Affinage

RBFOX1

RNA binding protein fox-1 homolog 1 · UniProt Q9NWB1

Length
397 aa
Mass
42.8 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBFOX1 (Fox-1/A2BP1) is a tissue-specific RNA-binding protein that governs alternative splicing programs and cytoplasmic mRNA regulation in neurons and striated muscle (PMID:12574126, PMID:16260614, PMID:26687839). It recognizes the (U)GCAUG element through an RRM that binds RNA by an unusual dual mechanism in which the canonical four-stranded beta-sheet reads the 3' UGU while two protein loops wrap the 5' UGCA, with conserved hydration sites contributing to binding energetics (PMID:16362037, PMID:28505313). Splicing outcome is positional: downstream intronic sites activate exon inclusion through the C-terminal Ala/Tyr/Gly-rich domain, while upstream binding represses by blocking early prespliceosomal (E' and E) complex assembly, including interference with U2AF65 and SF1 (PMID:17101796, PMID:17686786, PMID:18573872, PMID:18794351, PMID:22184459). In the nucleus RBFOX1 functions within the LASR multiprotein complex, contacting RNA at both GCAUG motifs and motifs for hnRNP M, H/F, C, and Matrin3 arranged in tandem modules, such that combinatorial occupancy shapes splicing decisions (PMID:39880658). Subcellular partitioning is autoregulated: alternative splicing of RBFOX1's own pre-mRNA in response to neuronal depolarization, and phosphorylation by WNK3, shift the protein between nuclear and cytoplasmic pools (PMID:19762510, PMID:23027929). Cytoplasmic isoforms bind target 3' UTRs to enhance mRNA stability and translation, often by competing with microRNAs, exemplified by stabilization of Vamp1 (via miR-9 blockade), CaMKIIalpha, and translational enhancement of Serca2a (PMID:26687839, PMID:29621484, PMID:32248729, PMID:40358188). Through these activities RBFOX1 controls neuronal excitability and inhibitory synaptic transmission, where CNS deletion produces seizure susceptibility and E/I imbalance (PMID:21623373, PMID:29621484), cortical neuronal migration and dendritic/axonal morphogenesis (PMID:27481563, PMID:26500751, PMID:39532536), and cardiac and skeletal muscle physiology including calcium handling, MEF2 isoform choice, and focal adhesion protein splicing (PMID:25575511, PMID:26619120, PMID:40358188, PMID:38253401).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established that Fox-1 is a sequence-specific splicing regulator, defining its core GCAUG recognition element and showing it can both activate and repress exons.

    Evidence In vitro RNA binding and minigene splicing assays across F1gamma, alpha-actinin, and fibronectin pre-mRNAs

    PMID:12574126

    Open questions at the time
    • Structural basis of GCAUG recognition not yet resolved
    • Endogenous target network unknown
    • Rules governing activation vs repression undefined
  2. 2005 High

    Defined the atomic mechanism of RNA recognition, explaining how a single RRM achieves high-affinity, specific UGCAUG binding through a non-canonical loop-mediated mode.

    Evidence NMR solution structure of the Fox-1 RBD bound to UGCAUGU with SPR validation

    PMID:16362037

    Open questions at the time
    • Does not address regulation of binding in vivo
    • Role of regions outside the RRM in splicing not addressed
  3. 2005 High

    Showed Fox proteins act in neurons as well as muscle and that isoform identity determines splicing competence, linking tissue-specific isoform expression to splicing output.

    Evidence Overexpression/RNAi splicing assays and isoform comparison in neural vs muscle cells with subcellular localization

    PMID:15824060 PMID:16260614

    Open questions at the time
    • Mechanism by which isoforms differ functionally not fully resolved
    • Genome-wide targets not yet mapped
  4. 2006 High

    Provided the first biochemical mechanism of Fox-mediated repression: blocking spliceosome assembly at the 3' splice site.

    Evidence Minigene and EMSA assays showing UGCAUG-bound Fox blocks U2AF65 recruitment to calcitonin exon 4

    PMID:17101796

    Open questions at the time
    • Generality beyond calcitonin not established at the time
    • Position-dependence of repression not yet formalized
  5. 2007 High

    Refined the repression mechanism to specific prespliceosomal steps and identified a non-RRM protein region required for repression.

    Evidence In vitro E-complex assembly assays with domain mutagenesis on F1gamma, plus C. elegans genetic epistasis with SUP-12 on egl-15

    PMID:17686786 PMID:17923701

    Open questions at the time
    • Identity of the repressive domain's protein partners unknown
    • How combinatorial partners (SUP-12) are recruited in mammals unclear
  6. 2008 High

    Resolved that Fox blocks two sequential prespliceosomal transitions and established the position-dependent rule that downstream sites activate while upstream sites repress, generalizing to thousands of targets.

    Evidence Biochemical E'/E complex assays plus computational target prediction with splicing microarray validation

    PMID:18573872 PMID:18794351

    Open questions at the time
    • Mechanism of downstream activation not biochemically defined
    • Protein cofactors mediating each step not identified
  7. 2009 High

    Discovered autoregulatory control of RBFOX1 localization: activity-dependent alternative splicing of its own exon 19 switches the protein between cytoplasmic and nuclear pools to tune target exon regulation.

