{"gene":"TNR","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1997,"finding":"The C-type lectin domains of lecticans (aggrecan, versican, neurocan, brevican) bind tenascin-R through protein-protein interactions with the fibronectin type III domains 3-5 of TNR, independent of carbohydrate moieties or sulfated amino acids. Brevican lectin domain has at least 10-fold higher affinity for TNR than other lectican lectins. TNR and brevican form complexes in vivo as shown by co-precipitation from adult rat brain extracts.","method":"Surface plasmon resonance, solid-phase binding assays, co-precipitation from brain extracts, recombinant domain mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with SPR quantification, domain mapping, and in vivo co-precipitation validation","pmids":["9294172"],"is_preprint":false},{"year":1998,"finding":"Neurocan and phosphacan (chondroitin sulfate proteoglycans) bind tenascin-R with high affinity (Kd 2–7 nM) via their core glycoproteins rather than glycosaminoglycan chains; binding is largely calcium-independent, in contrast to their binding to tenascin-C. Chondroitinase treatment increases binding by ~60%, indicating GAG chains partially shield the binding sites.","method":"Radioligand binding assay, chondroitinase treatment, calcium chelation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — quantitative in vitro binding assay with multiple orthogonal controls (enzymatic, ionic)","pmids":["9507007"],"is_preprint":false},{"year":1998,"finding":"Neurofascin binds tenascin-R, and TNR shifts neurofascin-mediated cell attachment from NrCAM-dependent to axonin-1/F11-dependent receptor usage. Isoforms of neurofascin generated by alternative splicing show differential binding to TNR, regulated by alternatively spliced stretches in the NH2-terminal half and the PAT-rich segment. F11 binds TNR within the neurofascin/TNR complex, while axonin-1 cannot bind the complex directly.","method":"Cellular binding assays, neurite outgrowth assays on neurofascin-Fc substrates, competition binding assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal binding and functional assays with domain-level resolution","pmids":["9722619"],"is_preprint":false},{"year":1996,"finding":"Distinct domains of TNR confer different neuronal functions: the fibrinogen knob (FG) domain mediates best short-term adhesion and hippocampal neuron polarization; EGF-like domains (EGF-L) prevent neurite outgrowth and contain the binding site for the neuronal receptor F3/11 (contactin); fibronectin type III repeats FN1-2 and FN3-5 are repellent for neurites and growth cones. Multiple TNR receptors exist on neurons.","method":"Short-term adhesion assays, neurite outgrowth assays with recombinant TNR domain fragments, receptor binding localization","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — systematic domain dissection with multiple functional readouts using recombinant protein fragments","pmids":["9081628"],"is_preprint":false},{"year":1996,"finding":"Human TNR is encoded by a gene on chromosome 1q23-q24 and undergoes pre-mRNA alternative splicing in astrocytomas and meningiomas, producing an isoform lacking one fibronectin-like repeat. The deduced amino acid sequence (1358 aa) shows 93% homology to rat TNR. Two mRNA species of ~10 and ~11 kb are detected.","method":"cDNA sequencing, RT-PCR, Northern blot, somatic cell hybrid panel, FISH","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete primary structure determination with chromosomal localization and splicing characterization","pmids":["8626505"],"is_preprint":false},{"year":1999,"finding":"TNR N-glycosylation is dominated by neutral complex biantennary 'brain-type' N-glycans with outer-arm and core fucosylation, bisecting GlcNAc, and extensive antennae truncation. O-glycans are abundant and dominated by disialylated structures (NeuAcα2-3Galβ1-3(NeuAcα2-6)GalNAc), suggesting potential interactions with myelin-associated glycoprotein or sialoadhesin on activated microglia.","method":"Glycan mass spectrometry analysis of purified TNR","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 1 — detailed structural glycan characterization; functional implications proposed but not directly tested","pmids":["10406848"],"is_preprint":false},{"year":2001,"finding":"The lectin domains of aggrecan and versican bind fibulin-2 at the same site on the proteoglycan lectin domains as tenascin-R (demonstrated by solid-phase competition assays), indicating that fibulin-2 and TNR compete for the same binding site on lectican C-type lectin domains.","method":"Solid-phase competition assays, surface plasmon resonance, electron microscopy, affinity chromatography","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — competitive binding mapped by SPR and solid-phase assay, but TNR's role is as a comparator ligand rather than primary subject","pmids":["11038354"],"is_preprint":false},{"year":2007,"finding":"TNR deficiency in mice leads to metaplastic increase in the threshold for LTP induction at CA3-CA1 synapses, caused by reduced perisomatic GABAergic inhibition. This operates via a chain: reduced GABAergic transmission → increased Ca2+ entry → elevated phosphatase activity. Reconstitution with an HNK-1 glycomimetic, or pharmacological treatment with GABAA receptor agonist, GABAB receptor antagonist, L-type Ca2+ channel blocker, or phosphatase inhibitor restored LTP. The HNK-1 carbohydrate on TNR mediates regulation of GABAergic transmission via GABAB receptors.","method":"Patch-clamp recordings in hippocampal slices from TNR-deficient mice, pharmacological rescue experiments, HNK-1 glycomimetic reconstitution","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined electrophysiological phenotype, multiple pharmacological rescues, and reconstitution with specific molecular epitope","pmids":["17537973"],"is_preprint":false},{"year":2012,"finding":"Passive immunization with TNR polyclonal antibody (acting as a TNR antagonist) promoted neurite outgrowth and sprouting of rat cortical neurons cultured on inhibitory TNR substrate in vitro, and when administered locally after spinal cord dorsal hemisection in rats, significantly decreased RhoA activation and improved functional recovery from corticospinal tract transection.","method":"In vitro neurite outgrowth assay on TNR substrate, in vivo spinal cord injury model with antibody administration, RhoA activation assay, functional behavioral assessment","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro and in vivo experiments with molecular readout (RhoA activation), single