{"gene":"LINGO1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"LINGO-1 is a component of the NgR1/p75 signaling complex: it binds both NgR1 and p75, and coexpression of NgR1, p75, and LINGO-1 in non-neuronal cells confers responsiveness to oligodendrocyte myelin glycoprotein (OMgp) as measured by RhoA activation. A dominant-negative LINGO-1 construct attenuated myelin inhibition in primary neuronal cultures.","method":"Co-immunoprecipitation/binding assays, RhoA activation assay in reconstituted non-neuronal cells, dominant-negative construct in primary neuronal cultures","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in non-neuronal cells with defined functional readout (RhoA activation), dominant-negative validation in primary neurons, foundational paper replicated by multiple subsequent studies","pmids":["14966521"],"is_preprint":false},{"year":2005,"finding":"LINGO-1 is expressed in oligodendrocytes and negatively regulates oligodendrocyte differentiation and myelination. Attenuation of LINGO-1 (dominant-negative, RNAi, or LINGO-1-Fc) leads to downregulation of RhoA activity and promotes differentiation and myelination; conversely, overexpression activates RhoA and inhibits differentiation. LINGO-1 knockout mice show increased myelination in vivo.","method":"Dominant-negative construct, RNAi knockdown, soluble LINGO-1-Fc fusion protein, RhoA activity assay, oligodendrocyte–neuron coculture myelination assay, LINGO-1 knockout mice","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal loss-of-function approaches (DN, RNAi, KO mice), RhoA mechanistic readout, and in vivo validation","pmids":["15895088"],"is_preprint":false},{"year":2006,"finding":"The crystal structure of the LINGO-1 ectodomain reveals a bimodular, kinked LRR–Ig fold. In crystals and in solution, LINGO-1 forms a stable ring-shaped tetramer in which each LRR domain fills an open cleft in an adjacent protomer, burying ~9,200 Ų of surface area; this self-assembly may scaffold simultaneous binding of NgR complex components.","method":"X-ray crystallography, biophysical solution analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biophysical solution validation; foundational structural paper","pmids":["17005555"],"is_preprint":false},{"year":2006,"finding":"LINGO-1-Fc (soluble antagonist that blocks LINGO-1 binding to NgR1) administered after spinal cord hemisection in rats significantly decreased RhoA activation, increased neuronal and oligodendrocyte survival, promoted axonal sprouting, and improved functional recovery.","method":"In vivo spinal cord injury model in rats, RhoA activation assay, immunohistochemistry, behavioral assessment","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO/antagonist with defined RhoA mechanistic readout, single lab","pmids":["17011208"],"is_preprint":false},{"year":2007,"finding":"Axonal LINGO-1 expression, regulated by NGF/TrkA signaling in a dose-dependent manner, inhibits oligodendrocyte differentiation and myelination with equal potency to oligodendrocyte-expressed LINGO-1. Disruption of LINGO-1 on either cell type is sufficient to promote myelination independent of axon diameter; transgenic mice overexpressing LINGO-1 under the neuronal synapsin promoter show greatly inhibited myelination.","method":"Neuronal-promoter transgenic mice (synapsin-LINGO-1), co-culture myelination assays, NGF/TrkA dose-response experiments","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — transgenic mouse model plus in vitro coculture, multiple orthogonal methods, regulatory mechanism identified","pmids":["17202489"],"is_preprint":false},{"year":2007,"finding":"LINGO-1 inhibition protects dopaminergic (DA) neurons in Parkinson's disease models: LINGO-1 KO mice show increased DA neuron survival and reduced behavioral abnormalities after 6-OHDA or MPTP treatment, accompanied by increased Akt phosphorylation. LINGO-1 antagonists (LINGO-1-Fc, dominant-negative, anti-LINGO-1 antibody) protect DA neurons in vitro partly through direct inhibition of LINGO-1 binding to EGFR, activating the EGFR/Akt signaling pathway.","method":"LINGO-1 KO mice, MPTP/6-OHDA PD models, LINGO-1-Fc/DN/antibody antagonism, Western blot for p-Akt, EGFR binding inhibition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO mice plus in vitro mechanistic pathway dissection (EGFR/Akt), multiple orthogonal antagonist approaches","pmids":["17726113"],"is_preprint":false},{"year":2007,"finding":"Loss of LINGO-1 function (gene knockout or anti-LINGO-1 antibody) leads to functional recovery from experimental autoimmune encephalomyelitis, with improved axonal integrity (confirmed by MR diffusion tensor imaging) and newly formed myelin sheaths (confirmed by electron microscopy), demonstrating LINGO-1 as a negative regulator of remyelination in vivo.","method":"Lingo1 KO mice, anti-LINGO-1 antibody treatment in EAE model, MR diffusion tensor imaging, electron microscopy","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic and pharmacological loss-of-function approaches with multiple orthogonal outcome measures in vivo","pmids":["17906634"],"is_preprint":false},{"year":2008,"finding":"Blocking LINGO-1 function with LINGO-1-Fc or anti-LINGO-1 mAb 1A7 promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection. The neuroprotective effect is mediated by blocking the RhoA/JNK pathway and promoting Akt phosphorylation (PI3K/Akt pathway); the survival effect is abolished by Akt phosphorylation inhibition.","method":"Ocular hypertension rat model, intravitreal injection of LINGO-1-Fc and antibody, Western blot for RhoA/JNK/Akt, specific kinase inhibitors","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two orthogonal antagonists, pathway dissection with kinase inhibitors, defined cellular phenotype","pmids":["18326721"],"is_preprint":false},{"year":2009,"finding":"LINGO-1 interacts with the serine-threonine kinase WNK1, identified by yeast two-hybrid screen and validated by FRET and co-immunoprecipitation. The interaction is intensified by Nogo66 treatment. WNK1 co-localizes with LINGO-1 in cortical neurons. Suppression of WNK1 (RNAi or dominant-negative fragment) attenuates Nogo66-induced inhibition of neurite extension and inhibits RhoA activation. WNK1 interacts with Rho-GDI1 and this interaction is attenuated by Nogo66, indicating WNK1 regulates RhoA activation downstream of LINGO-1.","method":"Yeast two-hybrid, FRET, co-immunoprecipitation, RNAi knockdown, dominant-negative overexpression, RhoA activation assay, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by FRET and co-IP, functional validation with RNAi and DN construct, multiple orthogonal methods","pmids":["19363035"],"is_preprint":false},{"year":2009,"finding":"LINGO-1 surface expression requires specific N-glycosylation sites located on the concave surface of the LRR domain. Residue-screening by mutagenesis in a mammalian high-throughput system identified key asparagines sufficient to support surface expression.","method":"High-throughput mammalian transient expression, PCR-based expression cassette mutagenesis, surface expression assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mutagenesis with functional surface expression readout, single lab, single study","pmids":["19254717"],"is_preprint":false},{"year":2010,"finding":"LINGO-1 forms a receptor complex with TrkB and negatively regulates TrkB activation (phosphorylation) in the retina after ocular hypertension injury. LINGO-1 antagonists (antibody 1A7, LINGO-1-Fc) upregulate phospho-TrkB and promote RGC survival; this neuroprotective effect is blocked by anti-BDNF antibody.","method":"Co-immunoprecipitation (LINGO-1/TrkB complex), Western blot for p-TrkB, anti-BDNF antibody blockade, ocular hypertension rat model","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP complex identification with functional validation in