    Evidence Splicing assays, subcellular fractionation, and endogenous target RT-PCR under chronic depolarization/CaMKIV signaling

    PMID:19762510

    Open questions at the time
    • Distinct molecular function of cytoplasmic isoform not yet defined
    • Direct kinase substrate relationships not established
  8. 2010 Medium

    Identified Mef2c as a direct neural splicing target, connecting RBFOX1 to a transcription-factor splicing program during differentiation.

    Evidence Minigene transfection with GCAUG mutagenesis in differentiated P19 cells

    PMID:20141540

    Open questions at the time
    • Functional consequence of Mef2c isoform switch in neurons not tested here
    • Single cell-line context
  9. 2011 High

    Mapped the activation vs repression activity to specific domains and identified C-terminal-domain protein interactors, while in vivo deletion established the physiological splicing program preventing neuronal hyperexcitation.

    Evidence MS2 tethering with domain dissection, IP-MS identifying hnRNP H1/RALY/TFG, and CNS-specific conditional KO with EEG/electrophysiology

    PMID:21623373 PMID:22184459

    Open questions at the time
    • How C-terminal-domain partners mechanistically drive activation unresolved
    • Causal target exons for hyperexcitability not individually validated
  10. 2012 Medium

    Showed phosphoregulation controls RBFOX1 localization: WNK3 phosphorylation drives cytoplasmic accumulation and suppresses splicing without altering RNA binding.

    Evidence Co-IP, kinase activity assay, localization, and splicing reporter

    PMID:23027929

    Open questions at the time
    • Phosphosite mapping not detailed
    • Single lab; physiological context of WNK3 regulation unconfirmed
  11. 2015 High

    Defined the cytoplasmic function of RBFOX1 as a 3' UTR-binding stabilizer/translational enhancer distinct from nuclear splicing, expanding the gene to a dual-compartment regulator.

    Evidence Subcellular iCLIP-seq, isoform-specific rescue, and mRNA stability/translation assays; conditional muscle and cardiac KOs with functional phenotypes; zebrafish loss-of-function

    PMID:25575511 PMID:26116573 PMID:26619120 PMID:26687839

    Open questions at the time
    • Mechanism of translational enhancement at molecular level incomplete
    • Crosstalk between nuclear and cytoplasmic functions in vivo not dissected
  12. 2018 High

    Connected cytoplasmic 3' UTR regulation to circuit physiology, showing RBFOX1 stabilizes Vamp1 by blocking miR-9 to maintain inhibitory synaptic transmission and E/I balance.

    Evidence Conditional KO with electrophysiology, 3' UTR binding/miRNA competition, and interneuron-specific Vamp1 rescue; cell-type-specific splicing programs in SST/PV interneurons

    PMID:29621484 PMID:30318414

    Open questions at the time
    • Full set of miRNA-competed targets unknown
    • How activity gates cell-type-specific programs mechanistically unclear
  13. 2018 Medium

    Revealed biophysical and pathogenic-repeat behaviors of RBFOX1: it phase-separates via low-complexity domains and competes with MBNL1 for CCUG repeats relevant to myotonic dystrophy.

    Evidence In vitro phase separation/fibril assays, Drosophila stress and DM2 models with rescue, MBNL1 competition assays

    PMID:25211016 PMID:29358748 PMID:29789616

    Open questions at the time
    • Functional role of phase separation in splicing/stability not established
    • Single-model evidence for repeat competition
  14. 2017 High

    Refined the structural energetics of RNA binding, identifying conserved hydration sites that contribute to affinity.

    Evidence X-ray crystallography of free RRM, NMR, MD simulation, switchSENSE binding, and mutagenesis

    PMID:28505313

    Open questions at the time
    • Functional consequence of hydration-site mutation in cells not tested
    • Does not address full-length protein behavior
  15. 2025 High

    Defined RBFOX1's nuclear context as the LASR complex, showing combinatorial RNA recognition where RBFOX1 contributes GCAUG contact but LASR subunits provide additional tandem-motif binding independent of RBFOX1's own RRM.

    Evidence Transcriptome-wide nuclease footprinting, F125A RNA-binding mutant, and minigene combinatorial splicing assays

    PMID:39880658

    Open questions at the time
    • Stoichiometry and architecture of RBFOX1-LASR assembly not resolved
    • How combinatorial occupancy maps to activate/repress outcomes incomplete
  16. 2025 Medium

    Extended cytoplasmic translational control and splicing to cardiac calcium handling and chemotherapy vulnerability, including direct Serca2a 3' UTR translational enhancement and a signaling cascade triggering RBFOX1 degradation.