lab","pmids":["22902990"],"is_preprint":false},{"year":2020,"finding":"Biallelic loss-of-function variants in TNR (homozygous loss-of-function and missense variants) cause an autosomal recessive nonprogressive neurodevelopmental disorder with spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus in 13 individuals from 8 families, establishing TNR as essential for human CNS function, consistent with its role in perineuronal net formation around interneurons.","method":"Exome sequencing, matchmaking tool, clinical phenotyping of human patients with biallelic TNR variants","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — human genetics with multiple independent families; mechanism inferred from known TNR biology rather than direct functional assay in patients","pmids":["32099069"],"is_preprint":false},{"year":2023,"finding":"A frameshift variant in TNR (c.831dupC, predicted to truncate >75% of the open reading frame) in Weimaraner dogs is perfectly associated with a paroxysmal dystonia-ataxia syndrome, extending TNR loss-of-function phenotypes to movement disorders in a non-human species.","method":"Whole genome sequencing, genotyping cohort of 74 dogs (4 affected, 70 unaffected)","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 — perfect genotype-phenotype association in animal model, consistent with human TNR disease findings","pmids":["37023257"],"is_preprint":false},{"year":2024,"finding":"Contactin-1 (CNTN1), a GPI-linked receptor protein, binds the TNR-RPTPζ complex at the neuronal cell surface and is critical for perineuronal net (PNN) structure. TNR-RPTPζ complex immobilization on the neuronal surface is mediated by CNTN1, establishing a molecular mechanism for PNN nucleation on neurons.","method":"Biochemical pulldown, structural analysis, GPI-anchored protein identification, PNN structural assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical and structural approach identifying receptor; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Piccolo regulates the secretion of TNR from astrocytes via Golgi-dependent mechanisms. Loss of Piccolo (Pclo gt/gt) leads to altered TNR secretion from astrocytes, correlating with fragmented Golgi, reduced synapse density, and altered neuronal network activity. These synaptic deficits are rescued by wild-type astrocyte-conditioned media, implicating astrocyte-secreted TNR in synapse formation.","method":"RNA-seq, immunohistochemistry, immunocytochemistry, astrocyte-conditioned media experiments, electrophysiology (mEPSC, mIPSC, RRP), co-culture experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in rat model; preprint, mechanistic rescue supports TNR secretion role","pmids":[],"is_preprint":true},{"year":2025,"finding":"Knockdown of TNR in vitro enhanced the expression of dopamine receptor D2 (DRD2), and gene co-expression analysis showed a negative correlation between TNR and DRD2 expression in the hippocampus (r = -0.298, P = 0.003), suggesting TNR negatively regulates dopaminergic signaling.","method":"siRNA knockdown in vitro, Western blot, immunofluorescence, mass spectrometry proteomics, gene co-expression network analysis","journal":"Neurotoxicity research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, KD with single molecular readout, co-expression correlation as supporting evidence","pmids":["41091226"],"is_preprint":false},{"year":2025,"finding":"Glucocorticoids (hydrocortisone) rapidly suppress TNR mRNA expression at 7 days in vitro in mouse cortical neurons, but this suppression is absent at 14 and 21 DIV, indicating a developmental stage-dependent regulation. At 14 DIV, glucocorticoid receptor antagonism elevated TNR protein levels without changing mRNA, suggesting post-transcriptional regulation.","method":"Cultured mouse cortical neurons, RT-qPCR for mRNA, protein level measurement, glucocorticoid receptor antagonist treatment","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — single lab preprint, expression-level findings with limited mechanistic follow-up","pmids":[],"is_preprint":true}],"current_model":"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that functions as a multivalent scaffolding molecule: it binds lecticans (brevican, neurocan, versican, aggrecan) via protein-protein interactions with its fibronectin type III domains 3-5, interacts with neural cell adhesion molecules (F3/11, neurofascin) through its EGF-like and FG domains to modulate neurite outgrowth and cell adhesion, and via its HNK-1 carbohydrate epitope regulates perisomatic GABAergic transmission through GABAB receptors, thereby setting the metaplastic threshold for LTP induction in the hippocampus; TNR also forms a complex with RPTPζ that is anchored to the neuronal surface by contactin-1 to nucleate perineuronal nets, and biallelic loss-of-function variants in humans and dogs cause nonprogressive neurodevelopmental/movement disorders characterized by spasticity, hypotonia, and paroxysmal dyskinesia."},"narrative":{"teleology":[{"year":1996,"claim":"Systematic domain dissection resolved how TNR's multidomain architecture maps to distinct neuronal functions — the FG domain mediates adhesion and polarization, EGF-like repeats bind the receptor F3/contactin and inhibit neurite outgrowth, and FN III repeats repel neurites — establishing TNR as a multivalent modulator rather than a simple adhesion molecule.","evidence":"Recombinant domain fragment adhesion and neurite outgrowth assays on hippocampal neurons","pmids":["9081628","8626505"],"confidence":"High","gaps":["Downstream signaling pathways initiated by each domain were not identified","Identity of multiple neuronal receptors beyond F3/11 was unresolved"]},{"year":1997,"claim":"Identification of lecticans as the principal proteoglycan partners of TNR established the molecular basis for ECM network assembly: the C-type lectin domains of brevican, neurocan, versican, and aggrecan bind TNR FN III domains 3–5 via protein–protein interactions, with brevican showing 10-fold higher affinity.","evidence":"Surface plasmon resonance, solid-phase binding, and co-precipitation from rat brain","pmids":["9294172","9507007"],"confidence":"High","gaps":["Stoichiometry of TNR–lectican complexes in vivo was not determined","Structural basis of the differential lectin-domain affinities was unknown"]},{"year":1998,"claim":"Demonstration that TNR redirects neurofascin-mediated adhesion from NrCAM-dependent to axonin-1/F11-dependent receptor usage revealed TNR as an active modulator of cell-surface receptor switching rather than a passive ECM scaffold.","evidence":"Cellular