{"gene":"RBFOX1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"In vitro RNA binding assay, transfection/minigene splicing assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay combined with multiple minigene transfection experiments across three distinct target pre-mRNAs, replicated across labs subsequently","pmids":["12574126"],"is_preprint":false},{"year":2005,"finding":"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.","method":"NMR structure determination, surface plasmon resonance (SPR)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution NMR structure with functional SPR validation, multiple orthogonal methods in a single study","pmids":["16362037"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Overexpression splicing assays, RNAi knockdown, RT-PCR","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined molecular readout, replicated across multiple isoforms and exon targets","pmids":["16260614"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro RNA binding, transfection splicing assay, subcellular localization by microscopy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding plus functional transfection assays, multiple isoforms tested, single lab","pmids":["15824060"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Minigene splicing assay, RNA electrophoretic mobility shift assay, U2AF65 competition assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of spliceosome blockade, minigene assays, multiple UGCAUG mutagenesis experiments, single lab","pmids":["17101796"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro splicing assay, spliceosomal complex assembly assay (E complex), domain mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E-complex inhibition with mutagenesis, single lab but multiple orthogonal methods","pmids":["17686786"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Genetic epistasis (double mutant), RNA-protein complex formation assay, in vivo reporter splicing assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis in C. elegans with defined phenotype, complex formation on RNA, in vivo splicing reporter, replicated across orthogonal approaches","pmids":["17923701"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Biochemical complex assembly assay (E' and E complex), RNA binding assay, mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of two sequential spliceosomal blockade steps, multiple UGCAUG mutations tested, single lab","pmids":["18573872"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Computational target prediction, splicing microarray, experimental splicing validation","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — position-dependent activation/repression rule validated experimentally for multiple targets, single lab, partially computational","pmids":["18794351"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Splicing assay, subcellular fractionation/localization, RT-PCR of endogenous targets","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism linking RBFOX1 autoregulatory splicing to subcellular redistribution and downstream target regulation, multiple orthogonal methods, single lab","pmids":["19762510"],"is_preprint":false},{"year":2011,"finding":"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.","method":"MS2 tethering assay, immunoprecipitation with mass spectrometry, RNAi knockdown","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain-dissection tethering assay combined with proteomic identification of interactors and functional RNAi validation, multiple methods in single study","pmids":["22184459"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Conditional knockout mouse, EEG recording, electrophysiology, transcriptome splicing analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with electrophysiological phenotype, genome-wide splicing analysis, well-defined molecular and physiological readouts","pmids":["21623373"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, kinase activity assay, subcellular localization, splicing reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding plus kinase-dependent functional effect with localization data, single lab, multiple orthogonal methods","pmids":["23027929"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Rbfox1 knockdown, overexpression, RNA-immunoprecipitation, splicing assay, muscle differentiation assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms direct binding, knockdown and OE with functional muscle readout, single lab","pmids":["23300487"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Transcriptome profiling, iCLIP-seq of subcellular fractions, rescue experiments with nuclear vs cytoplasmic isoforms, mRNA stability/translation assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific rescue combined with genome-wide iCLIP mapping and functional mRNA stability/translation assays, multiple orthogonal methods","pmids":["26687839"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Conditional knockout mouse, electron microscopy, immunostaining, calcium imaging, force measurement, deep RNA sequencing","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ultrastructural, functional (calcium handling, force), and splicing readouts, multiple orthogonal methods","pmids":["25575511"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Conditional knockout mouse, transcriptome/splicing analysis, minigene assay for MEF2 splicing, pressure overload mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO and overexpression in vivo with defined splicing target (MEF2) and functional cardiac phenotype, multiple orthogonal methods","pmids":["26619120"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Zebrafish morpholino knockdown, cardiac function assessment, RNA-seq","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with functional cardiac readout and splicing data, single lab","pmids":["26116573"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In utero electroporation knockdown, confocal imaging, electrophysiology, in vitro neuron culture","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined migration and morphological phenotypes, electrophysiological readout, single lab","pmids":["27481563"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In utero electroporation knockdown, time-lapse confocal imaging, in vitro hippocampal neuron culture","journal":"Molecular autism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with live imaging of migration, defined morphological readouts, single lab","pmids":["26500751"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Conditional knockout mouse, electrophysiology, 3' UTR binding assay, interneuron-specific rescue, miRNA blocking assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with electrophysiological phenotype, binding mechanism, miRNA competition, and isoform-specific interneuron rescue, multiple orthogonal methods","pmids":["29621484"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Conditional knockout in interneuron subtypes, transcriptome splicing analysis, circuit connectivity assay","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with splicing and connectivity readouts, single lab","pmids":["30318414"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RNA binding assay, RNA foci competition assay, Drosophila overexpression with phenotypic rescue, splicing assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assay plus in vivo rescue in Drosophila model and cell-based MBNL1 competition, single lab","pmids":["29789616"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Phase separation assay (liquid droplets, amyloid fibers), Drosophila in vivo stress response, miRNA manipulation, immunofluorescence","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phase separation plus in vivo Drosophila experiments, multiple methods, single lab","pmids":["29358748"],"is_preprint":false},{"year":2020,"finding":"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.","method":"RNA