    Evidence Cardiomyocyte-specific KO, RIP, luciferase reporter, puromycin translation assay; A2A/CAMKIIdelta phosphorylation-degradation cascade with chromatin accessibility analysis; Mbnl1 exon 7 splicing with ASO rescue in MI

    PMID:40358188 PMID:40715150 PMID:41294183

    Open questions at the time
    • Degradation cascade validated in single model
    • Relative contribution of splicing vs translational targets to cardiac phenotypes unclear
  17. 2024 Medium

    Documented additional disease- and development-relevant splicing targets across muscle, sensory, and cortical systems, broadening the target network.

    Evidence Minigene and KO/knockdown studies on vinculin/paxillin (cardiac), Nrcam (DRG/pain), CaV1.2 (vascular), LSD1 (primate evolution), and Ptbp1 (neocortex, triple Rbfox1/2/3 KO)

    PMID:35351830 PMID:35543237 PMID:38241164 PMID:38253401 PMID:39532536

    Open questions at the time
    • Many targets validated in single contexts
    • Redundancy among Rbfox paralogs incompletely separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RBFOX1 mechanistically switches between LASR-embedded nuclear splicing and cytoplasmic miRNA-competing translation/stability control within a single cell, and how phosphorylation/autoregulation quantitatively partitions these functions, remains unresolved.
  • No unified model linking compartment switching to target outcomes
  • Structural architecture of RBFOX1 within LASR unresolved
  • Direct phosphosites and their functional consequences incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0045182 translation regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-112316 Neuronal System 3 R-HSA-397014 Muscle contraction 3
Partners
HNRNP CHNRNP H1HNRNP MMATR3MBNL1RALYTFGWNK3
Complex memberships
LASR

