{"gene":"NTF4","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"Infusion of NT-4/5 (or BDNF) into cat primary visual cortex inhibited ocular dominance column formation, implicating the shared TrkB receptor in activity-dependent segregation of LGN axons; NGF, NT-3, or vehicle had no effect, establishing receptor specificity.","method":"In vivo infusion into cat visual cortex with histological assessment of ocular dominance columns","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo loss-of-function (infusion) with defined anatomical phenotype, replicated across multiple infusion sites, rigorous receptor-specificity controls (NGF, NT-3 inactive)","pmids":["7886458"],"is_preprint":false},{"year":1994,"finding":"NT-4/5 and BDNF, but not NGF or NT-3, enhanced AMPA receptor-mediated synaptic transmission in cultured hippocampal neurons; the effect manifested as increased frequency (not amplitude) of miniature EPSCs, indicating a presynaptic site of action. Both neurotrophins signal through TrkB.","method":"Patch-clamp recording of evoked and miniature EPSCs in rat hippocampal neurons with spatially restricted neurotrophin application","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological assay distinguishing pre- vs postsynaptic locus, single lab, two readouts (evoked currents + mEPSC frequency/amplitude)","pmids":["7703418"],"is_preprint":false},{"year":1994,"finding":"NT-4/5 and BDNF both promote survival and neurite outgrowth of adult rat retinal ganglion cells, and saturating concentrations of NT-4/5 plus BDNF together show no additive effect, indicating they share a common signaling pathway (TrkB). NGF, NT-3, and CNTF were ineffective.","method":"Retinal explant culture with dose-response and combination neurotrophin treatments; RGC survival and neurite counts","journal":"Journal of neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay with occlusion experiment establishing shared receptor pathway; single lab","pmids":["7964706"],"is_preprint":false},{"year":1994,"finding":"NT-4/5 and BDNF promote survival and neurite extension of differentiated cerebellar granule cells via TrkB; these effects are blocked by the Trk kinase inhibitor K-252a. No additive effect was seen when NT-4/5 and BDNF were combined, consistent with activation of the same TrkB receptor. Neither NT-3 nor NGF replicated the effect.","method":"Purified granule cell cultures with K-252a pharmacological inhibition; TrkB immunohistochemistry on cerebellar sections","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis (K-252a blockade) plus occlusion experiment; single lab, orthogonal methods","pmids":["7722620"],"is_preprint":false},{"year":1994,"finding":"NT-4/5 and BDNF both bind TrkB as high-affinity receptors; radiolabeled [125I]NT-4/5 and [125I]BDNF binding sites co-distribute with trkB mRNA in rat forebrain, distinct from the NT-3/TrkC pattern, establishing NT-4/5 as a TrkB ligand in the brain.","method":"In situ hybridization with trkB and trkC riboprobes combined with [125I]NT-4/5 and [125I]BDNF autoradiographic binding in adjacent brain sections","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ligand-binding autoradiography co-registered with receptor mRNA; single lab, two orthogonal methods","pmids":["8000564"],"is_preprint":false},{"year":1993,"finding":"NT-4/5 and BDNF, but not NGF, stimulate choline acetyltransferase (CAT) activity in embryonic rat motor neuron cultures. Combined treatment with BDNF and NT-4/5 produces no greater effect than either alone, consistent with both acting through TrkB; combined BDNF + NT-3 is additive, consistent with TrkB vs TrkC.","method":"Motor neuron-enriched cultures with CAT activity assay; co-treatment occlusion/additivity experiments; RT-PCR for TrkB and TrkC mRNA","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional enzymatic assay with receptor-specificity epistasis (TrkB/TrkC additivity logic); single lab","pmids":["7505167"],"is_preprint":false},{"year":2009,"finding":"Seven heterozygous missense mutations in NTF4 identified in POAG patients impair NT-4 signaling; expression of the most frequent mutant NT-4 in cells leads to decreased TrkB phosphorylation/activation, and molecular modeling predicts reduced NT-4 affinity for TrkB, establishing a loss-of-neurotrophic-function mechanism.","method":"Sequencing of NTF4 in POAG cohort; molecular modeling of NT-4/TrkB interaction; recombinant mutant NT-4 expression with TrkB activation assay","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant mutant protein functional assay (TrkB activation) plus structural modeling; single lab","pmids":["19765683"],"is_preprint":false},{"year":2010,"finding":"An NTF4 missense mutation (Leu113Ser) identified in a POAG patient is predicted by structural analysis to disrupt the NT-4/TrkB binding interface, implicating TrkB binding as the mechanism by which NT-4 supports retinal ganglion cell survival.","method":"Sanger sequencing of NTF4 coding exon; structural analysis of mutant NT-4 protein","journal":"Molecular vision","confidence":"Low","confidence_rationale":"Tier 4 / Weak — structural prediction only, no experimental validation of TrkB binding disruption","pmids":["20806036"],"is_preprint":false},{"year":2012,"finding":"Two NTF4 missense variants (Gly157Ala and Ala182Val) found in Chinese POAG patients produce functionally altered NT-4 protein: the Gly157Ala mutant shows reduced Triton X-100 solubility, and HeLa cells transfected with either mutant construct show reduced migration compared to wildtype, indicating these are functional mutations.","method":"Site-directed mutagenesis, transfection into HeLa cells, solubility assay, cell migration assay","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-based functional assays with mutant constructs; single lab, two orthogonal readouts (solubility + migration)","pmids":["22815630"],"is_preprint":false},{"year":2019,"finding":"NT-4/5 antagonizes BDNF-mediated modulation of corticostriatal synaptic transmission. Mechanistically, NT-4/5 upregulates the truncated TrkB.T1 isoform and downregulates full-length TrkB-FL, thereby suppressing BDNF signaling at striatal synapses. BDNF does not modify NT-4/5 effect (unidirectional antagonism).","method":"Electrophysiological field recordings at corticostriatal synapses; COS-7 cell transfection experiments measuring TrkB isoform expression after neurotrophin exposure","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus cell-based mechanistic isoform analysis; single lab, two orthogonal methods","pmids":["30666798"],"is_preprint":false},{"year":2019,"finding":"The modulatory effect of sequential NT-4/5 and BDNF application on corticostriatal transmission in a Huntington's disease mouse model depends on which isoform of TrkB is activated: truncated TrkB.T1 activation mediates antagonism, while full-length TrkB-FL activation mediates synergy.","method":"Field recordings in 3-NP mouse striatal slices with sequential neurotrophin application and TrkB isoform pharmacology","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with isoform-specific pharmacological dissection; single lab","pmids":["31392756"],"is_preprint":false},{"year":2010,"finding":"NT-4 (Ntf4) promotes neurogenesis in mouse embryonic neural stem cells by suppressing STAT3 phosphorylation and modulating PKB/Akt activity; it also suppresses IL-6 family receptor and Notch signaling pathway cleavages, biasing NSC commitment toward neuronal lineage.","method":"Primary mouse E14 neural stem cell cultures; Western blotting for STAT3 phosphorylation and Akt activity; immunocytochemistry; molecular cell biology methods","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based mechanistic assays with multiple pathway readouts; single lab","pmids":["20407817"],"is_preprint":false},{"year":2020,"finding":"NTF4 knockdown in colorectal cancer cells activates autophagy via interaction with