binding assay (RIP), miRNA binding competition, protein expression manipulation (overexpression/knockdown), calcium imaging","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-confirmed binding, miRNA competition mechanism, functional Ca2+ readout, single lab","pmids":["32248729"],"is_preprint":false},{"year":2017,"finding":"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.","method":"X-ray crystallography, NMR spectroscopy, molecular dynamics simulation, switchSENSE RNA binding assay, mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure + NMR + MD + mutagenesis + binding assay, multiple orthogonal methods in single study, single lab","pmids":["28505313"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA knockdown, whole-cell patch clamp, vascular myograph, RT-PCR splicing analysis","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with electrophysiology and functional vascular readout, splicing validation, single lab","pmids":["35543237"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Nuclease protection assay (transcriptome-wide footprinting), RNA-binding domain mutagenesis (F125A), splicing analysis, minigene assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — transcriptome-wide mapping + mutagenesis + splicing assays + minigene validation, multiple orthogonal methods, peer-reviewed","pmids":["39880658"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Minigene transfection assay, mutagenesis of GCAUG, RT-PCR in differentiated P19 cells","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene with GCAUG mutagenesis confirming RRM-dependent and sequence-specific splicing regulation, single lab","pmids":["20141540"],"is_preprint":false},{"year":2014,"finding":"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.","method":"RT-PCR splicing panel, cell culture and transgenic mouse DM1 models, isoform characterization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic splicing panel across multiple DM1 models, co-regulation established by correlation and RT-PCR, single lab","pmids":["25211016"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Cardiomyocyte-specific KO mouse, RNA immunoprecipitation, luciferase 3'UTR reporter, puromycin incorporation (translation) assay, calcium dynamics, TAC model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus luciferase reporter plus translation assay plus KO phenotype, multiple methods, single lab","pmids":["40358188"],"is_preprint":false},{"year":2024,"finding":"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.","method":"In silico target prediction, minigene splicing assay, siRNA knockdown, morphological/cytoskeletal analysis","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene validation of two targets plus functional morphological readout, single lab","pmids":["38253401"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Spinal nerve ligation model, Rbfox1 overexpression/knockdown, splicing assay (RT-PCR), behavioral pain assay","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined splicing target and behavioral readout, single lab","pmids":["38241164"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Minigene splicing assay, mutagenesis (archaic variant reversion), evolutionary sequence analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene with archaic variant rescue confirms mechanism, single lab, novel splice site creation validated by mutagenesis","pmids":["35351830"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Mass spectrometry, phosphorylation assay, caspase inhibition, chromatin accessibility analysis, cardiomyocyte apoptosis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-phosphorylation-degradation cascade identified with multiple biochemical methods, single lab","pmids":["40715150"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Conditional expression in vivo (rat MI model), splicing analysis, antisense oligonucleotide intervention, TUNEL/caspase assay","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo splicing target identification with ASO rescue, single lab","pmids":["41294183"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Conditional knockout (triple Rbfox1/2/3), cell-type specific RNA-seq, minigene assay, migration analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — triple KO with splicing and migration readouts, multiple targets, single lab","pmids":["39532536"],"is_preprint":false}],"current_model":"RBFOX1 (Fox-1/A2BP1) is a tissue-specific alternative splicing regulator that binds the RNA element (U)GCAUG through an unusually structured RRM domain; in the nucleus it operates within the LASR multi-protein complex to activate or repress exon inclusion in a position-dependent manner (downstream binding activates via its C-terminal domain, upstream binding represses by blocking early spliceosomal complex assembly); cytoplasmic isoforms—generated by alternative splicing of RBFOX1's own pre-mRNA in response to neuronal activity or phosphorylation by WNK3/CAMKIIδ—instead bind 3' UTRs of target mRNAs to enhance their stability and translation; through these dual nuclear splicing and cytoplasmic mRNA regulatory roles, RBFOX1 controls networks of genes essential for neuronal excitability (including inhibitory synapse function via Vamp1/interneurons), cardiac and skeletal muscle physiology (calcium handling, MEF2 isoforms, focal adhesion proteins), and cortical development (neuronal migration, dendritic arborization)."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12574126"],"confidence":"High","gaps":["Structural basis of GCAUG recognition not yet resolved","Endogenous target network unknown","Rules governing activation vs repression undefined"]},{"year":2005,"claim":"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","pmids":["16362037"],"confidence":"High","gaps":["Does not address regulation of binding in vivo","Role of regions outside the RRM in splicing not addressed"]},{"year":2005,"claim":"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","pmids":["16260614","15824060"],"confidence":"High","gaps":["Mechanism by which isoforms differ functionally not fully resolved","Genome-wide targets not yet mapped"]},{"year":2006,"claim":"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","pmids":["17101796"],"confidence":"High","gaps":["Generality beyond calcitonin not established at the time","Position-dependence of repression not yet formalized"]},{"year":2007,"claim":"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","pmids":["17686786","17923701"],"confidence":"High","gaps":["Identity of the repressive domain's protein partners unknown","How combinatorial partners (SUP-12) are recruited in mammals unclear"]},{"year":2008,"claim":"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","pmids":["18573872","18794351"],"confidence":"High","gaps":["Mechanism of downstream activation not biochemically defined","Protein cofactors mediating each step not identified"]},{"year":2009,"claim":"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","pmids":["19762510"],"confidence":"High","gaps":["Distinct molecular function of cytoplasmic isoform not yet defined","Direct kinase substrate relationships not established"]},{"year":2010,"claim":"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","pmids":["20141540"],"confidence":"Medium","gaps":["Functional consequence of Mef2c isoform switch in neurons not tested here","Single cell-line context"]},{"year":2011,"claim":"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","pmids":["22184459","21623373"],"confidence":"High","gaps":["How C-terminal-domain partners mechanistically drive activation unresolved","Causal target exons for hyperexcitability not individually validated"]},{"year":2012,"claim":"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","pmids":["23027929"],"confidence":"Medium","gaps":["Phosphosite mapping not detailed","Single lab; physiological context of WNK3 regulation