vivo, mechanistic dissection with neutralizing antibody","pmids":["20377621"],"is_preprint":false},{"year":2011,"finding":"Gangliosides mediate the interaction between NgR1 and LINGO-1 in a cell-free system. Solid-phase binding assays show that sialic acid moieties of gangliosides and the stalk of NgR1 are the principal determinants of NgR1–LINGO-1 molecular interactions. The tripartite complex NgR1/LINGO-1/ganglioside exhibits stronger binding to Nogo-A in the presence of p75.","method":"Cell-free solid-phase binding assay, ganglioside depletion/addition experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-free reconstitution with defined molecular determinants, single lab, single method","pmids":["21872576"],"is_preprint":false},{"year":2011,"finding":"Retinoic acid (RA), acting through RAR-β, transcriptionally represses Lingo-1 expression, thereby counteracting myelin-dependent inhibition of neurite outgrowth via the NgR complex. Suppression of Lingo-1 is required for RA-RAR-β to counteract extrinsic inhibition; RA treatment in vivo after dorsal column injury inhibits Lingo-1 expression specifically through RAR-β.","method":"RAR-β gain/loss-of-function, Lingo-1 promoter reporter assay, neurite outgrowth assay, in vivo dorsal column injury model","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional mechanism identified with promoter assay and in vivo validation, multiple experimental approaches","pmids":["21690307"],"is_preprint":false},{"year":2011,"finding":"The leucine-rich repeat domain and the transmembrane/cytoplasmic domain of LINGO-1 are not required for LINGO-1 self-interaction or interaction with APP; these interactions are mediated by other regions of the ectodomain.","method":"Deletional mutagenesis, binding assays","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, deletion mutant binding assay, limited mechanistic follow-up","pmids":["22133804"],"is_preprint":false},{"year":2012,"finding":"LINGO-1 inhibits oligodendrocyte differentiation through intercellular homophilic (trans) self-interactions: soluble LINGO-1 ectodomain binds to full-length LINGO-1 on CHO cells (trans interaction), surface-bound LINGO-1 on astrocytes inhibits OPCs through intercellular signaling, and soluble LINGO-1 ectodomain activates RhoA in OPCs. LINGO-1 acts as both a ligand and a receptor.","method":"Recombinant ectodomain binding to LINGO-1-expressing CHO cells, ectopic surface-bound LINGO-1 on astrocytes in coculture, RhoA activation assay in OPCs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches establishing homophilic trans-interaction and downstream RhoA activation, single lab","pmids":["22514275"],"is_preprint":false},{"year":2013,"finding":"LINGO-1 promotes neuronal apoptosis by binding the serine-threonine kinase WNK3 via the LINGO-1 intracellular domain, reducing WNK3 kinase activity. The LINGO-1/WNK3 co-association is enhanced by Nogo66 treatment. WNK3 suppresses serum-deprivation-induced neuronal apoptosis in a kinase-dependent manner, and inhibiting WNK3 activity mimics the pro-apoptotic effect of LINGO-1 activation.","method":"Co-immunoprecipitation (LINGO-1/WNK3), WNK3 kinase activity assay in vitro, shRNA knockdown, dominant-negative WNK3, serum-deprivation apoptosis model in cortical neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP validated by co-localization, in vitro kinase assay, multiple loss-of-function tools, defined mechanistic pathway","pmids":["23482566"],"is_preprint":false},{"year":2014,"finding":"LINGO-1 directly binds ErbB2, blocks ErbB2 translocation into lipid rafts, and inhibits ErbB2 phosphorylation/activation, thereby suppressing oligodendrocyte differentiation. In LINGO-1−/− oligodendrocytes, ErbB2 activation does not further enhance differentiation, suggesting LINGO-1 is a gating mechanism for ErbB2-dependent differentiation.","method":"Co-immunoprecipitation (LINGO-1/ErbB2), lipid raft fractionation, ErbB2 phosphorylation Western blot, LINGO-1 KO oligodendrocytes, ErbB2 inhibitor/activator pharmacology","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding by co-IP, lipid raft fractionation, KO rescue experiment, multiple orthogonal approaches, single lab","pmids":["24583087"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of LINGO-1 in complex with the anti-LINGO-1 Li81 Fab reveals that Li81 binds the convex surface of the LRR domain within repeats 4–8. Fab binding blocks oligomerization contact points of LINGO-1 and produces a stable 2:2 LINGO-1/Fab complex by rearranging the quaternary structure, and masks functional epitopes in the Ig domain required for LINGO-1 biological activity in oligodendrocyte differentiation.","method":"X-ray crystallography (LINGO-1–Fab co-crystal), biochemical binding studies, oligodendrocyte differentiation functional assay","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional validation of epitope masking, multiple orthogonal methods","pmids":["24756303"],"is_preprint":false},{"year":2014,"finding":"LINGO-1 forms constitutive cis-dimers (homodimers) at the plasma membrane, demonstrated by co-immunoprecipitation and BRET saturation analysis in HEK293 and SH-SY5Y cells. Cis-dimerization occurs early during biosynthesis. A small molecule (phenoxybenzamine), identified by BRET-based screening as a conformational modulator of LINGO-1 dimers, acts as a positive modulator of LINGO-1 function, increasing LINGO-1-mediated inhibition of EGF receptor signaling and Erk phosphorylation in HEK-293 cells.","method":"Co-immunoprecipitation, BRET saturation assay, small-molecule screen, Western blot for EGF receptor signaling/Erk phosphorylation","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BRET and co-IP orthogonal methods for dimerization, functional pharmacological validation, single lab","pmids":["25257685"],"is_preprint":false},{"year":2015,"finding":"LINGO-1 is predominantly localized intracellularly in neurons (cortex and cerebellum). Mutation or truncation of the conserved LINGO-1 C-terminus alters intracellular retention, causing increased plasma membrane expression. p75NTR associates predominantly with natively expressed, intracellular LINGO-1 containing immature N-glycans (pre-trans-Golgi), whereas mutant LINGO-1 with enhanced plasma membrane expression does not associate with p75NTR. Co-immunoprecipitation shows LINGO-1 and NgR compete for binding to p75NTR, contradicting a functional plasma membrane LINGO-1/p75NTR/NgR ternary complex.","method":"Subcellular fractionation, immunofluorescence, C-terminus mutagenesis, co-immunoprecipitation, N-glycan analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation with mutagenesis, co-IP competition experiment, multiple orthogonal methods, single lab; contradicts prior model","pmids":["25666623"],"is_preprint":false},{"year":2015,"finding":"LINGO-1 promotes lysosomal degradation of TrkA, TrkB, and TrkC (Trk neurotrophin receptors) as a negative feedback mechanism: Trk activation promotes Trk association with LINGO-1, and this association drives Trk degradation via a lysosomal pathway, partly within recycling endosomes. A LINGO-1 mutant with deleted extracellular domain enhances TrkA signaling in PC12 cells, likely by acting as an inhibitor of Trk downregulation by full-length LINGO-1.","method":"Co-immunoprecipitation (Trk/LINGO-1), lysosomal inhibitor experiments, recycling endosome co-localization, LINGO-1 deletion mutant in PC12 cells","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with pharmacological dissection and deletion mutant, multiple Trk paralogs tested, single lab","pmids":["26546150"],"is_preprint":false},{"year":2015,"finding":"LINGO-1 and its paralogs (LINGO-2, LINGO-3) decrease amyloidogenic processing of amyloid precursor protein (APP) by promoting lysosomal degradation of AβPP.","method":"Cell-based APP processing assay, lysosomal pathway analysis","journal":"Pathobiology