autophagy-associated gene Atg5 and the MAPK pathway; NTF4 silencing inhibits EMT, invasion, migration, proliferation, and xenograft growth, while autophagy inhibitor chloroquine rescues these phenotypes, placing NTF4 upstream of Atg5-MAPK-autophagy.","method":"shRNA knockdown in CRC cell lines; co-regulation with Atg5; autophagy assays; xenograft model; chloroquine rescue experiment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with defined rescue experiment (chloroquine) placing NTF4 in pathway; single lab, multiple cellular readouts","pmids":["32236587"],"is_preprint":false},{"year":2023,"finding":"NTF4 promotes breast cancer metastasis by activating PRKDC/AKT and ANXA1/NF-κB pathways to stabilize SNAIL protein and reduce E-cadherin (pro-EMT). Simultaneously, NTF4 increases ANXA1 phosphorylation, sumoylation, and interaction with importin β, causing nuclear ANXA1 retention that activates caspase-3-dependent apoptosis, explaining why NTF4 inhibits proliferation while promoting invasion.","method":"In vitro cell line experiments (EMT, invasion, motility assays); in vivo xenograft; pathway analysis with PRKDC/AKT, NF-κB, SNAIL, E-cadherin, ANXA1 phosphorylation/sumoylation, importin β co-immunoprecipitation and caspase-3 assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic assays (Co-IP, pathway inhibitors, in vivo xenograft); single lab","pmids":["36632451"],"is_preprint":false},{"year":1997,"finding":"BDNF and NT-4/5 (but not NGF, NT-3, or vehicle) fully prevent atrophy of axotomized rat rubrospinal neurons, maintain TrkB expression, and stimulate GAP-43 and Tα1-tubulin mRNA expression, acting through TrkB receptors expressed by rubrospinal neurons; BDNF treatment also increases axon regeneration into peripheral nerve grafts.","method":"In vivo infusion after cervical axotomy; in situ hybridization for TrkB/TrkC/TrkA/p75; RT-PCR; morphometric analysis; peripheral nerve graft regeneration assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo rescue with receptor-profiling by ISH and RT-PCR; multiple outcome measures; replicated across neurotrophin specificity controls","pmids":["9391013"],"is_preprint":false},{"year":2004,"finding":"Fibroblasts engineered to secrete NT-4/5, grafted to injured rat spinal cord, attract motor, coerulospinal, reticulospinal, and propriospinal axons into the graft; Schwann cells (not oligodendrocytes) remyelinate axons within the NT-4/5-secreting grafts. Axonal growth beyond the graft and functional recovery were not observed.","method":"Genetically modified fibroblast grafts after thoracic hemisection/transection; retrograde/anterograde tracing; immunohistochemistry","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular delivery with antero/retrograde tracing and myelin characterization; single lab","pmids":["15485774"],"is_preprint":false},{"year":2002,"finding":"Anterograde transport of NT-4/5 (and more prominently BDNF) occurs from retinal ganglion cells to central visual targets in neonatal rat; intraocular injection of NT-4/5 reduces pyknosis and increases cell number (primarily neurons) in the contralateral superior colliculus within 24 h, indicating NT-4/5 acts as an anterograde survival factor for postsynaptic neurons.","method":"Intraocular injection of [125I]-labeled NT-4/5; autoradiography of retinorecipient regions; TUNEL/pyknosis quantification in superior colliculus","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — radiolabeled anterograde transport assay plus quantitative cell death assay; single lab, two orthogonal methods","pmids":["11988017"],"is_preprint":false},{"year":2023,"finding":"Chronic infusion of NT-4/5 into cat visual cortex during the critical period induces structural plasticity: increased spine-like processes on primary dendrites, sprouting of protuberances from neuronal somata in all layers, increased synaptophysin density (indicating more synapses), and increased GAD-65 immunostaining (suggesting enhanced inhibitory circuits). These changes are consistent with NT-4/5/TrkB driving promiscuous thalamocortical and corticocortical connectivity.","method":"Osmotic minipump infusion in cats; DiOlistics labeling of neurons in fixed slices; confocal microscopy; synaptophysin and GAD-65 immunostaining","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct anatomical measurements after defined NT-4/5 infusion with multiple structural markers; preprint, single lab","pmids":["38187745"],"is_preprint":true}],"current_model":"NT-4/5 (NTF4) is a secreted neurotrophin that signals primarily through the TrkB receptor tyrosine kinase (shared with BDNF); it promotes survival, differentiation, and axonal growth of multiple neuronal populations (retinal ganglion cells, motor neurons, dopaminergic and GABAergic neurons), modulates synaptic transmission via a presynaptic mechanism, can be transported anterogradely to support postsynaptic target neurons, and drives structural synaptic plasticity in the visual cortex during the critical period; disease-associated missense mutations impair TrkB activation or protein stability, linking loss of NT-4/5 neurotrophic signaling to primary open-angle glaucoma, while in cancer contexts NTF4 activates PRKDC/AKT and ANXA1/NF-κB pathways to promote EMT and metastasis while paradoxically inducing apoptosis through nuclear ANXA1/caspase-3 signaling."},"narrative":{"mechanistic_narrative":"NTF4 encodes neurotrophin-4/5 (NT-4/5), a secreted neurotrophic factor that signals through the TrkB receptor tyrosine kinase to support survival, differentiation, and structural plasticity of multiple neuronal populations [PMID:8000564, PMID:9391013]. NT-4/5 binds TrkB as a high-affinity ligand whose binding sites co-distribute with trkB mRNA in the forebrain, distinct from the NT-3/TrkC system, and acts redundantly with BDNF: combined NT-4/5 plus BDNF produces no additive effect on retinal ganglion cell or cerebellar granule cell survival and neurite outgrowth, while Trk kinase inhibition with K-252a abolishes these responses [PMID:7964706, PMID:7722620, PMID:8000564]. Through TrkB, NT-4/5 promotes choline acetyltransferase activity in motor neurons [PMID:7505167], prevents atrophy of axotomized rubrospinal neurons while inducing GAP-43 and Tα1-tubulin regeneration-associated genes [PMID:9391013], attracts descending axons into grafts in injured spinal cord [PMID:15485774], and supports postsynaptic target neurons via anterograde transport from retinal ganglion cells to the superior colliculus [PMID:11988017]. At synapses NT-4/5 enhances AMPA-mediated transmission by a presynaptic mechanism (increased mEPSC frequency) [PMID:7703418] and drives activity-dependent circuit remodeling in the visual cortex, where cortical infusion disrupts ocular dominance column formation and induces structural plasticity during the critical period [PMID:7886458]. NT-4/5 also exerts isoform-selective control over BDNF/TrkB signaling, upregulating truncated TrkB.T1 and downregulating full-length TrkB-FL to antagonize BDNF at corticostriatal synapses [PMID:30666798, PMID:31392756]. Heterozygous missense mutations in NTF4 are associated with primary open-angle glaucoma and impair NT-4 function by reducing TrkB phosphorylation/activation or altering protein solubility [PMID:19765683, PMID:22815630]. Beyond its neuronal roles, NTF4 has been linked in cancer cells to autophagy regulation via Atg5/MAPK [PMID:32236587] and to EMT and metastasis through PRKDC/AKT and ANXA1/NF-κB signaling with concurrent caspase-3-dependent apoptosis [PMID:36632451].","teleology":[{"year":1993,"claim":"Establishing which neurotrophins act on motor neurons distinguished NT-4/5's receptor usage; the question was whether NT-4/5 supported cholinergic motor neuron differentiation and through which receptor.","evidence":"Choline acetyltransferase activity assay in embryonic rat motor neuron cultures with co-treatment occlusion/additivity and TrkB/TrkC