unconfirmed"]},{"year":2015,"claim":"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","pmids":["26687839","25575511","26619120","26116573"],"confidence":"High","gaps":["Mechanism of translational enhancement at molecular level incomplete","Crosstalk between nuclear and cytoplasmic functions in vivo not dissected"]},{"year":2018,"claim":"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","pmids":["29621484","30318414"],"confidence":"High","gaps":["Full set of miRNA-competed targets unknown","How activity gates cell-type-specific programs mechanistically unclear"]},{"year":2018,"claim":"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","pmids":["29358748","29789616","25211016"],"confidence":"Medium","gaps":["Functional role of phase separation in splicing/stability not established","Single-model evidence for repeat competition"]},{"year":2017,"claim":"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","pmids":["28505313"],"confidence":"High","gaps":["Functional consequence of hydration-site mutation in cells not tested","Does not address full-length protein behavior"]},{"year":2025,"claim":"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","pmids":["39880658"],"confidence":"High","gaps":["Stoichiometry and architecture of RBFOX1-LASR assembly not resolved","How combinatorial occupancy maps to activate/repress outcomes incomplete"]},{"year":2025,"claim":"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","pmids":["40358188","40715150","41294183"],"confidence":"Medium","gaps":["Degradation cascade validated in single model","Relative contribution of splicing vs translational targets to cardiac phenotypes unclear"]},{"year":2024,"claim":"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)","pmids":["38253401","38241164","35543237","35351830","39532536"],"confidence":"Medium","gaps":["Many targets validated in single contexts","Redundancy among Rbfox paralogs incompletely separated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,14,25,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,8,27]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[14,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,14,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,12,14]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[14,27]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,8,14,27]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[11,18,20]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[15,16,30]}],"complexes":["LASR"],"partners":["HNRNP H1","RALY","TFG","HNRNP M","MATR3","HNRNP C","WNK3","MBNL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWB1","full_name":"RNA binding protein fox-1 homolog 1","aliases":["Ataxin-2-binding protein 1","Fox-1 homolog A","Hexaribonucleotide-binding protein 1"],"length_aa":397,"mass_kda":42.8,"function":"RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NWB1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBFOX1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RBFOX1","total_profiled":1310},"omim":[{"mim_id":"605104","title":"RNA-BINDING FOX1 HOMOLOG 1; RBFOX1","url":"https://www.omim.org/entry/605104"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":65.9},{"tissue":"skeletal muscle","ntpm":80.8},{"tissue":"tongue","ntpm":41.2}],"url":"https://www.proteinatlas.org/search/RBFOX1"},"hgnc":{"alias_symbol":["A2BP1","FOX-1","HRNBP1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NWB1","domains":[{"cath_id":"3.30.70.330","chopping":"116-189","consensus_level":"high","plddt":96.9003,"start":116,"end":189}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWB1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWB1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWB1-F1-predicted_aligned_error_v6.png","plddt_mean":55.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBFOX1","jax_strain_url":"https://www.jax.org/strain/search?query=RBFOX1"},"sequence":{"accession":"Q9NWB1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWB1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWB1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWB1"}},"corpus_meta":[{"pmid":"19713214","id":"PMC_19713214","title":"Identification of neuronal nuclei (NeuN) as Fox-3, a new member of the Fox-1 gene family of splicing factors.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19713214","citation_count":318,"is_preprint":false},{"pmid":"21623373","id":"PMC_21623373","title":"The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21623373","citation_count":289,"is_preprint":false},{"pmid":"12574126","id":"PMC_12574126","title":"A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12574126","citation_count":272,"is_preprint":false},{"pmid":"18794351","id":"PMC_18794351","title":"Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18794351","citation_count":259,"is_preprint":false},{"pmid":"16260614","id":"PMC_16260614","title":"Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16260614","citation_count":243,"is_preprint":false},{"pmid":"16362037","id":"PMC_16362037","title":"Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16362037","citation_count":209,"is_preprint":false},{"pmid":"26687839","id":"PMC_26687839","title":"Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26687839","citation_count":194,"is_preprint":false},{"pmid":"17503474","id":"PMC_17503474","title":"Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.","date":"2007","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17503474","citation_count":175,"is_preprint":false},{"pmid":"22730494","id":"PMC_22730494","title":"RBFOX1 regulates both splicing and transcriptional networks in human neuronal development.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22730494","citation_count":175,"is_preprint":false},{"pmid":"15824060","id":"PMC_15824060","title":"Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15824060","citation_count":167,"is_preprint":false},{"pmid":"19688295","id":"PMC_19688295","title":"Fox-1 family of RNA-binding proteins.","date":"2009","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/19688295","citation_count":164,"is_preprint":false},{"pmid":"19762510","id":"PMC_19762510","title":"An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19762510","citation_count":136,"is_preprint":false},{"pmid":"26619120","id":"PMC_26619120","title":"RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26619120","citation_count":134,"is_preprint":false},{"pmid":"15148587","id":"PMC_15148587","title":"The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene.","date":"2004","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15148587","citation_count":129,"is_preprint":false},{"pmid":"23286373","id":"PMC_23286373","title":"Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion.","date":"2013","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23286373","citation_count":97,"is_preprint":false},{"pmid":"24039908","id":"PMC_24039908","title":"RBFOX1 and RBFOX3 mutations in rolandic epilepsy.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24039908","citation_count":91,"is_preprint":false},{"pmid":"30318414","id":"PMC_30318414","title":"Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30318414","citation_count":88,"is_preprint":false},{"pmid":"22184459","id":"PMC_22184459","title":"Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22184459","citation_count":86,"is_preprint":false},{"pmid":"7811034","id":"PMC_7811034","title":"Gene sequence and biochemical characterization of FOX-1 from Klebsiella pneumoniae, a new AmpC-type plasmid-mediated beta-lactamase with two molecular variants.","date":"1994","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/7811034","citation_count":82,"is_preprint":false},{"pmid":"17923701","id":"PMC_17923701","title":"The Fox-1 family and SUP-12 coordinately regulate tissue-specific alternative splicing in vivo.