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Fox-1 binds specifically to the pentanucleotide GCAUG in vitro and regulates tissue-specific alternative splicing: it induces muscle-specific exon skipping of the F1gamma gene via GCAUG sequences upstream of the regulated exon, and regulates mutually exclusive splicing of the alpha-actinin gene by antagonizing PTB; it also promotes inclusion of the fibronectin EIIIB exon, demonstrating both positive and negative splicing regulation. In vitro RNA binding assay, transfection/minigene splicing assay The EMBO journal High 12574126
2005 NMR solution structure of the Fox-1 RNA-binding domain (RBD) in complex with UGCAUGU reveals an unprecedented RNA recognition mechanism: the last three nucleotides (UGU) are recognized canonically by the four-stranded beta-sheet, while the first four nucleotides (UGCA) are bound by two protein loops—U1, G2, C3 are wrapped around a single phenylalanine, and G2/A4 form a base-pair—creating a novel binding site independent of the beta-sheet interface. SPR analyses quantified the energetic contributions of electrostatic and hydrogen bond interactions. NMR structure determination, surface plasmon resonance (SPR) The EMBO journal High 16362037
2005 Mouse Fox-1 (mFox-1) and Fox-2 are expressed in neurons as well as muscle/heart. Multiple isoforms with variable termini are produced from complex transcription units with multiple promoters and alternatively spliced exons. Overexpression of Fox-1 and Fox-2 isoforms specifically activates splicing of neuronally regulated exons in a UGCAUG-dependent manner; RNAi-mediated knockdown of Fox proteins inhibits splicing of UGCAUG-dependent exons, establishing a splicing enhancer function in neurons. Overexpression splicing assays, RNAi knockdown, RT-PCR Molecular and cellular biology High 16260614
2005 Tissue-specific isoforms of A2BP1 (Fox-1) and Fxh differ in splicing activity and nuclear distribution. All isoforms containing the RRM bind UGCAUG elements in vitro. Brain isoforms promote neural cell-specific N30 exon splicing much more efficiently than muscle isoforms; muscle-specific isoforms lacking part of the RRM cannot activate UGCAUG-dependent splicing and can inhibit it, demonstrating isoform-dependent regulation of tissue-specific splicing. In vitro RNA binding, transfection splicing assay, subcellular localization by microscopy Nucleic acids research High 15824060
2006 Fox-1 and Fox-2 repress calcitonin-specific exon 4 inclusion in calcitonin/CGRP pre-mRNA by binding to two flanking UGCAUG elements and blocking U2AF65 binding to the 3' splice site upstream of exon 4, establishing a mechanism of splicing repression by blocking spliceosome assembly. Minigene splicing assay, RNA electrophoretic mobility shift assay, U2AF65 competition assay Molecular and cellular biology High 17101796
2007 Fox-1 induces exon 9 skipping of the hF1gamma gene by preventing formation of the pre-spliceosomal early (E) complex on the downstream intron 9, via binding to GCAUG elements in the upstream intron 8. A region of the Fox-1 protein distinct from the RRM is required for this repression. In vitro splicing assay, spliceosomal complex assembly assay (E complex), domain mutagenesis Nucleic acids research High 17686786
2007 In C. elegans, the Fox-1 family proteins ASD-1 and FOX-1 coordinately regulate muscle-specific alternative splicing of the FGF receptor gene egl-15 together with the muscle-specific RNA-binding protein SUP-12. The Fox-1 family and SUP-12 form a stable complex on egl-15 RNA dependent on juxtaposed conserved cis elements; the asd-1; sup-12 double mutant phenocopies the egl-15(5A) isoform-specific mutant defective in sex myoblast migration. Genetic epistasis (double mutant), RNA-protein complex formation assay, in vivo reporter splicing assay Molecular and cellular biology High 17923701
2008 Fox-1/Fox-2 repress prespliceosome assembly at two distinct steps: (1) binding to an intronic UGCAUG element blocks SF1-dependent E' complex formation; (2) binding to an exonic UGCAUG element blocks the transition from the E' complex to the E complex, representing the first example of regulated E' complex formation. Biochemical complex assembly assay (E' and E complex), RNA binding assay, mutagenesis Molecular and cellular biology High 18573872
2008 Computational and experimental analysis defines the Fox-1/Fox-2 splicing regulatory network: the preferred position of UGCAUG binding sites relative to the regulated exon determines whether Fox-1/2 activates or represses exon recognition—downstream intronic sites activate and upstream intronic sites repress. Thousands of conserved Fox-1/2 targets were identified and validated, many important for neuromuscular functions. Computational target prediction, splicing microarray, experimental splicing validation Genes & development Medium 18794351
2009 Fox-1 exon 19 is itself repressed by chronic neuronal depolarization/CaMKIV signaling. Transcripts missing exon 19 encode a nuclear isoform of Fox-1 that replaces the cytoplasmic isoform during depolarization. The resulting increased nuclear Fox-1 reactivates Fox-1 target exons (including NMDA receptor 1 exon 5) that were initially repressed by depolarization, revealing that subcellular localization of RBFOX1 is controlled through alternative splicing of its own pre-mRNA. Splicing assay, subcellular fractionation/localization, RT-PCR of endogenous targets Genes & development High 19762510
2011 The C-terminal Ala/Tyr/Gly-rich domain of RBFOX1 is sufficient for exon activation when tethered downstream of the regulated exon, whereas both the C-terminal domain and the central RRM are required for exon repression when tethered upstream. hnRNP H1, RALY, and TFG were identified as interactors of the RBFOX1/2 C-terminal domain by immunoprecipitation and mass spectrometry. RNAi showed hnRNP H1 and TFG modulate RBFOX1/2 splicing activity (RALY had no effect); TFG localizes to the cytoplasm suggesting indirect modulation. MS2 tethering assay, immunoprecipitation with mass spectrometry, RNAi knockdown RNA High 22184459
2011 CNS-specific deletion of Rbfox1 in mice results in heightened susceptibility to spontaneous and kainic acid-induced seizures with increased neuronal excitability in the dentate gyrus. Whole-transcriptome analysis identified multiple splicing changes with few changes in transcript abundance, affecting synaptic transmission and membrane excitation proteins, establishing Rbfox1 as directing a splicing program required to prevent neuronal hyperexcitation. Conditional knockout mouse, EEG recording, electrophysiology, transcriptome splicing analysis Nature genetics High 21623373