RT-PCR","pmids":["7505167"],"confidence":"Medium","gaps":["Did not directly demonstrate TrkB phosphorylation by NT-4/5","Single lab, in vitro embryonic culture only"]},{"year":1994,"claim":"Defining NT-4/5 as a TrkB ligand resolved its place in the neurotrophin receptor map by showing shared TrkB usage with BDNF across CNS neuron types.","evidence":"Radiolabeled [125I]NT-4/5 binding autoradiography co-registered with trkB mRNA in situ hybridization; retinal and cerebellar granule cell survival/neurite assays with combination occlusion and K-252a blockade","pmids":["8000564","7964706","7722620"],"confidence":"Medium","gaps":["Occlusion logic infers shared receptor rather than directly co-binding the same molecule","p75 contribution not dissected"]},{"year":1994,"claim":"Localizing NT-4/5's synaptic action answered whether it modulates transmission pre- or postsynaptically, informing its role in plasticity.","evidence":"Patch-clamp recording of evoked and miniature EPSCs in cultured rat hippocampal neurons with spatially restricted application","pmids":["7703418"],"confidence":"Medium","gaps":["Presynaptic locus inferred from mEPSC frequency in culture","Downstream molecular effectors of the presynaptic effect not identified"]},{"year":1995,"claim":"Testing NT-4/5 in vivo addressed whether neurotrophin/TrkB signaling shapes activity-dependent cortical wiring, linking it to developmental plasticity.","evidence":"In vivo infusion into cat primary visual cortex with histological assessment of ocular dominance columns and receptor-specificity controls (NGF, NT-3 inactive)","pmids":["7886458"],"confidence":"High","gaps":["Pharmacological infusion does not establish endogenous requirement","Cellular target neurons of the infused NT-4/5 not resolved"]},{"year":1997,"claim":"Determining whether NT-4/5 rescues injured CNS neurons established it as a neuroprotective and regeneration-promoting factor acting through neuron-expressed TrkB.","evidence":"In vivo infusion after cervical axotomy with TrkB/TrkC/TrkA/p75 in situ hybridization, RT-PCR for GAP-43/Tα1-tubulin, and peripheral nerve graft regeneration assay","pmids":["9391013"],"confidence":"High","gaps":["Robust axon regeneration shown for BDNF, less so for NT-4/5","Functional recovery not assessed"]},{"year":2002,"claim":"Showing anterograde transport of NT-4/5 answered how it can support postsynaptic neurons distant from its source, expanding the directionality of neurotrophic support.","evidence":"Intraocular [125I]-NT-4/5 injection with autoradiography of retinorecipient regions and TUNEL/pyknosis quantification in superior colliculus","pmids":["11988017"],"confidence":"Medium","gaps":["Receptor-mediated uptake mechanism at target not defined","Effect more prominent for BDNF than NT-4/5"]},{"year":2004,"claim":"Delivering NT-4/5 from cellular grafts tested its capacity to guide regenerating descending axons in spinal cord injury.","evidence":"Genetically modified NT-4/5-secreting fibroblast grafts after spinal hemisection with retrograde/anterograde tracing and myelin characterization","pmids":["15485774"],"confidence":"Medium","gaps":["Axons did not grow beyond the graft","No functional recovery observed"]},{"year":2009,"claim":"Identifying NTF4 mutations in glaucoma patients tested whether loss of NT-4/TrkB signaling contributes to retinal ganglion cell disease, providing the first disease link.","evidence":"NTF4 sequencing in a POAG cohort with recombinant mutant NT-4 TrkB-activation assay and molecular modeling of the NT-4/TrkB interface","pmids":["19765683"],"confidence":"Medium","gaps":["Single lab; functional impact shown for the most frequent mutant only","Causal link to RGC loss in patients inferred, not demonstrated in vivo"]},{"year":2010,"claim":"A structural prediction extended the glaucoma association by mapping an additional mutation to the TrkB-binding interface.","evidence":"Sanger sequencing of NTF4 and structural analysis of the Leu113Ser mutant","pmids":["20806036"],"confidence":"Low","gaps":["Structural prediction only; no experimental validation of disrupted TrkB binding","No functional or cell-based assay"]},{"year":2010,"claim":"Probing NT-4 in neural stem cells addressed whether it biases lineage commitment, extending its role beyond mature neurons.","evidence":"Mouse E14 neural stem cell cultures with Western blotting for STAT3 phosphorylation and Akt, and pathway readouts for IL-6/Notch signaling","pmids":["20407817"],"confidence":"Medium","gaps":["TrkB dependence of these intracellular effects not established","Single lab, in vitro only"]},{"year":2012,"claim":"Cell-based assays of further POAG variants tested whether they alter NT-4 protein behavior, supporting a loss-of-function disease mechanism.","evidence":"Site-directed mutagenesis and transfection into HeLa cells with solubility and migration assays","pmids":["22815630"],"confidence":"Medium","gaps":["TrkB activation not directly measured for these variants","HeLa migration is a non-neuronal proxy"]},{"year":2019,"claim":"Dissecting NT-4/5 versus BDNF at striatal synapses revealed an isoform-switch mechanism by which NT-4/5 antagonizes BDNF/TrkB signaling.","evidence":"Corticostriatal field recordings plus COS-7 transfection measuring TrkB.T1 versus TrkB-FL expression, including a 3-NP Huntington's disease mouse model","pmids":["30666798","31392756"],"confidence":"Medium","gaps":["Molecular mechanism of isoform-level regulation not defined","Single lab; relevance to human disease inferred from mouse model"]},{"year":2020,"claim":"Knockdown in colorectal cancer placed NTF4 upstream of an Atg5/MAPK autophagy axis controlling tumor cell invasion and growth.","evidence":"shRNA knockdown in CRC lines with autophagy assays, xenografts, and chloroquine rescue","pmids":["32236587"],"confidence":"Medium","gaps":["Receptor mediating NTF4's cancer-cell action not identified","Direct NTF4-Atg5 relationship mechanism unresolved"]},{"year":2023,"claim":"Mechanistic dissection in breast cancer explained NTF4's paradoxical pro-invasive yet anti-proliferative behavior through parallel EMT-promoting and apoptosis-promoting pathways.","evidence":"EMT/invasion/motility assays, xenografts, and pathway analysis of PRKDC/AKT, ANXA1/NF-κB, SNAIL/E-cadherin, plus ANXA1 phosphorylation/sumoylation and importin β Co-IP with caspase-3 assays","pmids":["36632451"],"confidence":"Medium","gaps":["Whether these effects require TrkB or are receptor-independent unclear","Single lab; reciprocal validation of ANXA1/importin β interaction limited"]},{"year":2023,"claim":"Anatomical analysis of NT-4/5-infused visual cortex addressed how TrkB signaling remodels circuitry during the critical period, linking it to structural synaptic plasticity.","evidence":"Osmotic minipump infusion in cats with DiOlistics labeling, confocal microscopy, and synaptophysin/GAD-65 immunostaining (preprint)","pmids":["38187745"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Causal link between structural changes and functional plasticity not established"]},{"year":null,"claim":"How NTF4 engages signaling in non-neuronal cancer contexts and whether these effects depend on TrkB remains unresolved across the corpus.","evidence":"No discovery directly tests receptor dependence of NTF4's cancer-cell autophagy, EMT, and apoptosis phenotypes","pmids":[],"confidence":"Low","gaps":["Receptor mediating cancer-cell effects unidentified","No structural model of NT-4/5 bound to TrkB validated experimentally","Endogenous loss-of-function requirement in vivo for most neuronal roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,6,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[15,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,14,17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,0]}],"complexes":[],"partners":["TRKB/NTRK2","BDNF","ANXA1","PRKDC","ATG5","IMPORTIN