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17923701","citation_count":81,"is_preprint":false},{"pmid":"29621484","id":"PMC_29621484","title":"Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/29621484","citation_count":78,"is_preprint":false},{"pmid":"24290388","id":"PMC_24290388","title":"Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.","date":"2013","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/24290388","citation_count":72,"is_preprint":false},{"pmid":"32568366","id":"PMC_32568366","title":"Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.","date":"2020","source":"JAMA neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32568366","citation_count":70,"is_preprint":false},{"pmid":"7821230","id":"PMC_7821230","title":"Identification of a candidate primary sex determination locus, fox-1, on the X chromosome of Caenorhabditis elegans.","date":"1994","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7821230","citation_count":64,"is_preprint":false},{"pmid":"29789616","id":"PMC_29789616","title":"rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29789616","citation_count":63,"is_preprint":false},{"pmid":"23350840","id":"PMC_23350840","title":"Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.","date":"2013","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/23350840","citation_count":59,"is_preprint":false},{"pmid":"27481563","id":"PMC_27481563","title":"Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27481563","citation_count":58,"is_preprint":false},{"pmid":"25575511","id":"PMC_25575511","title":"The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25575511","citation_count":56,"is_preprint":false},{"pmid":"17101796","id":"PMC_17101796","title":"Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17101796","citation_count":54,"is_preprint":false},{"pmid":"26500751","id":"PMC_26500751","title":"Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.","date":"2015","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/26500751","citation_count":51,"is_preprint":false},{"pmid":"25211016","id":"PMC_25211016","title":"RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25211016","citation_count":47,"is_preprint":false},{"pmid":"35948661","id":"PMC_35948661","title":"Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35948661","citation_count":44,"is_preprint":false},{"pmid":"29174947","id":"PMC_29174947","title":"RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior.","date":"2017","source":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29174947","citation_count":44,"is_preprint":false},{"pmid":"9927456","id":"PMC_9927456","title":"Genetic and molecular analysis of fox-1, a numerator element involved in Caenorhabditis elegans primary sex determination.","date":"1999","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9927456","citation_count":44,"is_preprint":false},{"pmid":"11471052","id":"PMC_11471052","title":"Identification and expression of a mouse ortholog of A2BP1.","date":"2001","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/11471052","citation_count":41,"is_preprint":false},{"pmid":"26876166","id":"PMC_26876166","title":"MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26876166","citation_count":40,"is_preprint":false},{"pmid":"20141540","id":"PMC_20141540","title":"Alternative splicing of Mef2c promoted by Fox-1 during neural differentiation in P19 cells.","date":"2010","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20141540","citation_count":40,"is_preprint":false},{"pmid":"17686786","id":"PMC_17686786","title":"Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1gamma gene.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17686786","citation_count":38,"is_preprint":false},{"pmid":"22678932","id":"PMC_22678932","title":"Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.","date":"2012","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22678932","citation_count":36,"is_preprint":false},{"pmid":"29358748","id":"PMC_29358748","title":"Stress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29358748","citation_count":32,"is_preprint":false},{"pmid":"23300487","id":"PMC_23300487","title":"Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23300487","citation_count":31,"is_preprint":false},{"pmid":"26174448","id":"PMC_26174448","title":"Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.","date":"2015","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/26174448","citation_count":30,"is_preprint":false},{"pmid":"20724578","id":"PMC_20724578","title":"Evaluation of A2BP1 as an obesity gene.","date":"2010","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/20724578","citation_count":29,"is_preprint":false},{"pmid":"28505313","id":"PMC_28505313","title":"Structural study of the Fox-1 RRM protein hydration reveals a role for key water molecules in RRM-RNA recognition.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28505313","citation_count":28,"is_preprint":false},{"pmid":"32248729","id":"PMC_32248729","title":"Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124.","date":"2020","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32248729","citation_count":27,"is_preprint":false},{"pmid":"11401487","id":"PMC_11401487","title":"Androgens regulate the mammalian homologues of invertebrate sex determination genes tra-2 and fox-1.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11401487","citation_count":27,"is_preprint":false},{"pmid":"26116573","id":"PMC_26116573","title":"RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26116573","citation_count":26,"is_preprint":false},{"pmid":"18573872","id":"PMC_18573872","title":"Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18573872","citation_count":25,"is_preprint":false},{"pmid":"31301374","id":"PMC_31301374","title":"HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31301374","citation_count":21,"is_preprint":false},{"pmid":"26188062","id":"PMC_26188062","title":"Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26188062","citation_count":20,"is_preprint":false},{"pmid":"28346479","id":"PMC_28346479","title":"Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28346479","citation_count":20,"is_preprint":false},{"pmid":"34684200","id":"PMC_34684200","title":"A Broad-Based Mosquito Yeast Interfering RNA Pesticide Targeting Rbfox1 Represses Notch Signaling and Kills Both Larvae and Adult Mosquitoes.","date":"2021","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34684200","citation_count":20,"is_preprint":false},{"pmid":"21346316","id":"PMC_21346316","title":"Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).","date":"2011","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21346316","citation_count":19,"is_preprint":false},{"pmid":"27146458","id":"PMC_27146458","title":"RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27146458","citation_count":19,"is_preprint":false},{"pmid":"30001398","id":"PMC_30001398","title":"Downregulation of splicing regulator RBFOX1 compromises visual depth perception.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30001398","citation_count":18,"is_preprint":false},{"pmid":"32322670","id":"PMC_32322670","title":"RBFOX1 Regulates the Permeability of the Blood-Tumor Barrier via the LINC00673/MAFF Pathway.","date":"2020","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/32322670","citation_count":17,"is_preprint":false},{"pmid":"35059728","id":"PMC_35059728","title":"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.","date":"2022","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35059728","citation_count":17,"is_preprint":false},{"pmid":"23918472","id":"PMC_23918472","title":"Biochemical and morphological characterization of A2BP1 in neuronal tissue.","date":"2013","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/23918472","citation_count":16,"is_preprint":false},{"pmid":"23027929","id":"PMC_23027929","title":"Protein kinase WNK3 regulates the neuronal splicing factor Fox-1.