binding and neurite outgrowth assays with neurofascin splice isoforms and TNR","pmids":["9722619"],"confidence":"High","gaps":["Physiological consequence of receptor switching in vivo was not tested","Which neurofascin splice isoforms predominate in PNN-containing brain regions remained unknown"]},{"year":2007,"claim":"Electrophysiology in TNR-knockout mice answered whether TNR's ECM role translates to synaptic function: loss of TNR reduces perisomatic GABAergic inhibition, increases Ca²⁺ influx and phosphatase activity, and raises the LTP threshold — all rescued by an HNK-1 glycomimetic, pinpointing the HNK-1 epitope as the active moiety acting through GABA_B receptors.","evidence":"Patch-clamp recordings in hippocampal slices from TNR−/− mice with pharmacological and glycomimetic rescue","pmids":["17537973"],"confidence":"High","gaps":["Direct binding of HNK-1 to GABA_B receptor was not demonstrated biochemically","Behavioral consequences of the metaplastic shift were not reported"]},{"year":2012,"claim":"Anti-TNR antibody treatment after spinal cord hemisection reduced RhoA activation and improved functional recovery, establishing TNR as a growth-inhibitory ECM component that actively impedes axonal regeneration through Rho signaling.","evidence":"In vitro neurite outgrowth on TNR substrate and in vivo rat spinal cord injury model with antibody administration","pmids":["22902990"],"confidence":"Medium","gaps":["The receptor transducing TNR's inhibitory signal to RhoA was not identified","Single-lab study; independent replication in a second injury model was lacking"]},{"year":2020,"claim":"Exome sequencing in 13 individuals from 8 families demonstrated that biallelic TNR loss-of-function causes a nonprogressive neurodevelopmental disorder with spastic paresis and axial hypotonia, establishing TNR as essential for normal human CNS development.","evidence":"Exome sequencing, matchmaker exchange, clinical phenotyping across 8 unrelated families","pmids":["32099069"],"confidence":"Medium","gaps":["No functional assays (e.g., patient-derived neurons, protein rescue) validated pathogenicity of specific variants","Mechanism linking TNR loss to spasticity versus PNN disruption was inferred, not demonstrated"]},{"year":2023,"claim":"A truncating TNR frameshift in Weimaraner dogs causing paroxysmal dystonia-ataxia extended the genotype–phenotype relationship across species, strengthening the causal link between TNR deficiency and movement disorders.","evidence":"Whole genome sequencing and genotype–phenotype association in a cohort of 74 dogs","pmids":["37023257"],"confidence":"Medium","gaps":["No histopathological or PNN analysis in affected dog CNS tissue was reported","Whether canine phenotype maps to the same circuit (perisomatic inhibition) as the mouse KO was untested"]},{"year":2024,"claim":"Identification of contactin-1 (CNTN1) as the GPI-anchored receptor that immobilizes the TNR–RPTPζ complex on the neuronal surface provided a molecular mechanism for PNN nucleation on specific neuronal subtypes (preprint).","evidence":"Biochemical pulldown and structural analysis of TNR–RPTPζ–CNTN1 complex (preprint)","pmids":[],"confidence":"Medium","gaps":["Awaits peer review and independent replication","Whether CNTN1 loss phenocopies TNR loss with respect to PNN disruption was not shown in vivo","Stoichiometry and structural details of the tripartite complex remain to be resolved at high resolution"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structural basis of TNR–lectican and TNR–RPTPζ interactions, the identity of the neuronal receptor that transduces TNR's growth-inhibitory signal to RhoA, and whether the HNK-1 epitope directly binds GABA_B receptors or acts through an intermediary.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of any TNR complex exists","Direct biochemical evidence for HNK-1–GABA_B receptor binding is absent","The receptor mediating TNR-dependent RhoA activation is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,1,7,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,10]}],"complexes":["TNR–RPTPζ–CNTN1 perineuronal net nucleation complex"],"partners":["BCAN","NCAN","VCAN","ACAN","CNTN1","PTPRZ1","NFASC","CNTN2"],"other_free_text":[]},"mechanistic_narrative":"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that functions as a multivalent scaffolding molecule organizing perineuronal nets and modulating neuronal adhesion, neurite outgrowth, and synaptic plasticity. Its fibronectin type III domains 3–5 bind the C-type lectin domains of lecticans (brevican, neurocan, versican, aggrecan) with nanomolar affinity through protein–protein interactions, while its EGF-like repeats engage the neuronal receptor F3/contactin and its fibrinogen-like domain mediates cell adhesion and neuronal polarization [PMID:9294172, PMID:9507007, PMID:9081628]. TNR carries the HNK-1 carbohydrate epitope, which regulates perisomatic GABAergic inhibition via GABA_B receptors and thereby sets the metaplastic threshold for hippocampal LTP [PMID:17537973]. Biallelic loss-of-function variants in TNR cause an autosomal recessive nonprogressive neurodevelopmental disorder with spastic paresis, axial hypotonia, and movement abnormalities in humans and dogs [PMID:32099069, PMID:37023257]."},"prefetch_data":{"uniprot":{"accession":"Q92752","full_name":"Tenascin-R","aliases":["Janusin","Restrictin"],"length_aa":1358,"mass_kda":149.6,"function":"Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components. These interactions can influence cellular behavior by either evoking a stable adhesion and differentiation, or repulsion and inhibition of neurite growth. Binding to cell surface gangliosides inhibits RGD-dependent integrin-mediated cell adhesion and results in an inhibition of PTK2/FAK1 (FAK) phosphorylation and cell detachment. Binding to membrane surface sulfatides results in a oligodendrocyte adhesion and differentiation. Interaction with CNTN1 induces a repulsion of neurons and an inhibition of neurite outgrowth. Interacts with SCN2B may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier. TNR-linked chondroitin sulfate glycosaminoglycans are involved in the interaction with FN1 and mediate inhibition of cell adhesion and neurite outgrowth. The highly regulated addition of sulfated carbohydrate structure may modulate the adhesive properties of TNR over the course of development and during synapse maintenance (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q92752/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNR","total_profiled":1310},"omim":[{"mim_id":"619653","title":"NEURODEVELOPMENTAL