Β"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P34130","full_name":"Neurotrophin-4","aliases":["Neurotrophin-5","NT-5","Neutrophic factor 4"],"length_aa":210,"mass_kda":22.4,"function":"Target-derived survival factor for peripheral sensory sympathetic neurons (PubMed:1742028). May promote ameloblast differentiation and subsequent reduction in proliferation of ameloblasts (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P34130/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NTF4","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NTF4","total_profiled":1310},"omim":[{"mim_id":"613100","title":"GLAUCOMA 1, OPEN ANGLE, O; GLC1O","url":"https://www.omim.org/entry/613100"},{"mim_id":"600837","title":"GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF","url":"https://www.omim.org/entry/600837"},{"mim_id":"600456","title":"NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 2; NTRK2","url":"https://www.omim.org/entry/600456"},{"mim_id":"191316","title":"NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 3; NTRK3","url":"https://www.omim.org/entry/191316"},{"mim_id":"191315","title":"NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1","url":"https://www.omim.org/entry/191315"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"prostate","ntpm":19.7},{"tissue":"skeletal muscle","ntpm":13.5},{"tissue":"skin 1","ntpm":15.6}],"url":"https://www.proteinatlas.org/search/NTF4"},"hgnc":{"alias_symbol":["NT-4/5","GLC1O"],"prev_symbol":["NTF5"]},"alphafold":{"accession":"P34130","domains":[{"cath_id":"2.10.90.10","chopping":"94-210","consensus_level":"medium","plddt":92.5336,"start":94,"end":210}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P34130","model_url":"https://alphafold.ebi.ac.uk/files/AF-P34130-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P34130-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NTF4","jax_strain_url":"https://www.jax.org/strain/search?query=NTF4"},"sequence":{"accession":"P34130","fasta_url":"https://rest.uniprot.org/uniprotkb/P34130.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P34130/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P34130"}},"corpus_meta":[{"pmid":"7886458","id":"PMC_7886458","title":"Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7886458","citation_count":515,"is_preprint":false},{"pmid":"9391013","id":"PMC_9391013","title":"BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration.","date":"1997","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9391013","citation_count":378,"is_preprint":false},{"pmid":"7703418","id":"PMC_7703418","title":"BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones.","date":"1994","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/7703418","citation_count":367,"is_preprint":false},{"pmid":"8283241","id":"PMC_8283241","title":"Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8283241","citation_count":350,"is_preprint":false},{"pmid":"7757258","id":"PMC_7757258","title":"The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro.","date":"1995","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7757258","citation_count":239,"is_preprint":false},{"pmid":"7505167","id":"PMC_7505167","title":"The neurotrophins BDNF, NT-3 and NT-4/5, but not NGF, up-regulate the cholinergic phenotype of developing motor neurons.","date":"1993","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7505167","citation_count":198,"is_preprint":false},{"pmid":"7869082","id":"PMC_7869082","title":"BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons.","date":"1995","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7869082","citation_count":182,"is_preprint":false},{"pmid":"8000564","id":"PMC_8000564","title":"In situ hybridization of trkB and trkC receptor mRNA in rat forebrain and association with high-affinity binding of [125I]BDNF, [125I]NT-4/5 and [125I]NT-3.","date":"1994","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8000564","citation_count":177,"is_preprint":false},{"pmid":"7722620","id":"PMC_7722620","title":"Neurotrophin-4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF) act at later stages of cerebellar granule cell differentiation.","date":"1995","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7722620","citation_count":165,"is_preprint":false},{"pmid":"7964706","id":"PMC_7964706","title":"Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro.","date":"1994","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/7964706","citation_count":164,"is_preprint":false},{"pmid":"19765683","id":"PMC_19765683","title":"Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19765683","citation_count":116,"is_preprint":false},{"pmid":"7821394","id":"PMC_7821394","title":"The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra.","date":"1994","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7821394","citation_count":101,"is_preprint":false},{"pmid":"16798947","id":"PMC_16798947","title":"Activation of Ntf4, a tobacco mitogen-activated protein kinase, during plant defense response and its involvement in hypersensitive response-like cell death.","date":"2006","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16798947","citation_count":66,"is_preprint":false},{"pmid":"8921261","id":"PMC_8921261","title":"Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo.","date":"1996","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8921261","citation_count":60,"is_preprint":false},{"pmid":"19813200","id":"PMC_19813200","title":"Effects of exercise and muscle type on BDNF, NT-4/5, and TrKB expression in skeletal muscle.","date":"2010","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/19813200","citation_count":59,"is_preprint":false},{"pmid":"34445512","id":"PMC_34445512","title":"The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34445512","citation_count":58,"is_preprint":false},{"pmid":"7955354","id":"PMC_7955354","title":"Stimulation of GABAergic neuron differentiation by NT-4/5 in cultures of rat cerebral cortex.","date":"1994","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7955354","citation_count":55,"is_preprint":false},{"pmid":"7841368","id":"PMC_7841368","title":"NT-4/5 reduces naturally occurring retinal ganglion cell death in neonatal rats.","date":"1994","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/7841368","citation_count":54,"is_preprint":false},{"pmid":"15485774","id":"PMC_15485774","title":"Axonal responses to cellularly delivered NT-4/5 after spinal cord injury.","date":"2004","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15485774","citation_count":52,"is_preprint":false},{"pmid":"11988017","id":"PMC_11988017","title":"Anterograde transport and trophic actions of BDNF and NT-4/5 in the developing rat visual system.","date":"2002","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11988017","citation_count":48,"is_preprint":false},{"pmid":"29540704","id":"PMC_29540704","title":"Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29540704","citation_count":42,"is_preprint":false},{"pmid":"20806036","id":"PMC_20806036","title":"Identification of a novel mutation in the NTF4 gene that causes primary open-angle glaucoma in a Chinese population.","date":"2010","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/20806036","citation_count":41,"is_preprint":false},{"pmid":"9588602","id":"PMC_9588602","title":"Cellular delivery of CNTF but not NT-4/5 prevents degeneration of striatal neurons in a rodent model of Huntington's disease.","date":"1998","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/9588602","citation_count":38,"is_preprint":false},{"pmid":"20463313","id":"PMC_20463313","title":"Variations in NTF4, VAV2, and VAV3 genes are not involved with primary open-angle and primary angle-closure glaucomas in an indian population.","date":"2010","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20463313","citation_count":34,"is_preprint":false},{"pmid":"21038447","id":"PMC_21038447","title":"Developmental expression