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23027929","citation_count":16,"is_preprint":false},{"pmid":"20153395","id":"PMC_20153395","title":"A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients.","date":"2010","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20153395","citation_count":14,"is_preprint":false},{"pmid":"28949795","id":"PMC_28949795","title":"Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure.","date":"2018","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28949795","citation_count":13,"is_preprint":false},{"pmid":"21355681","id":"PMC_21355681","title":"Complex congenital heart defects in association with maternal diabetes and partial deletion of the A2BP1 gene.","date":"2011","source":"Fetal and pediatric pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21355681","citation_count":13,"is_preprint":false},{"pmid":"32431595","id":"PMC_32431595","title":"Rbfox1 Is Expressed in the Mouse Brain in the Form of Multiple Transcript Variants and Contains Functional E Boxes in Its Alternative Promoters.","date":"2020","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32431595","citation_count":12,"is_preprint":false},{"pmid":"21714144","id":"PMC_21714144","title":"Evidence that \"brain-specific\" FOX-1, FOX-2, and nPTB alternatively spliced isoforms are produced in the lens.","date":"2011","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/21714144","citation_count":12,"is_preprint":false},{"pmid":"35543237","id":"PMC_35543237","title":"Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension.","date":"2022","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/35543237","citation_count":11,"is_preprint":false},{"pmid":"37890537","id":"PMC_37890537","title":"TCF4 and RBFOX1 as peripheral biomarkers for the differential diagnosis and treatment of major depressive disorder.","date":"2023","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/37890537","citation_count":10,"is_preprint":false},{"pmid":"39880658","id":"PMC_39880658","title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules.","date":"2025","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/39880658","citation_count":9,"is_preprint":false},{"pmid":"25571999","id":"PMC_25571999","title":"Upregulation of RBFOX1 in the malformed cortex of patients with intractable epilepsy and in cultured rat neurons.","date":"2015","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25571999","citation_count":9,"is_preprint":false},{"pmid":"24664471","id":"PMC_24664471","title":"Outfoxed by RBFOX1-a caution about ascertainment bias.","date":"2014","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24664471","citation_count":9,"is_preprint":false},{"pmid":"37903506","id":"PMC_37903506","title":"Patient Brain Organoids Identify a Link between the 16p11.2 Copy Number Variant and the RBFOX1 Gene.","date":"2023","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37903506","citation_count":7,"is_preprint":false},{"pmid":"38273110","id":"PMC_38273110","title":"Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38273110","citation_count":7,"is_preprint":false},{"pmid":"38374212","id":"PMC_38374212","title":"Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in two zebrafish models.","date":"2024","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38374212","citation_count":7,"is_preprint":false},{"pmid":"36359797","id":"PMC_36359797","title":"Visual Function and Survival of Injured Retinal Ganglion Cells in Aged Rbfox1 Knockout Animals.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36359797","citation_count":7,"is_preprint":false},{"pmid":"33372658","id":"PMC_33372658","title":"Dose-dependent action of the RNA binding protein FOX-1 to relay X-chromosome number and determine C. elegans sex.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33372658","citation_count":7,"is_preprint":false},{"pmid":"34490042","id":"PMC_34490042","title":"Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34490042","citation_count":7,"is_preprint":false},{"pmid":"26092620","id":"PMC_26092620","title":"A2BP1 gene polymorphisms association with olanzapine-induced weight gain.","date":"2015","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/26092620","citation_count":6,"is_preprint":false},{"pmid":"35351830","id":"PMC_35351830","title":"Evolution Increases Primates Brain Complexity Extending RbFOX1 Splicing Activity to LSD1 Modulation.","date":"2022","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35351830","citation_count":6,"is_preprint":false},{"pmid":"37881587","id":"PMC_37881587","title":"RBFOX1 and Working Memory: From Genome to Transcriptome Revealed Posttranscriptional Mechanism Separate From Attention-Deficit/Hyperactivity Disorder.","date":"2022","source":"Biological psychiatry global open science","url":"https://pubmed.ncbi.nlm.nih.gov/37881587","citation_count":6,"is_preprint":false},{"pmid":"39532536","id":"PMC_39532536","title":"Cell-Type-Specific Splicing of Transcription Regulators and Ptbp1 by Rbfox1/2/3 in the Developing Neocortex.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39532536","citation_count":5,"is_preprint":false},{"pmid":"35730583","id":"PMC_35730583","title":"Rbfox1 expression in amacrine cells is restricted to GABAergic and VGlut3 glycinergic cells.","date":"2022","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/35730583","citation_count":5,"is_preprint":false},{"pmid":"34996845","id":"PMC_34996845","title":"Rbfox1 is required for myofibril development and maintaining fiber type-specific isoform expression in Drosophila muscles.","date":"2022","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/34996845","citation_count":5,"is_preprint":false},{"pmid":"38253401","id":"PMC_38253401","title":"Rbfox1 controls alternative splicing of focal adhesion genes in cardiac muscle cells.","date":"2024","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38253401","citation_count":5,"is_preprint":false},{"pmid":"38794806","id":"PMC_38794806","title":"Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Cav1.2 splicing and RbFox1/Fox2 downregulation.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/38794806","citation_count":5,"is_preprint":false},{"pmid":"34108862","id":"PMC_34108862","title":"Loss of Rbfox1 Does Not Affect Survival of Retinal Ganglion Cells Injured by Optic Nerve Crush.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34108862","citation_count":5,"is_preprint":false},{"pmid":"38575795","id":"PMC_38575795","title":"Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38575795","citation_count":4,"is_preprint":false},{"pmid":"38241164","id":"PMC_38241164","title":"Rbfox1 regulates alternative splicing of Nrcam in primary sensory neurons to mediate peripheral nerve injury-induced neuropathic pain.","date":"2023","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38241164","citation_count":4,"is_preprint":false},{"pmid":"38924416","id":"PMC_38924416","title":"Accelerated evolution in the human lineage led to gain and loss of transcriptional enhancers in the RBFOX1 locus.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38924416","citation_count":4,"is_preprint":false},{"pmid":"40358188","id":"PMC_40358188","title":"RBFOX1 Regulates Calcium Signaling and Enhances SERCA2 Translation.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40358188","citation_count":3,"is_preprint":false},{"pmid":"37398467","id":"PMC_37398467","title":"Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37398467","citation_count":3,"is_preprint":false},{"pmid":"40715150","id":"PMC_40715150","title":"Tumour initiated purinergic signalling promotes cardiomyocyte RBFOX1 degradation and cardiotoxicity from DNA damaging anticancer agents.