DISORDER, NONPROGRESSIVE, WITH SPASTICITY AND TRANSIENT OPISTHOTONUS; NEDSTO","url":"https://www.omim.org/entry/619653"},{"mim_id":"608751","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8; CMH8","url":"https://www.omim.org/entry/608751"},{"mim_id":"602272","title":"TRANSCRIPTION FACTOR 4; TCF4","url":"https://www.omim.org/entry/602272"},{"mim_id":"601995","title":"TENASCIN R; TNR","url":"https://www.omim.org/entry/601995"},{"mim_id":"600985","title":"TENASCIN XB; TNXB","url":"https://www.omim.org/entry/600985"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":38.9},{"tissue":"retina","ntpm":15.1}],"url":"https://www.proteinatlas.org/search/TNR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92752","domains":[{"cath_id":"-","chopping":"175-203","consensus_level":"medium","plddt":72.3883,"start":175,"end":203},{"cath_id":"2.60.40.10","chopping":"328-414","consensus_level":"high","plddt":87.8068,"start":328,"end":414},{"cath_id":"2.60.40.10","chopping":"420-485_496-502","consensus_level":"high","plddt":88.0926,"start":420,"end":502},{"cath_id":"2.60.40.10","chopping":"509-592","consensus_level":"high","plddt":84.8996,"start":509,"end":592},{"cath_id":"2.60.40.10","chopping":"599-684","consensus_level":"high","plddt":87.6744,"start":599,"end":684},{"cath_id":"2.60.40.10","chopping":"691-773","consensus_level":"medium","plddt":84.2257,"start":691,"end":773},{"cath_id":"2.60.40.10","chopping":"782-862","consensus_level":"high","plddt":82.8964,"start":782,"end":862},{"cath_id":"2.60.40.10","chopping":"958-1039","consensus_level":"medium","plddt":86.5957,"start":958,"end":1039},{"cath_id":"2.60.40.10","chopping":"1049-1128","consensus_level":"medium","plddt":83.8233,"start":1049,"end":1128},{"cath_id":"3.90.215.10","chopping":"1139-1355","consensus_level":"high","plddt":90.1522,"start":1139,"end":1355}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92752","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92752-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92752-F1-predicted_aligned_error_v6.png","plddt_mean":78.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNR","jax_strain_url":"https://www.jax.org/strain/search?query=TNR"},"sequence":{"accession":"Q92752","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92752.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92752/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92752"}},"corpus_meta":[{"pmid":"21507193","id":"PMC_21507193","title":"Development 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loss-of-function confirmed by homozygous null and missense alleles\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in multiple families with defined phenotype, but no direct biochemical reconstitution\",\n      \"pmids\": [\"32099069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tenascin-R (TN-R) inhibits axonal regeneration after spinal cord injury; antagonism of TN-R with a polyclonal antibody decreased RhoA activation at lesion sites and promoted functional recovery from corticospinal tract transection in rats, and promoted neurite outgrowth on inhibitory TN-R substrate in vitro.\",\n      \"method\": \"In vitro neurite outgrowth assay on TN-R substrate; in vivo passive immunization in rat spinal cord dorsal hemisection model with RhoA activation assay and functional behavioral readout\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with defined molecular readout (RhoA activation), single lab\",\n      \"pmids\": [\"22902990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of TNR (Tenascin-R) in vitro enhanced expression of dopamine receptor D2 (DRD2), revealing a negative regulatory relationship between TNR and DRD2 expression in the hippocampus, with TNR protein overexpressed in high novelty-response mice.\",\n      \"method\": \"siRNA knockdown in vitro with Western blot; proteomics (mass spectrometry) and immunofluorescence in mouse hippocampus; gene co-expression analysis in BXD strains\",\n      \"journal\": \"Neurotoxicity research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method for the mechanistic link (KD + Western blot), no pathway epistasis or rescue\",\n      \"pmids\": [\"41091226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A TNR frameshift variant (c.831dupC) predicted to truncate >75% of the open reading frame is associated with an exercise-induced paroxysmal dystonia-ataxia syndrome in Weimaraner dogs, extending the range of movement disorders caused by TNR loss of function.\",\n      \"method\": \"Whole genome sequencing; genotype-phenotype association in 4 affected and 70 unaffected Weimaraners\",\n      \"journal\": \"Movement disorders : official journal of the Movement Disorder Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic association in a canine model with perfect genotype-phenotype segregation, no biochemical mechanism demonstrated\",\n      \"pmids\": [\"37023257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tenascin-R (Tnr) forms a complex with receptor protein tyrosine phosphatase zeta (RPTPζ) within perineuronal nets (PNNs); this complex is anchored to the neuronal cell surface by the GPI-linked protein contactin-1 (Cntn1), and Cntn1 binding is critical for PNN structure.\",\n      \"method\": \"Biochemical pulldown and structural analysis identifying contactin-1 as the GPI-linked receptor for the Tnr-RPTPζ complex; functional validation of PNN structure disruption upon loss of Cntn1\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical and structural approach with functional validation of PNN structure, single preprint lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Piccolo, an astrocyte-expressed scaffolding protein, regulates secretion of Tenascin-R (TNR) from astrocytes; loss of Piccolo leads to altered TNR secretion, correlating with fragmented Golgi in astrocytes and impaired synaptogenesis in neuronal networks.\",\n      \"method\": \"Immunohistochemistry and immunocytochemistry in Pclo gt/gt rat model; astrocyte-conditioned media experiments; RNA-seq; synapse density and electrophysiology assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, indirect evidence for TNR secretion mechanism via Piccolo\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glucocorticoids (hydrocortisone) rapidly suppress Tenascin-R expression at the mRNA level in cultured mouse cortical neurons at 7 DIV via a mechanism that can be independent of glucocorticoid receptor at later developmental stages; at 14 DIV, glucocorticoid receptor antagonism elevates TnR protein levels, suggesting post-transcriptional or proteasomal regulation of TnR.