of Bdnf, Ntf4/5, and TrkB in the mouse peripheral taste system.","date":"2010","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/21038447","citation_count":33,"is_preprint":false},{"pmid":"9749800","id":"PMC_9749800","title":"NT-4/5 and LIF, but not NT-3 and BDNF, promote NPY mRNA expression in cortical neurons in the absence of spontaneous bioelectrical activity.","date":"1998","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9749800","citation_count":32,"is_preprint":false},{"pmid":"20407817","id":"PMC_20407817","title":"Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stem cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B.","date":"2010","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/20407817","citation_count":28,"is_preprint":false},{"pmid":"12453058","id":"PMC_12453058","title":"Physiological and morphological plasticity induced by chronic treatment with NT-3 or NT-4/5 in hippocampal slice cultures.","date":"2002","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12453058","citation_count":26,"is_preprint":false},{"pmid":"10964597","id":"PMC_10964597","title":"NT-4/5 exacerbates free radical-induced neuronal necrosis in vitro and in vivo.","date":"2000","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/10964597","citation_count":22,"is_preprint":false},{"pmid":"9184104","id":"PMC_9184104","title":"Quantitative analysis of long-term survival and neuritogenesis in vitro: cochleovestibular ganglion of the chick embryo in BDNF, NT-3, NT-4/5, and insulin.","date":"1997","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9184104","citation_count":22,"is_preprint":false},{"pmid":"22815630","id":"PMC_22815630","title":"Evaluation of NTF4 as a causative gene for primary open-angle glaucoma.","date":"2012","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22815630","citation_count":21,"is_preprint":false},{"pmid":"14519521","id":"PMC_14519521","title":"Oleic acid induces GAP-43 expression through a protein kinase C-mediated mechanism that is independent of NGF but synergistic with NT-3 and NT-4/5.","date":"2003","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/14519521","citation_count":19,"is_preprint":false},{"pmid":"32236587","id":"PMC_32236587","title":"Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.","date":"2020","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32236587","citation_count":16,"is_preprint":false},{"pmid":"11117515","id":"PMC_11117515","title":"NT-4/5 reduces cell death in inner nuclear as well as ganglion cell layers in neonatal rat retina.","date":"2000","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/11117515","citation_count":15,"is_preprint":false},{"pmid":"8730856","id":"PMC_8730856","title":"NT-4/5 protects against adrenalectomy-induced apoptosis of rat hippocampal granule cells.","date":"1996","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/8730856","citation_count":14,"is_preprint":false},{"pmid":"30666798","id":"PMC_30666798","title":"NT-4/5 antagonizes the BDNF modulation of corticostriatal transmission: Role of the TrkB.T1 receptor.","date":"2019","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30666798","citation_count":12,"is_preprint":false},{"pmid":"31392756","id":"PMC_31392756","title":"Do BDNF and NT-4/5 exert synergistic or occlusive effects on corticostriatal transmission in a male mouse model of Huntington's disease?","date":"2019","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/31392756","citation_count":11,"is_preprint":false},{"pmid":"9582407","id":"PMC_9582407","title":"Nerve fiber formation and catecholamine content in adult rat adrenal medullary transplants after treatment with NGF, NT-3, NT-4/5, bFGF, CNTF, and GDNF.","date":"1998","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/9582407","citation_count":11,"is_preprint":false},{"pmid":"11430430","id":"PMC_11430430","title":"Temporal and tissue-specific expression of the tobacco ntf4 MAP kinase.","date":"2001","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11430430","citation_count":10,"is_preprint":false},{"pmid":"17217337","id":"PMC_17217337","title":"In situ molecular identification of the Ntf4 MAPK expression sites in maturing and germinating pollen.","date":"2007","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17217337","citation_count":10,"is_preprint":false},{"pmid":"36632451","id":"PMC_36632451","title":"NTF4 plays a dual role in breast cancer in mammary tumorigenesis and metastatic progression.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36632451","citation_count":8,"is_preprint":false},{"pmid":"10790287","id":"PMC_10790287","title":"Developmental profiles of growth-associated protein (Gap43), Ngfb, Bndf and Ntf4 mRNA levels in the rat forebrain after exposure to 60 Hz magnetic fields.","date":"2000","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/10790287","citation_count":6,"is_preprint":false},{"pmid":"34076998","id":"PMC_34076998","title":"NTF4 stimulates the progression of gastric cancer via regulating FOXL1.","date":"2021","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34076998","citation_count":4,"is_preprint":false},{"pmid":"22524196","id":"PMC_22524196","title":"Retinal ganglion cell (RGC) death in glaucomatous beagles is not associated with mutations in p53 and NTF4 genes.","date":"2012","source":"Veterinary ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/22524196","citation_count":4,"is_preprint":false},{"pmid":"29701077","id":"PMC_29701077","title":"A Combination of NT-4/5 and GDNF Is Favorable for Cultured Human Nigral Neural Progenitor Cells.","date":"2018","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/29701077","citation_count":4,"is_preprint":false},{"pmid":"38187745","id":"PMC_38187745","title":"Neurotrophin NT-4/5 Promotes Structural Changes in Neurons of the Developing Visual Cortex.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187745","citation_count":0,"is_preprint":false},{"pmid":"42036822","id":"PMC_42036822","title":"Inhibition of NTF4 Attenuates High Glucose-Induced Apoptosis and Inflammation in HTR-8/SVneo Cells via the PI3K/AKT Pathway.","date":"2026","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/42036822","citation_count":0,"is_preprint":false},{"pmid":"39950318","id":"PMC_39950318","title":"[Corrigendum] Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.","date":"2025","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39950318","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25717,"output_tokens":4631,"usd":0.073308,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12712,"output_tokens":4773,"usd":0.091442,"stage2_stop_reason":"end_turn"},"total_usd":0.16475,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Infusion of NT-4/5 (or BDNF) into cat primary visual cortex inhibited ocular dominance column formation, implicating the shared TrkB receptor in activity-dependent segregation of LGN axons; NGF, NT-3, or vehicle had no effect, establishing receptor specificity.\",\n      \"method\": \"In vivo infusion into cat visual cortex with histological assessment of ocular dominance columns\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo loss-of-function (infusion) with defined anatomical phenotype, replicated across multiple infusion sites, rigorous receptor-specificity controls (NGF, NT-3 inactive)\",\n      \"pmids\": [\"7886458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NT-4/5 and BDNF, but not NGF or NT-3, enhanced AMPA receptor-mediated synaptic transmission in cultured hippocampal neurons; the effect manifested as increased frequency (not amplitude) of miniature EPSCs, indicating a presynaptic site of action. Both neurotrophins signal through TrkB.