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40715150","citation_count":3,"is_preprint":false},{"pmid":"33329073","id":"PMC_33329073","title":"Variants of the Aggression-Related RBFOX1 Gene in a Population Representative Birth Cohort Study: Aggressiveness, Personality, and Alcohol Use Disorder.","date":"2020","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33329073","citation_count":2,"is_preprint":false},{"pmid":"40429193","id":"PMC_40429193","title":"An Environmentally-Friendly RNAi Yeast-Attractive Targeted Sugar Bait Turns off the Drosophila suzukii Rbfox1 Gene.","date":"2025","source":"Insects","url":"https://pubmed.ncbi.nlm.nih.gov/40429193","citation_count":2,"is_preprint":false},{"pmid":"41294183","id":"PMC_41294183","title":"Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure.","date":"2025","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/41294183","citation_count":1,"is_preprint":false},{"pmid":"36865197","id":"PMC_36865197","title":"Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in a zebrafish model.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36865197","citation_count":1,"is_preprint":false},{"pmid":"41261149","id":"PMC_41261149","title":"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.","date":"2025","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41261149","citation_count":1,"is_preprint":false},{"pmid":"37033539","id":"PMC_37033539","title":"Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37033539","citation_count":1,"is_preprint":false},{"pmid":"38260517","id":"PMC_38260517","title":"Mutation of two intronic nucleotides alters RNA structure and dynamics inhibiting MBNL1 and RBFOX1 regulated splicing of the Insulin Receptor.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38260517","citation_count":1,"is_preprint":false},{"pmid":"39071271","id":"PMC_39071271","title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multi-part RNA regulatory modules.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39071271","citation_count":1,"is_preprint":false},{"pmid":"39464042","id":"PMC_39464042","title":"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.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39464042","citation_count":1,"is_preprint":false},{"pmid":"40395202","id":"PMC_40395202","title":"The Expression Characteristics of the RBFOX1 Gene in Colorectal Cancer.","date":"2025","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/40395202","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50467,"output_tokens":9341,"usd":0.145758,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19620,"output_tokens":5388,"usd":0.1164,"stage2_stop_reason":"end_turn"},"total_usd":0.262158,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro RNA binding assay, transfection/minigene splicing assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay combined with multiple minigene transfection experiments across three distinct target pre-mRNAs, replicated across labs subsequently\",\n      \"pmids\": [\"12574126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"NMR structure determination, surface plasmon resonance (SPR)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution NMR structure with functional SPR validation, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"16362037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression splicing assays, RNAi knockdown, RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined molecular readout, replicated across multiple isoforms and exon targets\",\n      \"pmids\": [\"16260614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro RNA binding, transfection splicing assay, subcellular localization by microscopy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding plus functional transfection assays, multiple isoforms tested, single lab\",\n      \"pmids\": [\"15824060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Minigene splicing assay, RNA electrophoretic mobility shift assay, U2AF65 competition assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of spliceosome blockade, minigene assays, multiple UGCAUG mutagenesis experiments, single lab\",\n      \"pmids\": [\"17101796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro splicing assay, spliceosomal complex assembly assay (E complex), domain mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E-complex inhibition with mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17686786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis (double mutant), RNA-protein complex formation assay, in vivo reporter splicing assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis in C. elegans with defined phenotype, complex formation on RNA, in vivo splicing reporter, replicated across orthogonal approaches\",\n      \"pmids\": [\"17923701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical complex assembly assay (E' and E complex), RNA binding assay, mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of two sequential spliceosomal blockade steps, multiple UGCAUG mutations tested, single lab\",\n      \"pmids\": [\"18573872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Computational target prediction, splicing microarray, experimental splicing validation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — position-dependent activation/repression rule validated experimentally for multiple targets, single lab, partially computational\",\n      \"pmids\": [\"18794351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Splicing assay, subcellular fractionation/localization, RT-PCR of endogenous targets\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism linking RBFOX1 autoregulatory splicing to subcellular redistribution and downstream target regulation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19762510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"MS2 tethering assay, immunoprecipitation with mass spectrometry, RNAi knockdown\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-dissection tethering assay combined with proteomic identification of interactors and functional RNAi validation, multiple methods in single study\",\n      \"pmids\": [\"22184459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, EEG recording, electrophysiology, transcriptome splicing analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with electrophysiological phenotype, genome-wide splicing analysis, well-defined molecular and physiological readouts\",\n      \"pmids\": [\"21623373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, subcellular localization, splicing reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding plus kinase-dependent functional effect with localization data, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23027929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Rbfox1 knockdown, overexpression, RNA-immunoprecipitation, splicing assay, muscle differentiation assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms direct binding, knockdown and OE with functional muscle readout, single lab\",\n      \"pmids\": [\"23300487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptome profiling, iCLIP-seq of subcellular fractions, rescue experiments with nuclear vs cytoplasmic isoforms, mRNA stability/translation assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific rescue combined with genome-wide iCLIP mapping and functional mRNA stability/translation assays, multiple orthogonal methods\",\n      \"pmids\": [\"26687839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, electron microscopy, immunostaining, calcium imaging, force measurement, deep RNA sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ultrastructural, functional (calcium handling, force), and splicing readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25575511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, transcriptome/splicing analysis, minigene assay for MEF2 splicing, pressure overload mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO and overexpression in vivo with defined splicing target (MEF2) and functional cardiac phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26619120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish morpholino knockdown, cardiac function assessment, RNA-seq\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with functional cardiac readout and splicing data, single lab\",\n      \"pmids\": [\"26116573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In utero electroporation