2012 Protein kinase WNK3 binds Fox-1 and inhibits its splicing activity in a kinase activity-dependent manner. WNK3 phosphorylation of Fox-1 does not change its RNA binding capacity but increases its cytoplasmic localization, thereby suppressing Fox-1-dependent splicing. Co-immunoprecipitation, kinase activity assay, subcellular localization, splicing reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 23027929
2013 FRG1 overexpression is associated with the RNA and reduced stability of Rbfox1 mRNA; Rbfox1 is downregulated in FRG1-overexpressing mice and FSHD patients. Rbfox1 knockdown and RNA-IP confirm direct regulation of a subset of FRG1-affected splicing events including Calpain 3 exon 6. Reduced Rbfox1 leads to increased Capn3 E6- isoform, and both Rbfox1 knockdown and Capn3 E6- overexpression inhibit muscle differentiation. Rbfox1 knockdown, overexpression, RNA-immunoprecipitation, splicing assay, muscle differentiation assay PLoS genetics Medium 23300487
2015 Cytoplasmic isoform of Rbfox1 rescues mRNA-level (not splicing) changes when nuclear Rbfox1 is knocked down. iCLIP-seq showed nuclear Rbfox1 binds predominantly intronic nascent RNA while cytoplasmic Rbfox1 binds 3' UTRs. Cytoplasmic Rbfox1 binding increases target mRNA stability and translation, and its binding sites overlap significantly with miRNA binding sites. Target mRNAs are enriched in cortical development and autism-related genes. Transcriptome profiling, iCLIP-seq of subcellular fractions, rescue experiments with nuclear vs cytoplasmic isoforms, mRNA stability/translation assay Neuron High 26687839
2015 Rbfox1 conditional knockout in mouse skeletal muscle (adult) results in impaired muscle function (decreased force generation), calcium handling defects, and mislocalization of sarcoplasmic reticulum proteins Serca1 and Ryr1 co-localizing with tubular aggregates. Deep sequencing identified aberrant splicing of myofibrillar, cytoskeletal, and calcium-handling genes as the mechanism. Conditional knockout mouse, electron microscopy, immunostaining, calcium imaging, force measurement, deep RNA sequencing Human molecular genetics High 25575511
2015 RBFox1 regulates alternative splicing of MEF2 family transcription factors in the heart, yielding isoforms with differential effects on cardiac hypertrophic gene expression. RBFox1 is induced during postnatal cardiac maturation but diminished in failing hearts; its deficiency promotes pressure overload-induced heart failure, and its induction attenuates cardiac hypertrophy. Conditional knockout mouse, transcriptome/splicing analysis, minigene assay for MEF2 splicing, pressure overload mouse model The Journal of clinical investigation High 26619120
2015 In zebrafish, loss of rbfox1 leads to progressive cardiac contractile dysfunction and heart failure. Deep transcriptome sequencing showed depletion of rbfox1 alters isoform expression of crucial target genes including actn3a. Zebrafish morpholino knockdown, cardiac function assessment, RNA-seq Journal of cell science Medium 26116573
2016 Knockdown of nuclear Rbfox1-isoform1 (iso1) in mouse cortical neurons by in utero electroporation causes defective radial migration (including impaired nucleokinesis) and terminal translocation, suppressed axon extension and dendritic arborization in vivo, and significant defects in membrane and synaptic properties. In vitro knockdown in hippocampal neurons reduced primary axon length, dendritic length, and spine density/maturity. In utero electroporation knockdown, confocal imaging, electrophysiology, in vitro neuron culture Scientific reports Medium 27481563
2015 Cytoplasmic Rbfox1-isoform2 (iso2) knockdown in utero causes defects in radial migration, terminal translocation, nucleokinesis (by time-lapse imaging), axon extension to the opposite hemisphere, and dendritic arborization; in vitro knockdown reduces spine density and mature spine number. In utero electroporation knockdown, time-lapse confocal imaging, in vitro hippocampal neuron culture Molecular autism Medium 26500751
2018 Rbfox1 loss in mice leads to downregulation of the vSNARE Vamp1 due to loss of 3' UTR binding by cytoplasmic RBFOX1. Cytoplasmic Rbfox1 stimulates Vamp1 expression in part by blocking microRNA-9. Vamp1 is specifically expressed in inhibitory neurons; both Vamp1 knockdown and Rbfox1 loss decrease inhibitory synaptic transmission causing E/I imbalance. Re-expression of Vamp1 selectively in interneurons rescues electrophysiological changes in the Rbfox1 cKO. Conditional knockout mouse, electrophysiology, 3' UTR binding assay, interneuron-specific rescue, miRNA blocking assay Neuron High 29621484
2018 Rbfox1 mediates largely non-overlapping alternative splicing programs in somatostatin- and parvalbumin-expressing cortical interneurons in an activity-dependent manner, controlling subtype-specific efferent connectivity integration into nascent cortical circuits. Conditional knockout in interneuron subtypes, transcriptome splicing analysis, circuit connectivity assay Neuron Medium 30318414
2018 rbFOX1 binds to expanded CCUG RNA repeats (but not expanded CUG repeats) and competes with MBNL1 for binding to CCUG repeats. Overexpression of rbFOX1 partly releases MBNL1 from sequestration in CCUG RNA foci in DM2 muscle cells and corrects alternative splicing alterations and muscle atrophy/behavioral defects in a Drosophila DM2 model. RNA binding assay, RNA foci competition assay, Drosophila overexpression with phenotypic rescue, splicing assay Nature communications Medium 29789616
2018 Rbfox1 is an LCD-containing protein that forms liquid droplets and amyloid-like fibers and joins nuclear and cytoplasmic RNP granules. In Drosophila oogenesis under stress, reduced miR-980 (which targets extended-3'UTR Rbfox1 transcripts) increases Rbfox1 levels, promotes widespread RNP granule formation, and increases cell viability. Human RBFOX proteins also contain multiple LCDs and form membraneless compartments. Phase separation assay (liquid droplets, amyloid fibers), Drosophila in vivo stress response, miRNA manipulation, immunofluorescence Nature communications Medium 29358748