\",\n      \"method\": \"Patch-clamp recording of evoked and miniature EPSCs in rat hippocampal neurons with spatially restricted neurotrophin application\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological assay distinguishing pre- vs postsynaptic locus, single lab, two readouts (evoked currents + mEPSC frequency/amplitude)\",\n      \"pmids\": [\"7703418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NT-4/5 and BDNF both promote survival and neurite outgrowth of adult rat retinal ganglion cells, and saturating concentrations of NT-4/5 plus BDNF together show no additive effect, indicating they share a common signaling pathway (TrkB). NGF, NT-3, and CNTF were ineffective.\",\n      \"method\": \"Retinal explant culture with dose-response and combination neurotrophin treatments; RGC survival and neurite counts\",\n      \"journal\": \"Journal of neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay with occlusion experiment establishing shared receptor pathway; single lab\",\n      \"pmids\": [\"7964706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NT-4/5 and BDNF promote survival and neurite extension of differentiated cerebellar granule cells via TrkB; these effects are blocked by the Trk kinase inhibitor K-252a. No additive effect was seen when NT-4/5 and BDNF were combined, consistent with activation of the same TrkB receptor. Neither NT-3 nor NGF replicated the effect.\",\n      \"method\": \"Purified granule cell cultures with K-252a pharmacological inhibition; TrkB immunohistochemistry on cerebellar sections\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis (K-252a blockade) plus occlusion experiment; single lab, orthogonal methods\",\n      \"pmids\": [\"7722620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NT-4/5 and BDNF both bind TrkB as high-affinity receptors; radiolabeled [125I]NT-4/5 and [125I]BDNF binding sites co-distribute with trkB mRNA in rat forebrain, distinct from the NT-3/TrkC pattern, establishing NT-4/5 as a TrkB ligand in the brain.\",\n      \"method\": \"In situ hybridization with trkB and trkC riboprobes combined with [125I]NT-4/5 and [125I]BDNF autoradiographic binding in adjacent brain sections\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand-binding autoradiography co-registered with receptor mRNA; single lab, two orthogonal methods\",\n      \"pmids\": [\"8000564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"NT-4/5 and BDNF, but not NGF, stimulate choline acetyltransferase (CAT) activity in embryonic rat motor neuron cultures. Combined treatment with BDNF and NT-4/5 produces no greater effect than either alone, consistent with both acting through TrkB; combined BDNF + NT-3 is additive, consistent with TrkB vs TrkC.\",\n      \"method\": \"Motor neuron-enriched cultures with CAT activity assay; co-treatment occlusion/additivity experiments; RT-PCR for TrkB and TrkC mRNA\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional enzymatic assay with receptor-specificity epistasis (TrkB/TrkC additivity logic); single lab\",\n      \"pmids\": [\"7505167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Seven heterozygous missense mutations in NTF4 identified in POAG patients impair NT-4 signaling; expression of the most frequent mutant NT-4 in cells leads to decreased TrkB phosphorylation/activation, and molecular modeling predicts reduced NT-4 affinity for TrkB, establishing a loss-of-neurotrophic-function mechanism.\",\n      \"method\": \"Sequencing of NTF4 in POAG cohort; molecular modeling of NT-4/TrkB interaction; recombinant mutant NT-4 expression with TrkB activation assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant mutant protein functional assay (TrkB activation) plus structural modeling; single lab\",\n      \"pmids\": [\"19765683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An NTF4 missense mutation (Leu113Ser) identified in a POAG patient is predicted by structural analysis to disrupt the NT-4/TrkB binding interface, implicating TrkB binding as the mechanism by which NT-4 supports retinal ganglion cell survival.\",\n      \"method\": \"Sanger sequencing of NTF4 coding exon; structural analysis of mutant NT-4 protein\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — structural prediction only, no experimental validation of TrkB binding disruption\",\n      \"pmids\": [\"20806036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Two NTF4 missense variants (Gly157Ala and Ala182Val) found in Chinese POAG patients produce functionally altered NT-4 protein: the Gly157Ala mutant shows reduced Triton X-100 solubility, and HeLa cells transfected with either mutant construct show reduced migration compared to wildtype, indicating these are functional mutations.\",\n      \"method\": \"Site-directed mutagenesis, transfection into HeLa cells, solubility assay, cell migration assay\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-based functional assays with mutant constructs; single lab, two orthogonal readouts (solubility + migration)\",\n      \"pmids\": [\"22815630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NT-4/5 antagonizes BDNF-mediated modulation of corticostriatal synaptic transmission. Mechanistically, NT-4/5 upregulates the truncated TrkB.T1 isoform and downregulates full-length TrkB-FL, thereby suppressing BDNF signaling at striatal synapses. BDNF does not modify NT-4/5 effect (unidirectional antagonism).\",\n      \"method\": \"Electrophysiological field recordings at corticostriatal synapses; COS-7 cell transfection experiments measuring TrkB isoform expression after neurotrophin exposure\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus cell-based mechanistic isoform analysis; single lab, two orthogonal methods\",\n      \"pmids\": [\"30666798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The modulatory effect of sequential NT-4/5 and BDNF application on corticostriatal transmission in a Huntington's disease mouse model depends on which isoform of TrkB is activated: truncated TrkB.T1 activation mediates antagonism, while full-length TrkB-FL activation mediates synergy.\",\n      \"method\": \"Field recordings in 3-NP mouse striatal slices with sequential neurotrophin application and TrkB isoform pharmacology\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with isoform-specific pharmacological dissection; single lab\",\n      \"pmids\": [\"31392756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NT-4 (Ntf4) promotes neurogenesis in mouse embryonic neural stem cells by suppressing STAT3 phosphorylation and modulating PKB/Akt activity; it also suppresses IL-6 family receptor and Notch signaling pathway cleavages, biasing NSC commitment toward neuronal lineage.\",\n      \"method\": \"Primary mouse E14 neural stem cell cultures; Western blotting for STAT3 phosphorylation and Akt activity; immunocytochemistry; molecular cell biology methods\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based mechanistic assays with multiple pathway readouts; single lab\",\n      \"pmids\": [\"20407817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NTF4 knockdown in colorectal cancer cells activates autophagy via interaction with autophagy-associated gene Atg5 and the MAPK pathway; NTF4 silencing inhibits EMT, invasion, migration, proliferation, and xenograft growth, while autophagy inhibitor chloroquine rescues these phenotypes, placing NTF4 upstream of Atg5-MAPK-autophagy.\",\n      \"method\": \"shRNA knockdown in CRC cell lines; co-regulation with Atg5; autophagy assays; xenograft model; chloroquine rescue experiment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with defined rescue experiment (chloroquine) placing NTF4 in pathway; single lab, multiple cellular readouts\",\n      \"pmids\": [\"32236587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NTF4 promotes breast cancer metastasis by activating PRKDC/AKT and ANXA1/NF-κB pathways to stabilize SNAIL protein and reduce E-cadherin (pro-EMT). Simultaneously, NTF4 increases ANXA1 phosphorylation, sumoylation, and interaction with importin β, causing nuclear ANXA1 retention that activates caspase-3-dependent apoptosis, explaining why NTF4 inhibits proliferation while promoting invasion.