knockdown, confocal imaging, electrophysiology, in vitro neuron culture\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined migration and morphological phenotypes, electrophysiological readout, single lab\",\n      \"pmids\": [\"27481563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In utero electroporation knockdown, time-lapse confocal imaging, in vitro hippocampal neuron culture\",\n      \"journal\": \"Molecular autism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with live imaging of migration, defined morphological readouts, single lab\",\n      \"pmids\": [\"26500751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse, electrophysiology, 3' UTR binding assay, interneuron-specific rescue, miRNA blocking assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with electrophysiological phenotype, binding mechanism, miRNA competition, and isoform-specific interneuron rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29621484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout in interneuron subtypes, transcriptome splicing analysis, circuit connectivity assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with splicing and connectivity readouts, single lab\",\n      \"pmids\": [\"30318414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RNA binding assay, RNA foci competition assay, Drosophila overexpression with phenotypic rescue, splicing assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assay plus in vivo rescue in Drosophila model and cell-based MBNL1 competition, single lab\",\n      \"pmids\": [\"29789616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Phase separation assay (liquid droplets, amyloid fibers), Drosophila in vivo stress response, miRNA manipulation, immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phase separation plus in vivo Drosophila experiments, multiple methods, single lab\",\n      \"pmids\": [\"29358748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"RNA binding assay (RIP), miRNA binding competition, protein expression manipulation (overexpression/knockdown), calcium imaging\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-confirmed binding, miRNA competition mechanism, functional Ca2+ readout, single lab\",\n      \"pmids\": [\"32248729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, molecular dynamics simulation, switchSENSE RNA binding assay, mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure + NMR + MD + mutagenesis + binding assay, multiple orthogonal methods in single study, single lab\",\n      \"pmids\": [\"28505313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, whole-cell patch clamp, vascular myograph, RT-PCR splicing analysis\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with electrophysiology and functional vascular readout, splicing validation, single lab\",\n      \"pmids\": [\"35543237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclease protection assay (transcriptome-wide footprinting), RNA-binding domain mutagenesis (F125A), splicing analysis, minigene assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — transcriptome-wide mapping + mutagenesis + splicing assays + minigene validation, multiple orthogonal methods, peer-reviewed\",\n      \"pmids\": [\"39880658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Minigene transfection assay, mutagenesis of GCAUG, RT-PCR in differentiated P19 cells\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene with GCAUG mutagenesis confirming RRM-dependent and sequence-specific splicing regulation, single lab\",\n      \"pmids\": [\"20141540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR splicing panel, cell culture and transgenic mouse DM1 models, isoform characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic splicing panel across multiple DM1 models, co-regulation established by correlation and RT-PCR, single lab\",\n      \"pmids\": [\"25211016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cardiomyocyte-specific KO mouse, RNA immunoprecipitation, luciferase 3'UTR reporter, puromycin incorporation (translation) assay, calcium dynamics, TAC model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus luciferase reporter plus translation assay plus KO phenotype, multiple methods, single lab\",\n      \"pmids\": [\"40358188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"In silico target prediction, minigene splicing assay, siRNA knockdown, morphological/cytoskeletal analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene validation of two targets plus functional morphological readout, single lab\",\n      \"pmids\": [\"38253401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Spinal nerve ligation model, Rbfox1 overexpression/knockdown, splicing assay (RT-PCR), behavioral pain assay\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined splicing target and behavioral readout, single lab\",\n      \"pmids\": [\"38241164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Minigene splicing assay, mutagenesis (archaic variant reversion), evolutionary sequence analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene with archaic variant rescue confirms mechanism, single lab, novel splice site creation validated by mutagenesis\",\n      \"pmids\": [\"35351830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry, phosphorylation assay, caspase inhibition, chromatin accessibility analysis, cardiomyocyte apoptosis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-phosphorylation-degradation cascade identified with multiple biochemical methods, single lab\",\n      \"pmids\": [\"40715150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional expression in vivo (rat MI model), splicing analysis, antisense oligonucleotide intervention, TUNEL/caspase assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo splicing target identification with ASO rescue, single lab\",\n      \"pmids\": [\"41294183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout (triple Rbfox1/2/3), cell-type specific RNA-seq, minigene assay, migration analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — triple KO with splicing and migration readouts, multiple targets, single lab\",\n      \"pmids\": [\"39532536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBFOX1 (Fox-1/A2BP1) is a tissue-specific alternative splicing regulator that binds the RNA element (U)GCAUG through an unusually structured RRM domain; in the nucleus it operates within the LASR multi-protein complex to activate or repress exon inclusion in a position-dependent manner (downstream binding activates via its C-terminal domain, upstream binding represses by blocking early spliceosomal complex assembly); cytoplasmic isoforms—generated by alternative splicing of RBFOX1's own pre-mRNA in response to neuronal activity or phosphorylation by WNK3/CAMKIIδ—instead bind 3' UTRs of target mRNAs to enhance their stability and translation; through these dual nuclear splicing and cytoplasmic mRNA regulatory roles, RBFOX1 controls networks of genes essential for neuronal excitability (including inhibitory synapse function via Vamp1/interneurons), cardiac and skeletal muscle physiology (calcium handling, MEF2 isoforms, focal adhesion proteins), and cortical development (neuronal migration, dendritic arborization).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2, #14]. 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 [#1, #25]. 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 [#4, #5, #7, #8, #10]. 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 [#27]. 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 [#9, #12]. 