\",\n      \"method\": \"In vitro glucocorticoid treatment of mouse cortical neurons at multiple developmental timepoints; qRT-PCR for mRNA; protein level measurement; glucocorticoid receptor inhibition experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, in vitro only, mechanism not fully resolved\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mice with conditional PV-interneuron-specific deletion of DNMT1, cell-cell interaction analyses revealed disrupted TNR-integrin signaling, consistent with weakened perisomatic adhesion and perineuronal net integrity, linking TNR's extracellular function to integrin-mediated adhesion at interneuron surfaces.\",\n      \"method\": \"Single-cell RNA-seq cell-cell interaction analysis; conditional knockout mouse model; in vivo electrophysiology and histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, indirect inference from transcriptomic interaction analysis, no direct biochemical demonstration of TNR-integrin binding\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that forms perineuronal nets ensheathing interneurons by complexing with RPTPζ and anchoring to the neuronal surface via contactin-1; it inhibits axonal regeneration partly through RhoA activation, is secreted from astrocytes in a Piccolo-dependent manner, negatively regulates DRD2 expression, and its loss-of-function causes autosomal recessive neurodevelopmental disorders with spasticity and movement abnormalities.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The C-type lectin domains of lecticans (aggrecan, versican, neurocan, brevican) bind tenascin-R through protein-protein interactions with the fibronectin type III domains 3-5 of TNR, independent of carbohydrate moieties or sulfated amino acids. Brevican lectin domain has at least 10-fold higher affinity for TNR than other lectican lectins. TNR and brevican form complexes in vivo as shown by co-precipitation from adult rat brain extracts.\",\n      \"method\": \"Surface plasmon resonance, solid-phase binding assays, co-precipitation from brain extracts, recombinant domain mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with SPR quantification, domain mapping, and in vivo co-precipitation validation\",\n      \"pmids\": [\"9294172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Neurocan and phosphacan (chondroitin sulfate proteoglycans) bind tenascin-R with high affinity (Kd 2–7 nM) via their core glycoproteins rather than glycosaminoglycan chains; binding is largely calcium-independent, in contrast to their binding to tenascin-C. Chondroitinase treatment increases binding by ~60%, indicating GAG chains partially shield the binding sites.\",\n      \"method\": \"Radioligand binding assay, chondroitinase treatment, calcium chelation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro binding assay with multiple orthogonal controls (enzymatic, ionic)\",\n      \"pmids\": [\"9507007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Neurofascin binds tenascin-R, and TNR shifts neurofascin-mediated cell attachment from NrCAM-dependent to axonin-1/F11-dependent receptor usage. Isoforms of neurofascin generated by alternative splicing show differential binding to TNR, regulated by alternatively spliced stretches in the NH2-terminal half and the PAT-rich segment. F11 binds TNR within the neurofascin/TNR complex, while axonin-1 cannot bind the complex directly.\",\n      \"method\": \"Cellular binding assays, neurite outgrowth assays on neurofascin-Fc substrates, competition binding assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding and functional assays with domain-level resolution\",\n      \"pmids\": [\"9722619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Distinct domains of TNR confer different neuronal functions: the fibrinogen knob (FG) domain mediates best short-term adhesion and hippocampal neuron polarization; EGF-like domains (EGF-L) prevent neurite outgrowth and contain the binding site for the neuronal receptor F3/11 (contactin); fibronectin type III repeats FN1-2 and FN3-5 are repellent for neurites and growth cones. Multiple TNR receptors exist on neurons.\",\n      \"method\": \"Short-term adhesion assays, neurite outgrowth assays with recombinant TNR domain fragments, receptor binding localization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic domain dissection with multiple functional readouts using recombinant protein fragments\",\n      \"pmids\": [\"9081628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human TNR is encoded by a gene on chromosome 1q23-q24 and undergoes pre-mRNA alternative splicing in astrocytomas and meningiomas, producing an isoform lacking one fibronectin-like repeat. The deduced amino acid sequence (1358 aa) shows 93% homology to rat TNR. Two mRNA species of ~10 and ~11 kb are detected.\",\n      \"method\": \"cDNA sequencing, RT-PCR, Northern blot, somatic cell hybrid panel, FISH\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete primary structure determination with chromosomal localization and splicing characterization\",\n      \"pmids\": [\"8626505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TNR N-glycosylation is dominated by neutral complex biantennary 'brain-type' N-glycans with outer-arm and core fucosylation, bisecting GlcNAc, and extensive antennae truncation. O-glycans are abundant and dominated by disialylated structures (NeuAcα2-3Galβ1-3(NeuAcα2-6)GalNAc), suggesting potential interactions with myelin-associated glycoprotein or sialoadhesin on activated microglia.\",\n      \"method\": \"Glycan mass spectrometry analysis of purified TNR\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — detailed structural glycan characterization; functional implications proposed but not directly tested\",\n      \"pmids\": [\"10406848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The lectin domains of aggrecan and versican bind fibulin-2 at the same site on the proteoglycan lectin domains as tenascin-R (demonstrated by solid-phase competition assays), indicating that fibulin-2 and TNR compete for the same binding site on lectican C-type lectin domains.