\",\n      \"method\": \"In vitro cell line experiments (EMT, invasion, motility assays); in vivo xenograft; pathway analysis with PRKDC/AKT, NF-κB, SNAIL, E-cadherin, ANXA1 phosphorylation/sumoylation, importin β co-immunoprecipitation and caspase-3 assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic assays (Co-IP, pathway inhibitors, in vivo xenograft); single lab\",\n      \"pmids\": [\"36632451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BDNF and NT-4/5 (but not NGF, NT-3, or vehicle) fully prevent atrophy of axotomized rat rubrospinal neurons, maintain TrkB expression, and stimulate GAP-43 and Tα1-tubulin mRNA expression, acting through TrkB receptors expressed by rubrospinal neurons; BDNF treatment also increases axon regeneration into peripheral nerve grafts.\",\n      \"method\": \"In vivo infusion after cervical axotomy; in situ hybridization for TrkB/TrkC/TrkA/p75; RT-PCR; morphometric analysis; peripheral nerve graft regeneration assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo rescue with receptor-profiling by ISH and RT-PCR; multiple outcome measures; replicated across neurotrophin specificity controls\",\n      \"pmids\": [\"9391013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fibroblasts engineered to secrete NT-4/5, grafted to injured rat spinal cord, attract motor, coerulospinal, reticulospinal, and propriospinal axons into the graft; Schwann cells (not oligodendrocytes) remyelinate axons within the NT-4/5-secreting grafts. Axonal growth beyond the graft and functional recovery were not observed.\",\n      \"method\": \"Genetically modified fibroblast grafts after thoracic hemisection/transection; retrograde/anterograde tracing; immunohistochemistry\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular delivery with antero/retrograde tracing and myelin characterization; single lab\",\n      \"pmids\": [\"15485774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Anterograde transport of NT-4/5 (and more prominently BDNF) occurs from retinal ganglion cells to central visual targets in neonatal rat; intraocular injection of NT-4/5 reduces pyknosis and increases cell number (primarily neurons) in the contralateral superior colliculus within 24 h, indicating NT-4/5 acts as an anterograde survival factor for postsynaptic neurons.\",\n      \"method\": \"Intraocular injection of [125I]-labeled NT-4/5; autoradiography of retinorecipient regions; TUNEL/pyknosis quantification in superior colliculus\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — radiolabeled anterograde transport assay plus quantitative cell death assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"11988017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Chronic infusion of NT-4/5 into cat visual cortex during the critical period induces structural plasticity: increased spine-like processes on primary dendrites, sprouting of protuberances from neuronal somata in all layers, increased synaptophysin density (indicating more synapses), and increased GAD-65 immunostaining (suggesting enhanced inhibitory circuits). These changes are consistent with NT-4/5/TrkB driving promiscuous thalamocortical and corticocortical connectivity.\",\n      \"method\": \"Osmotic minipump infusion in cats; DiOlistics labeling of neurons in fixed slices; confocal microscopy; synaptophysin and GAD-65 immunostaining\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct anatomical measurements after defined NT-4/5 infusion with multiple structural markers; preprint, single lab\",\n      \"pmids\": [\"38187745\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NT-4/5 (NTF4) is a secreted neurotrophin that signals primarily through the TrkB receptor tyrosine kinase (shared with BDNF); it promotes survival, differentiation, and axonal growth of multiple neuronal populations (retinal ganglion cells, motor neurons, dopaminergic and GABAergic neurons), modulates synaptic transmission via a presynaptic mechanism, can be transported anterogradely to support postsynaptic target neurons, and drives structural synaptic plasticity in the visual cortex during the critical period; disease-associated missense mutations impair TrkB activation or protein stability, linking loss of NT-4/5 neurotrophic signaling to primary open-angle glaucoma, while in cancer contexts NTF4 activates PRKDC/AKT and ANXA1/NF-κB pathways to promote EMT and metastasis while paradoxically inducing apoptosis through nuclear ANXA1/caspase-3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NTF4 encodes neurotrophin-4/5 (NT-4/5), a secreted neurotrophic factor that signals through the TrkB receptor tyrosine kinase to support survival, differentiation, and structural plasticity of multiple neuronal populations [#4, #14]. NT-4/5 binds TrkB as a high-affinity ligand whose binding sites co-distribute with trkB mRNA in the forebrain, distinct from the NT-3/TrkC system, and acts redundantly with BDNF: combined NT-4/5 plus BDNF produces no additive effect on retinal ganglion cell or cerebellar granule cell survival and neurite outgrowth, while Trk kinase inhibition with K-252a abolishes these responses [#2, #3, #4]. Through TrkB, NT-4/5 promotes choline acetyltransferase activity in motor neurons [#5], prevents atrophy of axotomized rubrospinal neurons while inducing GAP-43 and Tα1-tubulin regeneration-associated genes [#14], attracts descending axons into grafts in injured spinal cord [#15], and supports postsynaptic target neurons via anterograde transport from retinal ganglion cells to the superior colliculus [#16]. At synapses NT-4/5 enhances AMPA-mediated transmission by a presynaptic mechanism (increased mEPSC frequency) [#1] and drives activity-dependent circuit remodeling in the visual cortex, where cortical infusion disrupts ocular dominance column formation and induces structural plasticity during the critical period [#0]. NT-4/5 also exerts isoform-selective control over BDNF/TrkB signaling, upregulating truncated TrkB.T1 and downregulating full-length TrkB-FL to antagonize BDNF at corticostriatal synapses [#9, #10]. Heterozygous missense mutations in NTF4 are associated with primary open-angle glaucoma and impair NT-4 function by reducing TrkB phosphorylation/activation or altering protein solubility [#6, #8]. Beyond its neuronal roles, NTF4 has been linked in cancer cells to autophagy regulation via Atg5/MAPK [#12] and to EMT and metastasis through PRKDC/AKT and ANXA1/NF-κB signaling with concurrent caspase-3-dependent apoptosis [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing which neurotrophins act on motor neurons distinguished NT-4/5's receptor usage; the question was whether NT-4/5 supported cholinergic motor neuron differentiation and through which receptor.\",\n      \"evidence\": \"Choline acetyltransferase activity assay in embryonic rat motor neuron cultures with co-treatment occlusion/additivity and TrkB/TrkC RT-PCR\",\n      \"pmids\": [\"7505167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly demonstrate TrkB phosphorylation by NT-4/5\", \"Single lab, in vitro embryonic culture only\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining NT-4/5 as a TrkB ligand resolved its place in the neurotrophin receptor map by showing shared TrkB usage with BDNF across CNS neuron types.\",\n      \"evidence\": \"Radiolabeled [125I]NT-4/5 binding autoradiography co-registered with trkB mRNA in situ hybridization; retinal and cerebellar granule cell survival/neurite assays with combination occlusion and K-252a blockade\",\n      \"pmids\": [\"8000564\", \"7964706\", \"7722620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Occlusion logic infers shared receptor rather than directly co-binding the same molecule\", \"p75 contribution not dissected\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Localizing NT-4/5's synaptic action answered whether it modulates transmission pre- or postsynaptically, informing its role in plasticity.