of aging & age related diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell-based assay, limited mechanistic detail in abstract","pmids":["25758563"],"is_preprint":false},{"year":2017,"finding":"LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin (cGSN) signaling pathway: anti-LINGO-1 antibody-promoted OPC differentiation is accompanied by upregulation of cGSN (an actin-severing protein). cGSN siRNA reduces OPC differentiation; cGSN overexpression promotes differentiation in vitro and remyelination in vivo. Coexpression of cGSN and LINGO-1 blocks the inhibitory effect of LINGO-1, placing cGSN downstream of LINGO-1.","method":"Anti-LINGO-1 antibody treatment, cGSN siRNA knockdown, cGSN overexpression in vitro and in vivo, OPC differentiation assay, remyelination in vivo","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment (cGSN overexpression blocks LINGO-1 inhibition), in vitro and in vivo validation, multiple orthogonal approaches","pmids":["28193690"],"is_preprint":false},{"year":2017,"finding":"Lingo1 is the NgR1 co-receptor that mediates Nogo-66 restriction of LTP at hippocampal Schaffer collateral–CA1 synapses. Loss of function for Lingo1 significantly increases LTP. p75NTR is not involved in mediating Nogo-66 effects on LTP. The downstream intracellular mechanism involves the ROCK2-Cofilin pathway to control actin cytoskeleton dynamics.","method":"Electrophysiology in acute hippocampal slices (LTP measurement), Lingo1 loss-of-function, p75NTR loss-of-function, ROCK2-Cofilin pathway biochemistry","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology with genetic loss-of-function and biochemical pathway dissection, clear negative control (p75NTR not involved), multiple orthogonal methods","pmids":["27166169"],"is_preprint":false},{"year":2020,"finding":"LINGO1 is a regulatory subunit of large conductance Ca2+-activated K+ (BK) channels: LINGO1 co-immunoprecipitates with BK channels in human brain; coexpression of LINGO1 and BK channels produces rapidly inactivating BK currents; LINGO1 reduces plasma membrane surface expression of BK channels, causing functional knockdown of BK currents.","method":"Co-immunoprecipitation from human brain tissue, electrophysiology (patch clamp) of coexpressed LINGO1/BK channels, surface expression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP from human brain plus electrophysiological functional characterization, multiple orthogonal methods establishing both physical interaction and functional consequence","pmids":["31932443"],"is_preprint":false},{"year":2020,"finding":"SP1 transcription factor is upregulated in optic nerve crush-injured RGCs, binds the LINGO-1 promoter (confirmed by luciferase assay), and drives increased LINGO-1 expression. Silencing SP1 in vivo reduces LINGO-1 expression and protects RGC structure.","method":"Luciferase reporter assay for SP1 binding to LINGO-1 promoter, SP1 overexpression qRT-PCR, SP1 shRNA in vivo, optic nerve crush model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter luciferase assay plus in vivo shRNA validation, two orthogonal approaches identifying upstream transcriptional regulator","pmids":["32562344"],"is_preprint":false},{"year":2021,"finding":"LINGO-1 regulates Wnt5a protein expression (but not mRNA) during neural stem and progenitor cell (NSPC) differentiation by modulating miR-15b-3p levels: LINGO-1 shRNA increases neuronal differentiation, elevates Wnt5a protein, and decreases miR-15b-3p (which suppresses Wnt5a translation). Transplantation of LINGO-1 shRNA-treated NSPCs into SCI mice promotes neural differentiation and motor recovery.","method":"LINGO-1 shRNA lentiviral knockdown in NSPCs, miRNA sequencing, Western blot and RT-qPCR for Wnt5a and pathway components, in vivo NSPC transplantation in SCI mice","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA sequencing plus functional validation, in vitro and in vivo evidence, single lab","pmids":["34187584"],"is_preprint":false},{"year":2025,"finding":"The extracellular domain of LINGO1 (but not the transmembrane or intracellular C-terminal tail domain, ITD) is required to inhibit plasmalemmal BK channel expression; this inhibitory effect does not require the 12 LRR repeats. The ITD controls the shift in voltage of half-maximal activation of BK:LINGO currents at different Ca2+ concentrations. The last 8 amino acids of the ITD specifically confer BK current inactivation.","method":"Chimeric LINGO1/LINGO2 domain-swap constructs, electrophysiology (patch clamp), surface expression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain-swap mutagenesis combined with electrophysiology and surface expression assays, clear structure-function dissection","pmids":["40752573"],"is_preprint":false},{"year":2025,"finding":"In hippocampal neurons after surgery/aging, elevated LINGO1 activates the RhoA/ROCK1 signaling pathway through interactions with NgR and p75NTR, promoting myelin loss and abnormal tau phosphorylation, and also inhibits the EGFR/PI3K/Akt pathway, increasing neuronal apoptosis. LINGO1 knockdown reverses these pathological changes and attenuates cognitive decline.","method":"LINGO1 AAV knockdown in aged mice after surgery, Western blot for RhoA/ROCK1/NgR/p75NTR and EGFR/PI3K/Akt pathways, behavioral testing","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV knockdown with pathway-level Western blot dissection, single lab","pmids":["39781463"],"is_preprint":false},{"year":2025,"finding":"LINGO-1 negatively regulates CB1R/TrkB signaling in hippocampal neurons: overexpressing LINGO-1 reduces CB1R protein levels and impairs spatial memory in vivo; antagonizing LINGO-1 increases CB1R/TrkB signaling and rescues CCK-GABAergic interneurons. Competitive inhibition between LINGO-1 and CB1R was observed in vitro, and LINGO-1 antagonism reverses CB1R inhibition-induced decreases in DCX, TrkB, and p-TrkB.","method":"AAV-mediated LINGO-1 overexpression/silencing in vivo, CB1R agonist/antagonist pharmacology in HT22 neurons, Western blot for CB1R/TrkB/p-TrkB/DCX, spatial memory behavioral testing","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV manipulation plus in vitro pharmacological dissection, multiple pathway readouts, single lab","pmids":["40441519"],"is_preprint":false}],"current_model":"LINGO-1 is a CNS-specific single-pass transmembrane protein that forms a stable tetramer (crystal structure resolved) and functions as a multivalent negative regulator of neural repair: it is an essential functional component of the NgR1/p75/LINGO-1 and NgR1/TROY/LINGO-1 receptor complexes that mediate RhoA activation and inhibition of axonal outgrowth in response to myelin-associated inhibitors; it is expressed in oligodendrocytes and inhibits their differentiation and myelination by suppressing RhoA downregulation, blocking ErbB2 translocation into lipid rafts, and suppressing cytoplasmic gelsolin (cGSN)-dependent actin dynamics; it engages in homophilic trans-interactions (acting as both ligand and receptor) to inhibit OPC differentiation; it promotes apoptosis by binding and inhibiting WNK3 kinase activity; it negatively regulates TrkA/B/C and EGF receptor signaling by promoting lysosomal receptor degradation; it is predominantly intracellular in neurons where it associates with p75NTR in pre-Golgi compartments; it restricts hippocampal LTP through the ROCK2-Cofilin pathway downstream of Nogo-66/NgR1; it is a regulatory subunit of BK channels, inhibiting their surface expression via its extracellular domain and controlling inactivation kinetics via its intracellular tail; and its transcription is driven by SP1 after neural injury and repressed by the RA-RAR-β pathway."