\",\n      \"method\": \"Solid-phase competition assays, surface plasmon resonance, electron microscopy, affinity chromatography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — competitive binding mapped by SPR and solid-phase assay, but TNR's role is as a comparator ligand rather than primary subject\",\n      \"pmids\": [\"11038354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TNR deficiency in mice leads to metaplastic increase in the threshold for LTP induction at CA3-CA1 synapses, caused by reduced perisomatic GABAergic inhibition. This operates via a chain: reduced GABAergic transmission → increased Ca2+ entry → elevated phosphatase activity. Reconstitution with an HNK-1 glycomimetic, or pharmacological treatment with GABAA receptor agonist, GABAB receptor antagonist, L-type Ca2+ channel blocker, or phosphatase inhibitor restored LTP. The HNK-1 carbohydrate on TNR mediates regulation of GABAergic transmission via GABAB receptors.\",\n      \"method\": \"Patch-clamp recordings in hippocampal slices from TNR-deficient mice, pharmacological rescue experiments, HNK-1 glycomimetic reconstitution\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined electrophysiological phenotype, multiple pharmacological rescues, and reconstitution with specific molecular epitope\",\n      \"pmids\": [\"17537973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Passive immunization with TNR polyclonal antibody (acting as a TNR antagonist) promoted neurite outgrowth and sprouting of rat cortical neurons cultured on inhibitory TNR substrate in vitro, and when administered locally after spinal cord dorsal hemisection in rats, significantly decreased RhoA activation and improved functional recovery from corticospinal tract transection.\",\n      \"method\": \"In vitro neurite outgrowth assay on TNR substrate, in vivo spinal cord injury model with antibody administration, RhoA activation assay, functional behavioral assessment\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro and in vivo experiments with molecular readout (RhoA activation), single lab\",\n      \"pmids\": [\"22902990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic loss-of-function variants in TNR (homozygous loss-of-function and missense variants) cause an autosomal recessive nonprogressive neurodevelopmental disorder with spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus in 13 individuals from 8 families, establishing TNR as essential for human CNS function, consistent with its role in perineuronal net formation around interneurons.\",\n      \"method\": \"Exome sequencing, matchmaking tool, clinical phenotyping of human patients with biallelic TNR variants\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with multiple independent families; mechanism inferred from known TNR biology rather than direct functional assay in patients\",\n      \"pmids\": [\"32099069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A frameshift variant in TNR (c.831dupC, predicted to truncate >75% of the open reading frame) in Weimaraner dogs is perfectly associated with a paroxysmal dystonia-ataxia syndrome, extending TNR loss-of-function phenotypes to movement disorders in a non-human species.\",\n      \"method\": \"Whole genome sequencing, genotyping cohort of 74 dogs (4 affected, 70 unaffected)\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — perfect genotype-phenotype association in animal model, consistent with human TNR disease findings\",\n      \"pmids\": [\"37023257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Contactin-1 (CNTN1), a GPI-linked receptor protein, binds the TNR-RPTPζ complex at the neuronal cell surface and is critical for perineuronal net (PNN) structure. TNR-RPTPζ complex immobilization on the neuronal surface is mediated by CNTN1, establishing a molecular mechanism for PNN nucleation on neurons.\",\n      \"method\": \"Biochemical pulldown, structural analysis, GPI-anchored protein identification, PNN structural assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical and structural approach identifying receptor; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Piccolo regulates the secretion of TNR from astrocytes via Golgi-dependent mechanisms. Loss of Piccolo (Pclo gt/gt) leads to altered TNR secretion from astrocytes, correlating with fragmented Golgi, reduced synapse density, and altered neuronal network activity. These synaptic deficits are rescued by wild-type astrocyte-conditioned media, implicating astrocyte-secreted TNR in synapse formation.\",\n      \"method\": \"RNA-seq, immunohistochemistry, immunocytochemistry, astrocyte-conditioned media experiments, electrophysiology (mEPSC, mIPSC, RRP), co-culture experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in rat model; preprint, mechanistic rescue supports TNR secretion role\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of TNR in vitro enhanced the expression of dopamine receptor D2 (DRD2), and gene co-expression analysis showed a negative correlation between TNR and DRD2 expression in the hippocampus (r = -0.298, P = 0.003), suggesting TNR negatively regulates dopaminergic signaling.\",\n      \"method\": \"siRNA knockdown in vitro, Western blot, immunofluorescence, mass spectrometry proteomics, gene co-expression network analysis\",\n      \"journal\": \"Neurotoxicity research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with single molecular readout, co-expression correlation as supporting evidence\",\n      \"pmids\": [\"41091226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glucocorticoids (hydrocortisone) rapidly suppress TNR mRNA expression at 7 days in vitro in mouse cortical neurons, but this suppression is absent at 14 and 21 DIV, indicating a developmental stage-dependent regulation. At 14 DIV, glucocorticoid receptor antagonism elevated TNR protein levels without changing mRNA, suggesting post-transcriptional regulation.\",\n      \"method\": \"Cultured mouse cortical neurons, RT-qPCR for mRNA, protein level measurement, glucocorticoid receptor antagonist treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab preprint, expression-level findings with limited mechanistic follow-up\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that functions as a multivalent scaffolding molecule: it binds lecticans (brevican, neurocan, versican, aggrecan) via protein-protein interactions with its fibronectin type III domains 3-5, interacts with neural cell adhesion molecules (F3/11, neurofascin) through its EGF-like and FG domains to modulate neurite outgrowth and cell adhesion, and via its HNK-1 carbohydrate epitope regulates perisomatic GABAergic transmission through GABAB receptors, thereby setting the metaplastic threshold for LTP induction in the hippocampus; TNR also forms a complex with RPTPζ that is anchored to the neuronal surface by contactin-1 to nucleate perineuronal nets, and biallelic loss-of-function variants in humans and dogs cause nonprogressive neurodevelopmental/movement disorders characterized by spasticity, hypotonia, and paroxysmal dyskinesia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein essential for the formation and structural integrity of perineuronal nets (PNNs) that ensheath interneurons, and for normal neurodevelopment and motor function. TNR forms a complex with receptor protein tyrosine phosphatase ζ (RPTPζ) that is anchored to the neuronal surface via the GPI-linked protein contactin-1, and this interaction is critical for PNN architecture [PMID:32099069]. TNR acts as an inhibitor of axonal regeneration after spinal cord injury, at least partly through activation of RhoA signaling at lesion sites [PMID:22902990]. Biallelic loss-of-function variants in TNR cause an autosomal recessive nonprogressive neurodevelopmental disorder characterized by spasticity and transient opisthotonus [PMID:32099069].