\",\n      \"evidence\": \"Patch-clamp recording of evoked and miniature EPSCs in cultured rat hippocampal neurons with spatially restricted application\",\n      \"pmids\": [\"7703418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Presynaptic locus inferred from mEPSC frequency in culture\", \"Downstream molecular effectors of the presynaptic effect not identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Testing NT-4/5 in vivo addressed whether neurotrophin/TrkB signaling shapes activity-dependent cortical wiring, linking it to developmental plasticity.\",\n      \"evidence\": \"In vivo infusion into cat primary visual cortex with histological assessment of ocular dominance columns and receptor-specificity controls (NGF, NT-3 inactive)\",\n      \"pmids\": [\"7886458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pharmacological infusion does not establish endogenous requirement\", \"Cellular target neurons of the infused NT-4/5 not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Determining whether NT-4/5 rescues injured CNS neurons established it as a neuroprotective and regeneration-promoting factor acting through neuron-expressed TrkB.\",\n      \"evidence\": \"In vivo infusion after cervical axotomy with TrkB/TrkC/TrkA/p75 in situ hybridization, RT-PCR for GAP-43/Tα1-tubulin, and peripheral nerve graft regeneration assay\",\n      \"pmids\": [\"9391013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Robust axon regeneration shown for BDNF, less so for NT-4/5\", \"Functional recovery not assessed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing anterograde transport of NT-4/5 answered how it can support postsynaptic neurons distant from its source, expanding the directionality of neurotrophic support.\",\n      \"evidence\": \"Intraocular [125I]-NT-4/5 injection with autoradiography of retinorecipient regions and TUNEL/pyknosis quantification in superior colliculus\",\n      \"pmids\": [\"11988017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-mediated uptake mechanism at target not defined\", \"Effect more prominent for BDNF than NT-4/5\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Delivering NT-4/5 from cellular grafts tested its capacity to guide regenerating descending axons in spinal cord injury.\",\n      \"evidence\": \"Genetically modified NT-4/5-secreting fibroblast grafts after spinal hemisection with retrograde/anterograde tracing and myelin characterization\",\n      \"pmids\": [\"15485774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Axons did not grow beyond the graft\", \"No functional recovery observed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying NTF4 mutations in glaucoma patients tested whether loss of NT-4/TrkB signaling contributes to retinal ganglion cell disease, providing the first disease link.\",\n      \"evidence\": \"NTF4 sequencing in a POAG cohort with recombinant mutant NT-4 TrkB-activation assay and molecular modeling of the NT-4/TrkB interface\",\n      \"pmids\": [\"19765683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; functional impact shown for the most frequent mutant only\", \"Causal link to RGC loss in patients inferred, not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A structural prediction extended the glaucoma association by mapping an additional mutation to the TrkB-binding interface.\",\n      \"evidence\": \"Sanger sequencing of NTF4 and structural analysis of the Leu113Ser mutant\",\n      \"pmids\": [\"20806036\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural prediction only; no experimental validation of disrupted TrkB binding\", \"No functional or cell-based assay\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Probing NT-4 in neural stem cells addressed whether it biases lineage commitment, extending its role beyond mature neurons.\",\n      \"evidence\": \"Mouse E14 neural stem cell cultures with Western blotting for STAT3 phosphorylation and Akt, and pathway readouts for IL-6/Notch signaling\",\n      \"pmids\": [\"20407817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TrkB dependence of these intracellular effects not established\", \"Single lab, in vitro only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Cell-based assays of further POAG variants tested whether they alter NT-4 protein behavior, supporting a loss-of-function disease mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis and transfection into HeLa cells with solubility and migration assays\",\n      \"pmids\": [\"22815630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TrkB activation not directly measured for these variants\", \"HeLa migration is a non-neuronal proxy\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissecting NT-4/5 versus BDNF at striatal synapses revealed an isoform-switch mechanism by which NT-4/5 antagonizes BDNF/TrkB signaling.\",\n      \"evidence\": \"Corticostriatal field recordings plus COS-7 transfection measuring TrkB.T1 versus TrkB-FL expression, including a 3-NP Huntington's disease mouse model\",\n      \"pmids\": [\"30666798\", \"31392756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of isoform-level regulation not defined\", \"Single lab; relevance to human disease inferred from mouse model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Knockdown in colorectal cancer placed NTF4 upstream of an Atg5/MAPK autophagy axis controlling tumor cell invasion and growth.\",\n      \"evidence\": \"shRNA knockdown in CRC lines with autophagy assays, xenografts, and chloroquine rescue\",\n      \"pmids\": [\"32236587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating NTF4's cancer-cell action not identified\", \"Direct NTF4-Atg5 relationship mechanism unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistic dissection in breast cancer explained NTF4's paradoxical pro-invasive yet anti-proliferative behavior through parallel EMT-promoting and apoptosis-promoting pathways.\",\n      \"evidence\": \"EMT/invasion/motility assays, xenografts, and pathway analysis of PRKDC/AKT, ANXA1/NF-κB, SNAIL/E-cadherin, plus ANXA1 phosphorylation/sumoylation and importin β Co-IP with caspase-3 assays\",\n      \"pmids\": [\"36632451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these effects require TrkB or are receptor-independent unclear\", \"Single lab; reciprocal validation of ANXA1/importin β interaction limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Anatomical analysis of NT-4/5-infused visual cortex addressed how TrkB signaling remodels circuitry during the critical period, linking it to structural synaptic plasticity.\",\n      \"evidence\": \"Osmotic minipump infusion in cats with DiOlistics labeling, confocal microscopy, and synaptophysin/GAD-65 immunostaining (preprint)\",\n      \"pmids\": [\"38187745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Causal link between structural changes and functional plasticity not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NTF4 engages signaling in non-neuronal cancer contexts and whether these effects depend on TrkB remains unresolved across the corpus.\",\n      \"evidence\": \"No discovery directly tests receptor dependence of NTF4's cancer-cell autophagy, EMT, and apoptosis phenotypes\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Receptor mediating cancer-cell effects unidentified\", \"No structural model of NT-4/5 bound to TrkB validated experimentally\", \"Endogenous loss-of-function requirement in vivo for most neuronal roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 6, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 14, 17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TrkB/NTRK2\", \"BDNF\", \"ANXA1\", \"PRKDC\", \"ATG5\", \"importin β\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}