},"narrative":{"mechanistic_narrative":"LINGO-1 is a CNS single-pass transmembrane LRR-Ig protein that acts as a multivalent negative regulator of neural repair, axonal outgrowth, and myelination [PMID:14966521, PMID:15895088]. It is an essential functional component of the NgR1/p75 receptor complex that confers responsiveness to myelin-associated inhibitors such as OMgp and signals through RhoA activation to restrict neurite extension [PMID:14966521]. Its ectodomain adopts a bimodular kinked LRR-Ig fold that self-assembles into a ring-shaped tetramer, a quaternary arrangement that scaffolds receptor-complex assembly and whose disruption by the Li81 Fab abolishes biological activity [PMID:17005555, PMID:24756303]. In oligodendrocytes LINGO-1 suppresses differentiation and myelination by sustaining RhoA activity [PMID:15895088], blocking ErbB2 translocation into lipid rafts and ErbB2 activation [PMID:24583087], and repressing the actin-severing protein cytoplasmic gelsolin downstream of the receptor [PMID:28193690]; it can act simultaneously as ligand and receptor through homophilic trans-interactions that activate RhoA in OPCs [PMID:22514275]. Beyond myelin inhibition, LINGO-1 transduces neuronal RhoA signaling through the kinase WNK1, which controls RhoA activation via Rho-GDI1 [PMID:19363035], and it couples to neuronal survival pathways by binding and inhibiting WNK3 to promote apoptosis [PMID:23482566] and by negatively regulating neurotrophin and growth-factor receptors—it complexes with TrkB and EGFR to restrain their signaling and Akt activation [PMID:17726113, PMID:20377621] and drives lysosomal degradation of TrkA/B/C as a negative-feedback mechanism [PMID:26546150]. At hippocampal synapses LINGO-1 serves as the NgR1 co-receptor that restricts LTP through the ROCK2-Cofilin pathway [PMID:27166169]. LINGO1 also operates as a regulatory subunit of large-conductance Ca2+-activated (BK) channels, where its extracellular domain reduces channel surface expression and its intracellular tail confers current inactivation and Ca2+-dependent gating [PMID:31932443, PMID:40752573]. Loss of LINGO-1 function promotes remyelination, axonal survival, and functional recovery across spinal cord injury, EAE, Parkinsonian, and retinal injury models [PMID:17011208, PMID:17906634, PMID:18326721, PMID:17726113], and its transcription is induced by SP1 after injury [PMID:32562344] and repressed by retinoic-acid signaling through RAR-β [PMID:21690307].","teleology":[{"year":2004,"claim":"Established LINGO-1 as the missing functional component of the myelin-inhibitory receptor complex, answering how NgR1/p75 transduces inhibitory signals.","evidence":"Co-IP/binding, RhoA activation reconstituted in non-neuronal cells, dominant-negative in primary neurons","pmids":["14966521"],"confidence":"High","gaps":["Stoichiometry of the ternary complex unresolved","Did not address localization of the complex"]},{"year":2005,"claim":"Extended LINGO-1's role from neurons to oligodendrocytes, showing it cell-autonomously gates differentiation and myelination via RhoA.","evidence":"DN, RNAi, LINGO-1-Fc, KO mice, RhoA assay, coculture myelination","pmids":["15895088"],"confidence":"High","gaps":["Downstream effectors of RhoA in OPCs not defined","Ligand on oligodendrocytes unidentified"]},{"year":2006,"claim":"Provided the structural basis for LINGO-1 self-assembly, showing a tetrameric ectodomain that could scaffold receptor complex components.","evidence":"X-ray crystallography plus solution biophysics","pmids":["17005555"],"confidence":"High","gaps":["Tetramer relevance in vivo not demonstrated","No structure of full receptor complex"]},{"year":2006,"claim":"Demonstrated therapeutic potential of LINGO-1 antagonism in spinal cord injury through the same RhoA mechanism.","evidence":"LINGO-1-Fc in rat spinal cord hemisection, RhoA assay, behavior","pmids":["17011208"],"confidence":"Medium","gaps":["Single lab","Contributions of neuronal vs glial LINGO-1 not separated"]},{"year":2007,"claim":"Showed LINGO-1 acts from both axon and oligodendrocyte and is regulated by NGF/TrkA, refining where the inhibitory signal originates.","evidence":"Synapsin-LINGO-1 transgenic mice, coculture, NGF/TrkA dose-response","pmids":["17202489"],"confidence":"High","gaps":["Trans vs cis signaling not distinguished here","Molecular link from TrkA to LINGO-1 transcription not defined"]},{"year":2007,"claim":"Broadened LINGO-1 function to neuronal survival, linking its inhibition to EGFR/Akt activation and neuroprotection in Parkinson's models.","evidence":"KO mice, MPTP/6-OHDA, antagonists, p-Akt blot, EGFR binding assay","pmids":["17726113"],"confidence":"High","gaps":["Direct mechanism of EGFR inhibition not structurally resolved","Relationship to RhoA pathway unclear"]},{"year":2007,"claim":"Established LINGO-1 as a negative regulator of remyelination in vivo, validating it as a demyelinating-disease target.","evidence":"Lingo1 KO and anti-LINGO-1 antibody in EAE, MR DTI, electron microscopy","pmids":["17906634"],"confidence":"High","gaps":["Cellular source of relevant LINGO-1 in EAE not pinpointed","Antibody mechanism of action not detailed"]},{"year":2008,"claim":"Defined the neuroprotective signaling logic in retinal ganglion cells, placing LINGO-1 upstream of a RhoA/JNK vs PI3K/Akt switch.","evidence":"Ocular hypertension model, LINGO-1-Fc/mAb, RhoA/JNK/Akt blots, kinase inhibitors","pmids":["18326721"],"confidence":"High","gaps":["How LINGO-1 bifurcates RhoA and Akt arms unclear","Receptor partner in RGCs not identified"]},{"year":2009,"claim":"Identified WNK1 as an intracellular effector linking LINGO-1 to RhoA activation via Rho-GDI1.","evidence":"Yeast two-hybrid, FRET, co-IP, RNAi, DN, RhoA and neurite assays","pmids":["19363035"],"confidence":"High","gaps":["Direct biochemical contact between LINGO-1 tail and WNK1 not mapped","Kinase substrate landscape unresolved"]},{"year":2009,"claim":"Showed N-glycosylation on the LRR concave surface is required for LINGO-1 surface trafficking.","evidence":"High-throughput mammalian expression, mutagenesis, surface expression assay","pmids":["19254717"],"confidence":"Medium","gaps":["Single study","Functional consequence beyond surface expression untested"]},{"year":2010,"claim":"Identified LINGO-1/TrkB complex as a brake on BDNF-dependent RGC survival, extending negative regulation to neurotrophin receptors.","evidence":"Co-IP, p-TrkB blot, anti-BDNF blockade, ocular hypertension model","pmids":["20377621"],"confidence":"Medium","gaps":["Direct vs indirect TrkB binding unresolved","Single lab in vivo"]},{"year":2011,"claim":"Defined the molecular determinants of NgR1-LINGO-1 association, implicating gangliosides and the NgR1 stalk.","evidence":"Cell-free solid-phase binding with ganglioside manipulation","pmids":["21872576"],"confidence":"Medium","gaps":["Cell-free system only","Physiological relevance of ganglioside bridging untested in neurons"]},{"year":2011,"claim":"Identified RA-RAR-β as a transcriptional repressor of Lingo-1, explaining how retinoic acid overcomes myelin inhibition.","evidence":"RAR-β gain/loss, promoter reporter, neurite assay, dorsal column injury","pmids":["21690307"],"confidence":"Medium","gaps":["RAR-β binding site on promoter not mapped","Single lab"]},{"year":2011,"claim":"Mapped self- and APP-interaction to ectodomain regions outside the LRR and TM/cytoplasmic domains.","evidence":"Deletional mutagenesis and binding assays","pmids":["22133804"],"confidence":"Low","gaps":["Single lab deletion-mapping with limited follow-up","Functional significance of APP binding untested"]},{"year":2012,"claim":"Established LINGO-1 as a homophilic trans-acting ligand/receptor that activates RhoA in OPCs.","evidence":"Recombinant ectodomain binding, surface-bound LINGO-1 coculture, RhoA assay","pmids":["22514275"],"confidence":"High","gaps":["Trans-interaction interface not structurally defined","Single lab"]},{"year":2013,"claim":"Showed LINGO-1 promotes neuronal apoptosis by binding and inhibiting