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 [#14, #20, #24, #30]. Through these activities RBFOX1 controls neuronal excitability and inhibitory synaptic transmission, where CNS deletion produces seizure susceptibility and E/I imbalance [#11, #20], cortical neuronal migration and dendritic/axonal morphogenesis [#18, #19, #36], and cardiac and skeletal muscle physiology including calcium handling, MEF2 isoform choice, and focal adhesion protein splicing [#15, #16, #30, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro RNA binding and minigene splicing assays across F1gamma, alpha-actinin, and fibronectin pre-mRNAs\",\n      \"pmids\": [\"12574126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GCAUG recognition not yet resolved\", \"Endogenous target network unknown\", \"Rules governing activation vs repression undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"NMR solution structure of the Fox-1 RBD bound to UGCAUGU with SPR validation\",\n      \"pmids\": [\"16362037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address regulation of binding in vivo\", \"Role of regions outside the RRM in splicing not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression/RNAi splicing assays and isoform comparison in neural vs muscle cells with subcellular localization\",\n      \"pmids\": [\"16260614\", \"15824060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which isoforms differ functionally not fully resolved\", \"Genome-wide targets not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the first biochemical mechanism of Fox-mediated repression: blocking spliceosome assembly at the 3' splice site.\",\n      \"evidence\": \"Minigene and EMSA assays showing UGCAUG-bound Fox blocks U2AF65 recruitment to calcitonin exon 4\",\n      \"pmids\": [\"17101796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond calcitonin not established at the time\", \"Position-dependence of repression not yet formalized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Refined the repression mechanism to specific prespliceosomal steps and identified a non-RRM protein region required for repression.\",\n      \"evidence\": \"In vitro E-complex assembly assays with domain mutagenesis on F1gamma, plus C. elegans genetic epistasis with SUP-12 on egl-15\",\n      \"pmids\": [\"17686786\", \"17923701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the repressive domain's protein partners unknown\", \"How combinatorial partners (SUP-12) are recruited in mammals unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical E'/E complex assays plus computational target prediction with splicing microarray validation\",\n      \"pmids\": [\"18573872\", \"18794351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of downstream activation not biochemically defined\", \"Protein cofactors mediating each step not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Splicing assays, subcellular fractionation, and endogenous target RT-PCR under chronic depolarization/CaMKIV signaling\",\n      \"pmids\": [\"19762510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct molecular function of cytoplasmic isoform not yet defined\", \"Direct kinase substrate relationships not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified Mef2c as a direct neural splicing target, connecting RBFOX1 to a transcription-factor splicing program during differentiation.\",\n      \"evidence\": \"Minigene transfection with GCAUG mutagenesis in differentiated P19 cells\",\n      \"pmids\": [\"20141540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Mef2c isoform switch in neurons not tested here\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS2 tethering with domain dissection, IP-MS identifying hnRNP H1/RALY/TFG, and CNS-specific conditional KO with EEG/electrophysiology\",\n      \"pmids\": [\"22184459\", \"21623373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How C-terminal-domain partners mechanistically drive activation unresolved\", \"Causal target exons for hyperexcitability not individually validated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed phosphoregulation controls RBFOX1 localization: WNK3 phosphorylation drives cytoplasmic accumulation and suppresses splicing without altering RNA binding.\",\n      \"evidence\": \"Co-IP, kinase activity assay, localization, and splicing reporter\",\n      \"pmids\": [\"23027929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite mapping not detailed\", \"Single lab; physiological context of WNK3 regulation unconfirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular iCLIP-seq, isoform-specific rescue, and mRNA stability/translation assays; conditional muscle and cardiac KOs with functional phenotypes; zebrafish loss-of-function\",\n      \"pmids\": [\"26687839\", \"25575511\", \"26619120\", \"26116573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of translational enhancement at molecular level incomplete\", \"Crosstalk between nuclear and cytoplasmic functions in vivo not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional KO with electrophysiology, 3' UTR binding/miRNA competition, and interneuron-specific Vamp1 rescue; cell-type-specific splicing programs in SST/PV interneurons\",\n      \"pmids\": [\"29621484\", \"30318414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of miRNA-competed targets unknown\", \"How activity gates cell-type-specific programs mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro phase separation/fibril assays, Drosophila stress and DM2 models with rescue, MBNL1 competition assays\",\n      \"pmids\": [\"29358748\", \"29789616\", \"25211016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of phase separation in splicing/stability not established\", \"Single-model evidence for repeat competition\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the structural energetics of RNA binding, identifying conserved hydration sites that contribute to affinity.\",\n      \"evidence\": \"X-ray crystallography of free RRM, NMR, MD simulation, switchSENSE binding, and mutagenesis\",\n      \"pmids\": [\"28505313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of hydration-site mutation in cells not tested\", \"Does not address full-length protein behavior\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Transcriptome-wide nuclease footprinting, F125A RNA-binding mutant, and minigene combinatorial splicing assays\",\n      \"pmids\": [\"39880658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of RBFOX1-LASR assembly not resolved\", \"How combinatorial occupancy maps to activate/repress outcomes incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"40358188\", \"40715150\", \"41294183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation cascade validated in single model\", \"Relative contribution of splicing vs translational targets to cardiac phenotypes unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Documented additional disease- and development-relevant splicing targets across muscle, sensory, and cortical systems, broadening the target network.\",\n      \"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)\",\n      \"pmids\": [\"38253401\", \"38241164\", \"35543237\", \"35351830\", \"39532536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many targets validated in single contexts\", \"Redundancy among Rbfox paralogs incompletely separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking compartment switching to target outcomes\", \"Structural architecture of RBFOX1 within LASR unresolved\", \"Direct phosphosites and their functional consequences incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 14, 25, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 8, 27]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [14, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 14, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 12, 14]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [14, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 8, 14, 27]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [11, 18, 20]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [15, 16, 30]}\n    ],\n    \"complexes\": [\"LASR\"],\n    \"partners\": [\"hnRNP H1\", \"RALY\", \"TFG\", \"hnRNP M\", \"MATR3\", \"hnRNP C\", \"WNK3\", \"MBNL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}