP2 Affects the Active Maintenance of Learned Vocalizations in Adulthood. eNeuro 19 31001575
2016 FoxP2 directly regulates the reelin receptor VLDLR developmentally and by singing. Molecular and cellular neurosciences 19 27105823
2016 FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures. Oncotarget 18 27224915
2018 FOXP2 Promotes Tumor Proliferation and Metastasis by Targeting GRP78 in Triple-negative Breast Cancer. Current cancer drug targets 17 29484998
2017 Phonological working memory and FOXP2. Neuropsychologia 17 29174050
2015 Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain. Biochemistry 17 26055196
2015 FoxP2 protein levels regulate cell morphology changes and migration patterns in the vertebrate developing telencephalon. Brain structure & function 17 26163006
2011 Cntnap2 expression in the cerebellum of Foxp2(R552H) mice, with a mutation related to speech-language disorder. Neuroscience letters 16 22133810
2020 β-catenin regulates FOXP2 transcriptional activity via multiple binding sites. The FEBS journal 15 33284517
2016 Cell type-specific expression of FoxP2 in the ferret and mouse retina. Neuroscience research 15 27888071

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