WNK3 through its intracellular domain.","evidence":"Co-IP, in vitro kinase assay, shRNA, DN WNK3, serum-deprivation apoptosis","pmids":["23482566"],"confidence":"High","gaps":["WNK3 anti-apoptotic substrates unidentified","Relationship to WNK1/RhoA arm unclear"]},{"year":2014,"claim":"Demonstrated LINGO-1 gates oligodendrocyte differentiation by blocking ErbB2 entry into lipid rafts.","evidence":"Co-IP, lipid raft fractionation, p-ErbB2 blot, KO oligodendrocytes, pharmacology","pmids":["24583087"],"confidence":"High","gaps":["Mechanism of raft exclusion unresolved","Single lab"]},{"year":2014,"claim":"Resolved how a therapeutic antibody works structurally, showing Li81 disrupts LINGO-1 oligomerization to block function.","evidence":"LINGO-1-Fab co-crystal, binding studies, oligodendrocyte differentiation assay","pmids":["24756303"],"confidence":"High","gaps":["In vivo correlation of quaternary rearrangement not shown"]},{"year":2014,"claim":"Established constitutive cis-dimerization of LINGO-1 and that conformational modulators can tune EGFR-inhibitory activity.","evidence":"Co-IP, BRET saturation, small-molecule screen, EGFR/Erk blots","pmids":["25257685"],"confidence":"Medium","gaps":["Reconciliation of cis-dimer with tetramer model unaddressed","Single lab"]},{"year":2015,"claim":"Challenged the surface ternary-complex model by showing LINGO-1 is predominantly intracellular and competes with NgR for p75NTR.","evidence":"Fractionation, immunofluorescence, C-terminus mutagenesis, co-IP competition, N-glycan analysis","pmids":["25666623"],"confidence":"Medium","gaps":["Physiological site of LINGO-1/p75 signaling unresolved","Single lab contradicting prior model"]},{"year":2015,"claim":"Identified LINGO-1-driven lysosomal degradation of Trk receptors as a negative-feedback brake on neurotrophin signaling.","evidence":"Co-IP, lysosomal inhibitors, recycling endosome colocalization, deletion mutant in PC12","pmids":["26546150"],"confidence":"Medium","gaps":["Ubiquitin/sorting machinery not identified","Single lab"]},{"year":2015,"claim":"Linked LINGO-1 and paralogs to reduced amyloidogenic APP processing via lysosomal degradation.","evidence":"Cell-based APP processing assay, lysosomal pathway analysis","pmids":["25758563"],"confidence":"Low","gaps":["Limited mechanistic detail; abstract-level only","No in vivo validation"]},{"year":2017,"claim":"Placed cytoplasmic gelsolin downstream of LINGO-1 as an actin-severing effector in OPC differentiation and remyelination.","evidence":"Anti-LINGO-1 antibody, cGSN siRNA/overexpression in vitro and in vivo, epistasis rescue","pmids":["28193690"],"confidence":"High","gaps":["Connection from RhoA to cGSN regulation not detailed","Single lab"]},{"year":2017,"claim":"Defined LINGO-1 as the NgR1 co-receptor restricting hippocampal LTP via ROCK2-Cofilin, excluding p75NTR involvement.","evidence":"Hippocampal slice electrophysiology, Lingo1 and p75NTR loss-of-function, pathway biochemistry","pmids":["27166169"],"confidence":"High","gaps":["Receptor partner replacing p75 in synaptic context unclear","Single lab"]},{"year":2020,"claim":"Revealed an entirely distinct role for LINGO1 as a regulatory subunit of BK channels controlling inactivation and surface expression.","evidence":"Co-IP from human brain, patch-clamp of coexpressed channels, surface expression assay","pmids":["31932443"],"confidence":"High","gaps":["Native neuronal context of BK regulation not demonstrated","Stoichiometry of LINGO1:BK unresolved"]},{"year":2020,"claim":"Identified SP1 as the injury-induced transcription factor driving LINGO-1 expression in retinal ganglion cells.","evidence":"Promoter luciferase, SP1 overexpression qRT-PCR, in vivo SP1 shRNA, optic nerve crush","pmids":["32562344"],"confidence":"Medium","gaps":["Upstream signal activating SP1 not defined","Single lab"]},{"year":2021,"claim":"Showed LINGO-1 controls neural stem cell differentiation by modulating miR-15b-3p and Wnt5a translation.","evidence":"shRNA in NSPCs, miRNA-seq, Western/RT-qPCR, NSPC transplantation in SCI mice","pmids":["34187584"],"confidence":"Medium","gaps":["Mechanism linking LINGO-1 to miR-15b-3p levels unknown","Single lab"]},{"year":2025,"claim":"Dissected the BK-regulatory structure-function, attributing surface inhibition to the ectodomain and inactivation/gating to the intracellular tail.","evidence":"LINGO1/LINGO2 chimera domain swaps, patch-clamp, surface expression","pmids":["40752573"],"confidence":"High","gaps":["Atomic interface with BK channel unresolved","LRR-independent mechanism not explained mechanistically"]},{"year":2025,"claim":"Integrated LINGO1 into postoperative/aging cognitive decline via dual RhoA/ROCK1 activation and EGFR/PI3K/Akt suppression.","evidence":"AAV knockdown in aged mice, pathway Western blots, behavior","pmids":["39781463"],"confidence":"Medium","gaps":["Causality between tau phosphorylation and LINGO1 not directly tested","Single lab"]},{"year":2025,"claim":"Showed LINGO-1 negatively regulates CB1R/TrkB signaling and GABAergic interneuron integrity affecting spatial memory.","evidence":"AAV overexpression/silencing, CB1R pharmacology in HT22, Western blots, behavior","pmids":["40441519"],"confidence":"Medium","gaps":["Direct LINGO-1/CB1R binding not biochemically confirmed","Single lab"]},{"year":null,"claim":"How LINGO-1's intracellular localization, cis-dimer/tetramer assembly, and competition with NgR for p75NTR are reconciled into a single coherent signaling topology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full NgR1/p75/LINGO-1 complex","Native subcellular site of signaling disputed across studies","Relationship between RhoA, WNK kinases, and BK-channel roles not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,24,27]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,14,23]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[24,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,18,24]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[19]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15,28]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[23,24]}],"complexes":["NgR1/p75/LINGO-1 receptor complex","BK channel complex"],"partners":["RTN4R","NGFR","WNK1","WNK3","ERBB2","NTRK2","EGFR","KCNMA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FE5","full_name":"Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1","aliases":["Leucine-rich repeat and immunoglobulin domain-containing protein 1","Leucine-rich repeat neuronal protein 1","Leucine-rich repeat neuronal protein 6A"],"length_aa":620,"mass_kda":69.9,"function":"Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors (PubMed:14966521, PubMed:15694321). Is also an important negative regulator of oligodentrocyte differentiation and axonal myelination (PubMed:15895088). Acts in conjunction with RTN4 and RTN4R in regulating neuronal precursor cell motility during cortical development (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96FE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LINGO1","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/LINGO1","total_profiled":1310},"omim":[{"mim_id":"618103","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 64; MRT64","url":"https://www.omim.org/entry/618103"},{"mim_id":"609794","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 4; LINGO4","url":"https://www.omim.org/entry/609794"},{"mim_id":"609793","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 2; LINGO2","url":"https://www.omim.org/entry/609793"},{"mim_id":"609792","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 3; LINGO3","url":"https://www.omim.org/entry/609792"},{"mim_id":"609791","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 1; LINGO1","url":"https://www.omim.org/entry/609791"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":109.9}],"url":"https://www.proteinatlas.org/search/LINGO1"},"hgnc":{"alias_symbol":["FLJ14594","LERN1"],"prev_symbol":["LRRN6A"]},"alphafold":{"accession":"Q96FE5","domains":[{"cath_id":"2.60.40.10","chopping":"422-514","consensus_level":"high","plddt":95.5763,"start":422,"end":514}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FE5-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LINGO1","jax_strain_url":"https://www.jax.org/strain/search?query=LINGO1"},"sequence":{"accession":"Q96FE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FE5"}},"corpus_meta":[{"pmid":"14966521","id":"PMC_14966521","title":"LINGO-1 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A dominant-negative LINGO-1 construct attenuated myelin inhibition in primary neuronal cultures.