2020 RBFOX1 promotes CaMKIIα expression in neurons following intracerebral hemorrhage by binding to CaMKIIα mRNA and blocking miR-124 binding to that mRNA; increased RBFOX1 and CaMKIIα cause intracellular Ca2+ overload and neuronal degeneration. RNA binding assay (RIP), miRNA binding competition, protein expression manipulation (overexpression/knockdown), calcium imaging Journal of cerebral blood flow and metabolism Medium 32248729
2017 X-ray crystal structure of free Fox-1 RRM at 1.8 Å resolution combined with molecular dynamics analyses identified key water molecules at two conserved hydration sites (at S155 and S122). NMR spectroscopy and switchSENSE RNA binding assays confirmed that abolishing the S155 hydration site reduces RNA binding free energy; the S155 hydration site is evolutionarily conserved among RRM domains. X-ray crystallography, NMR spectroscopy, molecular dynamics simulation, switchSENSE RNA binding assay, mutagenesis Nucleic acids research High 28505313
2022 Rbfox1 dynamically regulates alternative splicing of CaV1.2 exons 9* and 33 in vascular smooth muscle cells; Rbfox1 knockdown induces hyperpolarization of the CaV1.2 current-voltage relationship curve and increases K+-induced arterial constriction, demonstrating a role in vascular CaV1.2 channel function and vascular tone regulation. siRNA knockdown, whole-cell patch clamp, vascular myograph, RT-PCR splicing analysis Clinical science Medium 35543237
2025 Rbfox1 in the nucleus operates within the large assembly of splicing regulators (LASR) complex. Transcriptome-wide nuclease protection footprinting showed Rbfox1/LASR binds RNA at both GCAUG motifs and motifs for LASR subunits hnRNPs M, H/F, C, and Matrin3, arranged in tandem multipart modules. A Rbfox1(F125A) RNA-binding mutant loses GCAUG contact but retains LASR assembly and LASR-motif binding; splicing analyses show Rbfox1 can stimulate exons near LASR subunit binding sites, and minigene experiments demonstrate combinatorial regulatory effects. Nuclease protection assay (transcriptome-wide footprinting), RNA-binding domain mutagenesis (F125A), splicing analysis, minigene assay Genes & development High 39880658
2010 Fox-1 promotes inclusion of Mef2c exon β during neural differentiation of P19 cells, dependent on its RNA-binding activity and GCAUG sequences in the adjacent intron of exon β, establishing Mef2c as a direct splicing target of Fox-1 in neural differentiation. Minigene transfection assay, mutagenesis of GCAUG, RT-PCR in differentiated P19 cells Genes to cells Medium 20141540
2014 In DM1, MBNL1 and RBFOX1 co-regulate approximately half the same splicing events in muscle; a dominant negative isoform of RBFOX1 is produced by DM1-associated aberrant splicing. Reduced RBFOX1 activity in DM1 tissues is proposed to amplify MBNL1-dependent splicing alterations. RT-PCR splicing panel, cell culture and transgenic mouse DM1 models, isoform characterization PloS one Medium 25211016
2025 RBFOX1 binds the 3' UTR of Serca2a mRNA (confirmed by RNA immunoprecipitation) and enhances SERCA2 protein translation (demonstrated by puromycin incorporation assay and luciferase 3'UTR reporter), without affecting Serca2 mRNA levels or splicing. Cardiomyocyte-specific Rbfox1 knockout mice show decreased SERCA2 expression, delayed Ca2+ reuptake, and exaggerated pressure overload-induced heart failure. Cardiomyocyte-specific KO mouse, RNA immunoprecipitation, luciferase 3'UTR reporter, puromycin incorporation (translation) assay, calcium dynamics, TAC model Cells Medium 40358188
2024 Rbfox1 regulates alternative splicing of focal adhesion proteins vinculin (metavinculin isoform) and paxillin (extended paxillin isoform) in cardiac muscle cells via intronic RBFOX1 binding sites (demonstrated by minigene assay). Rbfox1 depletion changes cardiomyoblast morphology, cytoskeletal organization, and multinuclearity after differentiation. In silico target prediction, minigene splicing assay, siRNA knockdown, morphological/cytoskeletal analysis Journal of molecular cell biology Medium 38253401
2023 Rbfox1 regulates alternative splicing of Nrcam in dorsal root ganglion neurons; its downregulation after spinal nerve ligation amplifies exon 10 insertion in Nrcam transcripts, increasing the long Nrcam variant. Restoring Rbfox1 expression mitigates nociceptive hypersensitivity; mimicking downregulation generates neuropathic pain symptoms. Spinal nerve ligation model, Rbfox1 overexpression/knockdown, splicing assay (RT-PCR), behavioral pain assay Neurotherapeutics Medium 38241164
2022 In higher primates and humans, a single nucleotide variation (AA to AG) in the LSD1 gene created a new 3' splice site, enabling RbFOX1 to promote alternative usage of this site and extend LSD1 exon E9 (E9-long), which triggers nonsense-mediated mRNA decay to reduce LSD1 levels. Reintroduction of the archaic AA sequence abolishes E9-long splicing, confirming the novel 3' AG site is necessary. Minigene splicing assay, mutagenesis (archaic variant reversion), evolutionary sequence analysis The Journal of neuroscience Medium 35351830
2025 Tumor-derived inosine/hypoxanthine bind the A2A receptor on cardiomyocytes, activating CAMKIIδ which phosphorylates RBFOX1, leading to its caspase-dependent degradation. RBFOX1 loss reverts cardiomyocytes to a less mature (open chromatin) state susceptible to DNA damage and apoptosis from DNA-damaging chemotherapy agents. Mass spectrometry, phosphorylation assay, caspase inhibition, chromatin accessibility analysis, cardiomyocyte apoptosis assay Nature communications Medium 40715150
2025 RBFox1 regulates alternative splicing of Mbnl1 exon 7 in post-MI hearts; hypoxia-sensitive loss of exon 7 produces an Mbnl1-ΔExon7 isoform that promotes cell death. Selective inhibition of Mbnl1 exon 7 inclusion by antisense oligonucleotide protects the heart from MI-induced injury in vivo. Conditional expression in vivo (rat MI model), splicing analysis, antisense oligonucleotide intervention, TUNEL/caspase assay Cardiovascular research Medium 41294183
2025 Rbfox1/2 regulate alternative splicing of Ptbp1 in the developing neocortex, including promotion of a mammal-specific alternative exon and a poison exon in Ptbp1. Simultaneous ablation of Rbfox1/2/3 in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Conditional knockout (triple Rbfox1/2/3), cell-type specific RNA-seq, minigene assay, migration analysis The Journal of neuroscience Medium 39532536