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"The question of whether TNR actively inhibits axonal regeneration and through what intracellular pathway was answered: antibody-mediated antagonism of TNR reduced RhoA activation at spinal lesion sites and promoted functional recovery, establishing TNR as a regeneration-inhibitory ECM molecule that signals through RhoA.\",\n      \"evidence\": \"In vitro neurite outgrowth on TNR substrate and in vivo passive immunization in rat spinal cord dorsal hemisection model with RhoA activity assay\",\n      \"pmids\": [\"22902990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The receptor through which TNR activates RhoA on regenerating axons is unidentified\",\n        \"No genetic loss-of-function confirmation in vivo for the regeneration phenotype\",\n        \"Single lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The question of whether TNR is essential for human CNS development was resolved: biallelic loss-of-function variants in multiple families caused a nonprogressive neurodevelopmental disorder with spasticity, establishing TNR as a disease gene and linking its function to perineuronal net integrity in humans.\",\n      \"evidence\": \"Exome sequencing identifying biallelic variants in 13 individuals from 8 unrelated families with consistent neurological phenotype\",\n      \"pmids\": [\"32099069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical reconstitution showing how specific variants disrupt TNR protein function\",\n        \"Perineuronal net disruption inferred from mouse models rather than directly demonstrated in patient tissue\",\n        \"Genotype-phenotype correlation across variant classes not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The phenotypic spectrum of TNR loss of function was extended to paroxysmal movement disorders: a frameshift variant truncating >75% of the TNR open reading frame segregated with exercise-induced dystonia-ataxia in dogs, broadening the motor phenotype beyond spasticity.\",\n      \"evidence\": \"Whole genome sequencing with genotype-phenotype association in Weimaraner dogs\",\n      \"pmids\": [\"37023257\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-breed genetic association without functional confirmation of variant pathogenicity\",\n        \"No demonstration of PNN disruption or molecular mechanism in affected animals\",\n        \"Cross-species relevance to human paroxysmal dystonia not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The molecular basis of TNR anchorage within PNNs was elucidated: TNR forms a complex with RPTPζ that is tethered to the neuronal surface by the GPI-linked protein contactin-1, and loss of contactin-1 disrupts PNN structure, identifying the receptor mechanism for PNN assembly.\",\n      \"evidence\": \"Biochemical pulldown and structural analysis with functional validation of PNN disruption upon Cntn1 loss (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint awaiting peer review\",\n        \"Stoichiometry and binding affinity of the ternary complex not quantified\",\n        \"Whether contactin-1 mediates all or only a subset of TNR's PNN functions is unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TNR was shown to negatively regulate dopamine receptor D2 (DRD2) expression: siRNA-mediated TNR knockdown elevated DRD2 protein levels, linking TNR to dopaminergic signaling modulation in the hippocampus.\",\n      \"evidence\": \"siRNA knockdown in vitro with Western blot; proteomics and immunofluorescence in mouse hippocampus\",\n      \"pmids\": [\"41091226\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method (knockdown + Western blot) without rescue or epistasis experiment\",\n        \"Mechanism by which an extracellular matrix protein regulates receptor expression is unknown\",\n        \"In vivo functional consequence of TNR-DRD2 relationship not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) the identity of the neuronal receptor(s) through which TNR activates RhoA to inhibit axonal regeneration, (2) how TNR loss disrupts PNN formation in human patients, and (3) whether TNR-integrin interactions contribute to PNN adhesion at interneuron surfaces.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of full-length TNR or its receptor complexes\",\n        \"Direct TNR-integrin binding has not been biochemically demonstrated\",\n        \"Signaling pathways downstream of the TNR-RPTPζ-contactin-1 complex are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"TNR-RPTPζ-contactin-1 PNN complex\"\n    ],\n    \"partners\": [\n      \"PTPRZ1\",\n      \"CNTN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Tenascin-R (TNR) is a CNS-specific extracellular matrix glycoprotein that functions as a multivalent scaffolding molecule organizing perineuronal nets and modulating neuronal adhesion, neurite outgrowth, and synaptic plasticity. Its fibronectin type III domains 3–5 bind the C-type lectin domains of lecticans (brevican, neurocan, versican, aggrecan) with nanomolar affinity through protein–protein interactions, while its EGF-like repeats engage the neuronal receptor F3/contactin and its fibrinogen-like domain mediates cell adhesion and neuronal polarization [PMID:9294172, PMID:9507007, PMID:9081628]. TNR carries the HNK-1 carbohydrate epitope, which regulates perisomatic GABAergic inhibition via GABA_B receptors and thereby sets the metaplastic threshold for hippocampal LTP [PMID:17537973]. Biallelic loss-of-function variants in TNR cause an autosomal recessive nonprogressive neurodevelopmental disorder with spastic paresis, axial hypotonia, and movement abnormalities in humans and dogs [PMID:32099069, PMID:37023257].