\",\n      \"method\": \"Co-immunoprecipitation/binding assays, RhoA activation assay in reconstituted non-neuronal cells, dominant-negative construct in primary neuronal cultures\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in non-neuronal cells with defined functional readout (RhoA activation), dominant-negative validation in primary neurons, foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"14966521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LINGO-1 is expressed in oligodendrocytes and negatively regulates oligodendrocyte differentiation and myelination. Attenuation of LINGO-1 (dominant-negative, RNAi, or LINGO-1-Fc) leads to downregulation of RhoA activity and promotes differentiation and myelination; conversely, overexpression activates RhoA and inhibits differentiation. LINGO-1 knockout mice show increased myelination in vivo.\",\n      \"method\": \"Dominant-negative construct, RNAi knockdown, soluble LINGO-1-Fc fusion protein, RhoA activity assay, oligodendrocyte–neuron coculture myelination assay, LINGO-1 knockout mice\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal loss-of-function approaches (DN, RNAi, KO mice), RhoA mechanistic readout, and in vivo validation\",\n      \"pmids\": [\"15895088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of the LINGO-1 ectodomain reveals a bimodular, kinked LRR–Ig fold. In crystals and in solution, LINGO-1 forms a stable ring-shaped tetramer in which each LRR domain fills an open cleft in an adjacent protomer, burying ~9,200 Ų of surface area; this self-assembly may scaffold simultaneous binding of NgR complex components.\",\n      \"method\": \"X-ray crystallography, biophysical solution analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biophysical solution validation; foundational structural paper\",\n      \"pmids\": [\"17005555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LINGO-1-Fc (soluble antagonist that blocks LINGO-1 binding to NgR1) administered after spinal cord hemisection in rats significantly decreased RhoA activation, increased neuronal and oligodendrocyte survival, promoted axonal sprouting, and improved functional recovery.\",\n      \"method\": \"In vivo spinal cord injury model in rats, RhoA activation assay, immunohistochemistry, behavioral assessment\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO/antagonist with defined RhoA mechanistic readout, single lab\",\n      \"pmids\": [\"17011208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Axonal LINGO-1 expression, regulated by NGF/TrkA signaling in a dose-dependent manner, inhibits oligodendrocyte differentiation and myelination with equal potency to oligodendrocyte-expressed LINGO-1. Disruption of LINGO-1 on either cell type is sufficient to promote myelination independent of axon diameter; transgenic mice overexpressing LINGO-1 under the neuronal synapsin promoter show greatly inhibited myelination.\",\n      \"method\": \"Neuronal-promoter transgenic mice (synapsin-LINGO-1), co-culture myelination assays, NGF/TrkA dose-response experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — transgenic mouse model plus in vitro coculture, multiple orthogonal methods, regulatory mechanism identified\",\n      \"pmids\": [\"17202489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LINGO-1 inhibition protects dopaminergic (DA) neurons in Parkinson's disease models: LINGO-1 KO mice show increased DA neuron survival and reduced behavioral abnormalities after 6-OHDA or MPTP treatment, accompanied by increased Akt phosphorylation. LINGO-1 antagonists (LINGO-1-Fc, dominant-negative, anti-LINGO-1 antibody) protect DA neurons in vitro partly through direct inhibition of LINGO-1 binding to EGFR, activating the EGFR/Akt signaling pathway.\",\n      \"method\": \"LINGO-1 KO mice, MPTP/6-OHDA PD models, LINGO-1-Fc/DN/antibody antagonism, Western blot for p-Akt, EGFR binding inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO mice plus in vitro mechanistic pathway dissection (EGFR/Akt), multiple orthogonal antagonist approaches\",\n      \"pmids\": [\"17726113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of LINGO-1 function (gene knockout or anti-LINGO-1 antibody) leads to functional recovery from experimental autoimmune encephalomyelitis, with improved axonal integrity (confirmed by MR diffusion tensor imaging) and newly formed myelin sheaths (confirmed by electron microscopy), demonstrating LINGO-1 as a negative regulator of remyelination in vivo.\",\n      \"method\": \"Lingo1 KO mice, anti-LINGO-1 antibody treatment in EAE model, MR diffusion tensor imaging, electron microscopy\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic and pharmacological loss-of-function approaches with multiple orthogonal outcome measures in vivo\",\n      \"pmids\": [\"17906634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Blocking LINGO-1 function with LINGO-1-Fc or anti-LINGO-1 mAb 1A7 promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection. The neuroprotective effect is mediated by blocking the RhoA/JNK pathway and promoting Akt phosphorylation (PI3K/Akt pathway); the survival effect is abolished by Akt phosphorylation inhibition.\",\n      \"method\": \"Ocular hypertension rat model, intravitreal injection of LINGO-1-Fc and antibody, Western blot for RhoA/JNK/Akt, specific kinase inhibitors\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal antagonists, pathway dissection with kinase inhibitors, defined cellular phenotype\",\n      \"pmids\": [\"18326721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LINGO-1 interacts with the serine-threonine kinase WNK1, identified by yeast two-hybrid screen and validated by FRET and co-immunoprecipitation. The interaction is intensified by Nogo66 treatment. WNK1 co-localizes with LINGO-1 in cortical neurons. Suppression of WNK1 (RNAi or dominant-negative fragment) attenuates Nogo66-induced inhibition of neurite extension and inhibits RhoA activation. WNK1 interacts with Rho-GDI1 and this interaction is attenuated by Nogo66, indicating WNK1 regulates RhoA activation downstream of LINGO-1.\",\n      \"method\": \"Yeast two-hybrid, FRET, co-immunoprecipitation, RNAi knockdown, dominant-negative overexpression, RhoA activation assay, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by FRET and co-IP, functional validation with RNAi and DN construct, multiple orthogonal methods\",\n      \"pmids\": [\"19363035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LINGO-1 surface expression requires specific N-glycosylation sites located on the concave surface of the LRR domain. Residue-screening by mutagenesis in a mammalian high-throughput system identified key asparagines sufficient to support surface expression.\",\n      \"method\": \"High-throughput mammalian transient expression, PCR-based expression cassette mutagenesis, surface expression assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis with functional surface expression readout, single lab, single study\",\n      \"pmids\": [\"19254717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LINGO-1 forms a receptor complex with TrkB and negatively regulates TrkB activation (phosphorylation) in the retina after ocular hypertension injury. LINGO-1 antagonists (antibody 1A7, LINGO-1-Fc) upregulate phospho-TrkB and promote RGC survival; this neuroprotective effect is blocked by anti-BDNF antibody.