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Identification of neuronal nuclei (NeuN) as Fox-3, a new member of the Fox-1 gene family of splicing factors. The Journal of biological chemistry 318 19713214
2011 The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nature genetics 289 21623373
2003 A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. The EMBO journal 272 12574126
2008 Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes & development 259 18794351
2005 Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals. Molecular and cellular biology 243 16260614
2005 Molecular basis of RNA recognition by the human alternative splicing factor Fox-1. The EMBO journal 209 16362037
2015 Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes. Neuron 194 26687839
2012 RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Human molecular genetics 175 22730494
2007 Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 175 17503474
2005 Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities. Nucleic acids research 167 15824060
2009 Fox-1 family of RNA-binding proteins. Cellular and molecular life sciences : CMLS 164 19688295
2009 An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons. Genes & development 136 19762510
2015 RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. The Journal of clinical investigation 134 26619120
2004 The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. Journal of human genetics 129 15148587
2013 Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion. Molecular cancer 97 23286373
2013 RBFOX1 and RBFOX3 mutations in rolandic epilepsy. PloS one 91 24039908
2018 Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons. Neuron 88 30318414
2011 Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2. RNA (New York, N.Y.) 86 22184459
1994 Gene sequence and biochemical characterization of FOX-1 from Klebsiella pneumoniae, a new AmpC-type plasmid-mediated beta-lactamase with two molecular variants. Antimicrobial agents and chemotherapy 82 7811034
2007 The Fox-1 family and SUP-12 coordinately regulate tissue-specific alternative splicing in vivo. Molecular and cellular biology 81 17923701
2018 Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1. Neuron 78 29621484
2013 Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder. International review of neurobiology 72 24290388
2020 Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease. JAMA neurology 70 32568366
1994 Identification of a candidate primary sex determination locus, fox-1, on the X chromosome of Caenorhabditis elegans. Development (Cambridge, England) 64 7821230
2018 rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nature communications 63 29789616
2013 Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 59 23350840
2016 Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development. Scientific reports 58 27481563
2015 The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function. Human molecular genetics 56 25575511
2006 Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing. Molecular and cellular biology 54 17101796
2015 Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. Molecular autism 51 26500751
2014 RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1. PloS one 47 25211016
2022 Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits. Molecular psychiatry 44 35948661
2017 RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 44 29174947
1999 Genetic and molecular analysis of fox-1, a numerator element involved in Caenorhabditis elegans primary sex determination. Genetics 44 9927456
2001 Identification and expression of a mouse ortholog of A2BP1. Mammalian genome : official journal of the International Mammalian Genome Society 41 11471052
2016 MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1. Cell reports 40 26876166
2010 Alternative splicing of Mef2c promoted by Fox-1 during neural differentiation in P19 cells. Genes to cells : devoted to molecular & cellular mechanisms 40 20141540
2007 Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1gamma gene. Nucleic acids research 38 17686786
2012 Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis. American journal of medical genetics. Part A 36 22678932
2018 Stress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival. Nature communications 32 29358748
2013 Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). PLoS genetics 31 23300487
2015 Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy. Epilepsia 30 26174448
2010 Evaluation of A2BP1 as an obesity gene. Diabetes 29 20724578
2017 Structural study of the Fox-1 RRM protein hydration reveals a role for key water molecules in RRM-RNA recognition. Nucleic acids research 28 28505313
2020 Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 27 32248729
2001 Androgens regulate the mammalian homologues of invertebrate sex determination genes tra-2 and fox-1. Biochemical and biophysical research communications 27 11401487
2015 RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish. Journal of cell science 26 26116573
2008 Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins. Molecular and cellular biology 25 18573872
2019 HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy. The Journal of allergy and clinical immunology 21 31301374
2021 A Broad-Based Mosquito Yeast Interfering RNA Pesticide Targeting Rbfox1 Represses Notch Signaling and Kills Both Larvae and Adult Mosquitoes. Pathogens (Basel, Switzerland) 20 34684200
2017 Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure. PLoS genetics 20 28346479
2015 Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy. Journal of immunology (Baltimore, Md. : 1950) 20 26188062
2016 RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing. Scientific reports 19 27146458
2011 Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1). Developmental neuroscience 19 21346316
2018 Downregulation of splicing regulator RBFOX1 compromises visual depth perception. PloS one 18 30001398