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Systematic domain dissection resolved how TNR's multidomain architecture maps to distinct neuronal functions — the FG domain mediates adhesion and polarization, EGF-like repeats bind the receptor F3/contactin and inhibit neurite outgrowth, and FN III repeats repel neurites — establishing TNR as a multivalent modulator rather than a simple adhesion molecule.\",\n      \"evidence\": \"Recombinant domain fragment adhesion and neurite outgrowth assays on hippocampal neurons\",\n      \"pmids\": [\"9081628\", \"8626505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream signaling pathways initiated by each domain were not identified\",\n        \"Identity of multiple neuronal receptors beyond F3/11 was unresolved\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of lecticans as the principal proteoglycan partners of TNR established the molecular basis for ECM network assembly: the C-type lectin domains of brevican, neurocan, versican, and aggrecan bind TNR FN III domains 3–5 via protein–protein interactions, with brevican showing 10-fold higher affinity.\",\n      \"evidence\": \"Surface plasmon resonance, solid-phase binding, and co-precipitation from rat brain\",\n      \"pmids\": [\"9294172\", \"9507007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry of TNR–lectican complexes in vivo was not determined\",\n        \"Structural basis of the differential lectin-domain affinities was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that TNR redirects neurofascin-mediated adhesion from NrCAM-dependent to axonin-1/F11-dependent receptor usage revealed TNR as an active modulator of cell-surface receptor switching rather than a passive ECM scaffold.\",\n      \"evidence\": \"Cellular binding and neurite outgrowth assays with neurofascin splice isoforms and TNR\",\n      \"pmids\": [\"9722619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological consequence of receptor switching in vivo was not tested\",\n        \"Which neurofascin splice isoforms predominate in PNN-containing brain regions remained unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Electrophysiology in TNR-knockout mice answered whether TNR's ECM role translates to synaptic function: loss of TNR reduces perisomatic GABAergic inhibition, increases Ca²⁺ influx and phosphatase activity, and raises the LTP threshold — all rescued by an HNK-1 glycomimetic, pinpointing the HNK-1 epitope as the active moiety acting through GABA_B receptors.\",\n      \"evidence\": \"Patch-clamp recordings in hippocampal slices from TNR−/− mice with pharmacological and glycomimetic rescue\",\n      \"pmids\": [\"17537973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding of HNK-1 to GABA_B receptor was not demonstrated biochemically\",\n        \"Behavioral consequences of the metaplastic shift were not reported\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Anti-TNR antibody treatment after spinal cord hemisection reduced RhoA activation and improved functional recovery, establishing TNR as a growth-inhibitory ECM component that actively impedes axonal regeneration through Rho signaling.\",\n      \"evidence\": \"In vitro neurite outgrowth on TNR substrate and in vivo rat spinal cord injury model with antibody administration\",\n      \"pmids\": [\"22902990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The receptor transducing TNR's inhibitory signal to RhoA was not identified\",\n        \"Single-lab study; independent replication in a second injury model was lacking\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Exome sequencing in 13 individuals from 8 families demonstrated that biallelic TNR loss-of-function causes a nonprogressive neurodevelopmental disorder with spastic paresis and axial hypotonia, establishing TNR as essential for normal human CNS development.\",\n      \"evidence\": \"Exome sequencing, matchmaker exchange, clinical phenotyping across 8 unrelated families\",\n      \"pmids\": [\"32099069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assays (e.g., patient-derived neurons, protein rescue) validated pathogenicity of specific variants\",\n        \"Mechanism linking TNR loss to spasticity versus PNN disruption was inferred, not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A truncating TNR frameshift in Weimaraner dogs causing paroxysmal dystonia-ataxia extended the genotype–phenotype relationship across species, strengthening the causal link between TNR deficiency and movement disorders.\",\n      \"evidence\": \"Whole genome sequencing and genotype–phenotype association in a cohort of 74 dogs\",\n      \"pmids\": [\"37023257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No histopathological or PNN analysis in affected dog CNS tissue was reported\",\n        \"Whether canine phenotype maps to the same circuit (perisomatic inhibition) as the mouse KO was untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of contactin-1 (CNTN1) as the GPI-anchored receptor that immobilizes the TNR–RPTPζ complex on the neuronal surface provided a molecular mechanism for PNN nucleation on specific neuronal subtypes (preprint).\",\n      \"evidence\": \"Biochemical pulldown and structural analysis of TNR–RPTPζ–CNTN1 complex (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Awaits peer review and independent replication\",\n        \"Whether CNTN1 loss phenocopies TNR loss with respect to PNN disruption was not shown in vivo\",\n        \"Stoichiometry and structural details of the tripartite complex remain to be resolved at high resolution\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structural basis of TNR–lectican and TNR–RPTPζ interactions, the identity of the neuronal receptor that transduces TNR's growth-inhibitory signal to RhoA, and whether the HNK-1 epitope directly binds GABA_B receptors or acts through an intermediary.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of any TNR complex exists\",\n        \"Direct biochemical evidence for HNK-1–GABA_B receptor binding is absent\",\n        \"The receptor mediating TNR-dependent RhoA activation is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 1, 7, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"TNR–RPTPζ–CNTN1 perineuronal net nucleation complex\"\n    ],\n    \"partners\": [\n      \"BCAN\",\n      \"NCAN\",\n      \"VCAN\",\n      \"ACAN\",\n      \"CNTN1\",\n      \"PTPRZ1\",\n      \"NFASC\",\n      \"CNTN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}