\",\n      \"method\": \"Co-immunoprecipitation (LINGO-1/TrkB complex), Western blot for p-TrkB, anti-BDNF antibody blockade, ocular hypertension rat model\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP complex identification with functional validation in vivo, mechanistic dissection with neutralizing antibody\",\n      \"pmids\": [\"20377621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Gangliosides mediate the interaction between NgR1 and LINGO-1 in a cell-free system. Solid-phase binding assays show that sialic acid moieties of gangliosides and the stalk of NgR1 are the principal determinants of NgR1–LINGO-1 molecular interactions. The tripartite complex NgR1/LINGO-1/ganglioside exhibits stronger binding to Nogo-A in the presence of p75.\",\n      \"method\": \"Cell-free solid-phase binding assay, ganglioside depletion/addition experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-free reconstitution with defined molecular determinants, single lab, single method\",\n      \"pmids\": [\"21872576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Retinoic acid (RA), acting through RAR-β, transcriptionally represses Lingo-1 expression, thereby counteracting myelin-dependent inhibition of neurite outgrowth via the NgR complex. Suppression of Lingo-1 is required for RA-RAR-β to counteract extrinsic inhibition; RA treatment in vivo after dorsal column injury inhibits Lingo-1 expression specifically through RAR-β.\",\n      \"method\": \"RAR-β gain/loss-of-function, Lingo-1 promoter reporter assay, neurite outgrowth assay, in vivo dorsal column injury model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional mechanism identified with promoter assay and in vivo validation, multiple experimental approaches\",\n      \"pmids\": [\"21690307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The leucine-rich repeat domain and the transmembrane/cytoplasmic domain of LINGO-1 are not required for LINGO-1 self-interaction or interaction with APP; these interactions are mediated by other regions of the ectodomain.\",\n      \"method\": \"Deletional mutagenesis, binding assays\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, deletion mutant binding assay, limited mechanistic follow-up\",\n      \"pmids\": [\"22133804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LINGO-1 inhibits oligodendrocyte differentiation through intercellular homophilic (trans) self-interactions: soluble LINGO-1 ectodomain binds to full-length LINGO-1 on CHO cells (trans interaction), surface-bound LINGO-1 on astrocytes inhibits OPCs through intercellular signaling, and soluble LINGO-1 ectodomain activates RhoA in OPCs. LINGO-1 acts as both a ligand and a receptor.\",\n      \"method\": \"Recombinant ectodomain binding to LINGO-1-expressing CHO cells, ectopic surface-bound LINGO-1 on astrocytes in coculture, RhoA activation assay in OPCs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches establishing homophilic trans-interaction and downstream RhoA activation, single lab\",\n      \"pmids\": [\"22514275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LINGO-1 promotes neuronal apoptosis by binding the serine-threonine kinase WNK3 via the LINGO-1 intracellular domain, reducing WNK3 kinase activity. The LINGO-1/WNK3 co-association is enhanced by Nogo66 treatment. WNK3 suppresses serum-deprivation-induced neuronal apoptosis in a kinase-dependent manner, and inhibiting WNK3 activity mimics the pro-apoptotic effect of LINGO-1 activation.\",\n      \"method\": \"Co-immunoprecipitation (LINGO-1/WNK3), WNK3 kinase activity assay in vitro, shRNA knockdown, dominant-negative WNK3, serum-deprivation apoptosis model in cortical neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP validated by co-localization, in vitro kinase assay, multiple loss-of-function tools, defined mechanistic pathway\",\n      \"pmids\": [\"23482566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LINGO-1 directly binds ErbB2, blocks ErbB2 translocation into lipid rafts, and inhibits ErbB2 phosphorylation/activation, thereby suppressing oligodendrocyte differentiation. In LINGO-1−/− oligodendrocytes, ErbB2 activation does not further enhance differentiation, suggesting LINGO-1 is a gating mechanism for ErbB2-dependent differentiation.\",\n      \"method\": \"Co-immunoprecipitation (LINGO-1/ErbB2), lipid raft fractionation, ErbB2 phosphorylation Western blot, LINGO-1 KO oligodendrocytes, ErbB2 inhibitor/activator pharmacology\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by co-IP, lipid raft fractionation, KO rescue experiment, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"24583087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of LINGO-1 in complex with the anti-LINGO-1 Li81 Fab reveals that Li81 binds the convex surface of the LRR domain within repeats 4–8. Fab binding blocks oligomerization contact points of LINGO-1 and produces a stable 2:2 LINGO-1/Fab complex by rearranging the quaternary structure, and masks functional epitopes in the Ig domain required for LINGO-1 biological activity in oligodendrocyte differentiation.\",\n      \"method\": \"X-ray crystallography (LINGO-1–Fab co-crystal), biochemical binding studies, oligodendrocyte differentiation functional assay\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional validation of epitope masking, multiple orthogonal methods\",\n      \"pmids\": [\"24756303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LINGO-1 forms constitutive cis-dimers (homodimers) at the plasma membrane, demonstrated by co-immunoprecipitation and BRET saturation analysis in HEK293 and SH-SY5Y cells. Cis-dimerization occurs early during biosynthesis. A small molecule (phenoxybenzamine), identified by BRET-based screening as a conformational modulator of LINGO-1 dimers, acts as a positive modulator of LINGO-1 function, increasing LINGO-1-mediated inhibition of EGF receptor signaling and Erk phosphorylation in HEK-293 cells.\",\n      \"method\": \"Co-immunoprecipitation, BRET saturation assay, small-molecule screen, Western blot for EGF receptor signaling/Erk phosphorylation\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRET and co-IP orthogonal methods for dimerization, functional pharmacological validation, single lab\",\n      \"pmids\": [\"25257685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LINGO-1 is predominantly localized intracellularly in neurons (cortex and cerebellum). Mutation or truncation of the conserved LINGO-1 C-terminus alters intracellular retention, causing increased plasma membrane expression. p75NTR associates predominantly with natively expressed, intracellular LINGO-1 containing immature N-glycans (pre-trans-Golgi), whereas mutant LINGO-1 with enhanced plasma membrane expression does not associate with p75NTR. Co-immunoprecipitation shows LINGO-1 and NgR compete for binding to p75NTR, contradicting a functional plasma membrane LINGO-1/p75NTR/NgR ternary complex.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, C-terminus mutagenesis, co-immunoprecipitation, N-glycan analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation with mutagenesis, co-IP competition experiment, multiple orthogonal methods, single lab; contradicts prior model\",\n      \"pmids\": [\"25666623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LINGO-1 promotes lysosomal degradation of TrkA, TrkB, and TrkC (Trk neurotrophin receptors) as a negative feedback mechanism: Trk activation promotes Trk association with LINGO-1, and this association drives Trk degradation via a lysosomal pathway, partly within recycling endosomes. A LINGO-1 mutant with deleted extracellular domain enhances TrkA signaling in PC12 cells, likely by acting as an inhibitor of Trk downregulation by full-length LINGO-1.