2022 Identification of inflammatory response and alternative splicing in acute kidney injury and experimental verification of the involvement of RNA‑binding protein RBFOX1 in this disease. International journal of molecular medicine 17 35059728
2020 RBFOX1 Regulates the Permeability of the Blood-Tumor Barrier via the LINC00673/MAFF Pathway. Molecular therapy oncolytics 17 32322670
2013 Biochemical and morphological characterization of A2BP1 in neuronal tissue. Journal of neuroscience research 16 23918472
2012 Protein kinase WNK3 regulates the neuronal splicing factor Fox-1. Proceedings of the National Academy of Sciences of the United States of America 16 23027929
2010 A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients. Human immunology 14 20153395
2018 Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure. Channels (Austin, Tex.) 13 28949795
2011 Complex congenital heart defects in association with maternal diabetes and partial deletion of the A2BP1 gene. Fetal and pediatric pathology 13 21355681
2020 Rbfox1 Is Expressed in the Mouse Brain in the Form of Multiple Transcript Variants and Contains Functional E Boxes in Its Alternative Promoters. Frontiers in molecular neuroscience 12 32431595
2011 Evidence that "brain-specific" FOX-1, FOX-2, and nPTB alternatively spliced isoforms are produced in the lens. Current eye research 12 21714144
2022 Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension. Clinical science (London, England : 1979) 11 35543237
2023 TCF4 and RBFOX1 as peripheral biomarkers for the differential diagnosis and treatment of major depressive disorder. Journal of affective disorders 10 37890537
2025 The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules. Genes & development 9 39880658
2015 Upregulation of RBFOX1 in the malformed cortex of patients with intractable epilepsy and in cultured rat neurons. International journal of molecular medicine 9 25571999
2014 Outfoxed by RBFOX1-a caution about ascertainment bias. American journal of medical genetics. Part A 9 24664471
2024 Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia. Molecular psychiatry 7 38273110
2024 Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in two zebrafish models. Translational psychiatry 7 38374212
2023 Patient Brain Organoids Identify a Link between the 16p11.2 Copy Number Variant and the RBFOX1 Gene. ACS chemical neuroscience 7 37903506
2022 Visual Function and Survival of Injured Retinal Ganglion Cells in Aged Rbfox1 Knockout Animals. Cells 7 36359797
2021 Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk. Frontiers in genetics 7 34490042
2020 Dose-dependent action of the RNA binding protein FOX-1 to relay X-chromosome number and determine C. elegans sex. eLife 7 33372658
2022 Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 6 35351830
2022 RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder. Biological psychiatry global open science 6 37881587
2015 A2BP1 gene polymorphisms association with olanzapine-induced weight gain. Pharmacological research 6 26092620
2025 Cell-Type-Specific Splicing of Transcription Regulators and Ptbp1 by Rbfox1/2/3 in the Developing Neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 5 39532536
2024 Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells. Journal of molecular cell biology 5 38253401
2024 Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Cav1.2 splicing and RbFox1/Fox2 downregulation. The FEBS journal 5 38794806
2022 Rbfox1 is required for myofibril development and maintaining fiber type-specific isoform expression in Drosophila muscles. Life science alliance 5 34996845
2022 Rbfox1 expression in amacrine cells is restricted to GABAergic and VGlut3 glycinergic cells. Bioscience reports 5 35730583
2021 Loss of Rbfox1 Does Not Affect Survival of Retinal Ganglion Cells Injured by Optic Nerve Crush. Frontiers in neuroscience 5 34108862
2024 Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia. Cellular and molecular life sciences : CMLS 4 38575795
2024 Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus. Science advances 4 38924416
2023 Rbfox1 regulates alternative splicing of Nrcam in primary sensory neurons to mediate peripheral nerve injury-induced neuropathic pain. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 4 38241164
2025 RBFOX1 Regulates Calcium Signaling and Enhances SERCA2 Translation. Cells 3 40358188
2025 Tumour initiated purinergic signalling promotes cardiomyocyte RBFOX1 degradation and cardiotoxicity from DNA damaging anticancer agents. Nature communications 3 40715150
2023 Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia. Research square 3 37398467
2025 An Environmentally-Friendly RNAi Yeast-Attractive Targeted Sugar Bait Turns off the Drosophila suzukii Rbfox1 Gene. Insects 2 40429193
2020 Variants of the Aggression-Related RBFOX1 Gene in a Population Representative Birth Cohort Study: Aggressiveness, Personality, and Alcohol Use Disorder. Frontiers in psychiatry 2 33329073
2025 rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood. bioRxiv : the preprint server for biology 1 39464042
2025 rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood. Translational psychiatry 1 41261149
2025 Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure. Cardiovascular research 1 41294183
2024 Mutation of two intronic nucleotides alters RNA structure and dynamics inhibiting MBNL1 and RBFOX1 regulated splicing of the Insulin Receptor. bioRxiv : the preprint server for biology 1 38260517
2024 The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multi-part RNA regulatory modules. bioRxiv : the preprint server for biology 1 39071271
2023 Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in a zebrafish model. bioRxiv : the preprint server for biology 1 36865197
2023 Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report. Cureus 1 37033539
2025 The Expression Characteristics of the RBFOX1 Gene in Colorectal Cancer. Technology in cancer research & treatment 0 40395202

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