\",\n      \"method\": \"Co-immunoprecipitation (Trk/LINGO-1), lysosomal inhibitor experiments, recycling endosome co-localization, LINGO-1 deletion mutant in PC12 cells\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with pharmacological dissection and deletion mutant, multiple Trk paralogs tested, single lab\",\n      \"pmids\": [\"26546150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LINGO-1 and its paralogs (LINGO-2, LINGO-3) decrease amyloidogenic processing of amyloid precursor protein (APP) by promoting lysosomal degradation of AβPP.\",\n      \"method\": \"Cell-based APP processing assay, lysosomal pathway analysis\",\n      \"journal\": \"Pathobiology of aging & age related diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell-based assay, limited mechanistic detail in abstract\",\n      \"pmids\": [\"25758563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin (cGSN) signaling pathway: anti-LINGO-1 antibody-promoted OPC differentiation is accompanied by upregulation of cGSN (an actin-severing protein). cGSN siRNA reduces OPC differentiation; cGSN overexpression promotes differentiation in vitro and remyelination in vivo. Coexpression of cGSN and LINGO-1 blocks the inhibitory effect of LINGO-1, placing cGSN downstream of LINGO-1.\",\n      \"method\": \"Anti-LINGO-1 antibody treatment, cGSN siRNA knockdown, cGSN overexpression in vitro and in vivo, OPC differentiation assay, remyelination in vivo\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment (cGSN overexpression blocks LINGO-1 inhibition), in vitro and in vivo validation, multiple orthogonal approaches\",\n      \"pmids\": [\"28193690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lingo1 is the NgR1 co-receptor that mediates Nogo-66 restriction of LTP at hippocampal Schaffer collateral–CA1 synapses. Loss of function for Lingo1 significantly increases LTP. p75NTR is not involved in mediating Nogo-66 effects on LTP. The downstream intracellular mechanism involves the ROCK2-Cofilin pathway to control actin cytoskeleton dynamics.\",\n      \"method\": \"Electrophysiology in acute hippocampal slices (LTP measurement), Lingo1 loss-of-function, p75NTR loss-of-function, ROCK2-Cofilin pathway biochemistry\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with genetic loss-of-function and biochemical pathway dissection, clear negative control (p75NTR not involved), multiple orthogonal methods\",\n      \"pmids\": [\"27166169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINGO1 is a regulatory subunit of large conductance Ca2+-activated K+ (BK) channels: LINGO1 co-immunoprecipitates with BK channels in human brain; coexpression of LINGO1 and BK channels produces rapidly inactivating BK currents; LINGO1 reduces plasma membrane surface expression of BK channels, causing functional knockdown of BK currents.\",\n      \"method\": \"Co-immunoprecipitation from human brain tissue, electrophysiology (patch clamp) of coexpressed LINGO1/BK channels, surface expression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP from human brain plus electrophysiological functional characterization, multiple orthogonal methods establishing both physical interaction and functional consequence\",\n      \"pmids\": [\"31932443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SP1 transcription factor is upregulated in optic nerve crush-injured RGCs, binds the LINGO-1 promoter (confirmed by luciferase assay), and drives increased LINGO-1 expression. Silencing SP1 in vivo reduces LINGO-1 expression and protects RGC structure.\",\n      \"method\": \"Luciferase reporter assay for SP1 binding to LINGO-1 promoter, SP1 overexpression qRT-PCR, SP1 shRNA in vivo, optic nerve crush model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter luciferase assay plus in vivo shRNA validation, two orthogonal approaches identifying upstream transcriptional regulator\",\n      \"pmids\": [\"32562344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LINGO-1 regulates Wnt5a protein expression (but not mRNA) during neural stem and progenitor cell (NSPC) differentiation by modulating miR-15b-3p levels: LINGO-1 shRNA increases neuronal differentiation, elevates Wnt5a protein, and decreases miR-15b-3p (which suppresses Wnt5a translation). Transplantation of LINGO-1 shRNA-treated NSPCs into SCI mice promotes neural differentiation and motor recovery.\",\n      \"method\": \"LINGO-1 shRNA lentiviral knockdown in NSPCs, miRNA sequencing, Western blot and RT-qPCR for Wnt5a and pathway components, in vivo NSPC transplantation in SCI mice\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA sequencing plus functional validation, in vitro and in vivo evidence, single lab\",\n      \"pmids\": [\"34187584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The extracellular domain of LINGO1 (but not the transmembrane or intracellular C-terminal tail domain, ITD) is required to inhibit plasmalemmal BK channel expression; this inhibitory effect does not require the 12 LRR repeats. The ITD controls the shift in voltage of half-maximal activation of BK:LINGO currents at different Ca2+ concentrations. The last 8 amino acids of the ITD specifically confer BK current inactivation.\",\n      \"method\": \"Chimeric LINGO1/LINGO2 domain-swap constructs, electrophysiology (patch clamp), surface expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-swap mutagenesis combined with electrophysiology and surface expression assays, clear structure-function dissection\",\n      \"pmids\": [\"40752573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hippocampal neurons after surgery/aging, elevated LINGO1 activates the RhoA/ROCK1 signaling pathway through interactions with NgR and p75NTR, promoting myelin loss and abnormal tau phosphorylation, and also inhibits the EGFR/PI3K/Akt pathway, increasing neuronal apoptosis. LINGO1 knockdown reverses these pathological changes and attenuates cognitive decline.\",\n      \"method\": \"LINGO1 AAV knockdown in aged mice after surgery, Western blot for RhoA/ROCK1/NgR/p75NTR and EGFR/PI3K/Akt pathways, behavioral testing\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV knockdown with pathway-level Western blot dissection, single lab\",\n      \"pmids\": [\"39781463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LINGO-1 negatively regulates CB1R/TrkB signaling in hippocampal neurons: overexpressing LINGO-1 reduces CB1R protein levels and impairs spatial memory in vivo; antagonizing LINGO-1 increases CB1R/TrkB signaling and rescues CCK-GABAergic interneurons. Competitive inhibition between LINGO-1 and CB1R was observed in vitro, and LINGO-1 antagonism reverses CB1R inhibition-induced decreases in DCX, TrkB, and p-TrkB.\",\n      \"method\": \"AAV-mediated LINGO-1 overexpression/silencing in vivo, CB1R agonist/antagonist pharmacology in HT22 neurons, Western blot for CB1R/TrkB/p-TrkB/DCX, spatial memory behavioral testing\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV manipulation plus in vitro pharmacological dissection, multiple pathway readouts, single lab\",\n      \"pmids\": [\"40441519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LINGO-1 is a CNS-specific single-pass transmembrane protein that forms a stable tetramer (crystal structure resolved) and functions as a multivalent negative regulator of neural repair: it is an essential functional component of the NgR1/p75/LINGO-1 and NgR1/TROY/LINGO-1 receptor complexes that mediate RhoA activation and inhibition of axonal outgrowth in response to myelin-associated inhibitors; it is expressed in oligodendrocytes and inhibits their differentiation and myelination by suppressing RhoA downregulation, blocking ErbB2 translocation into lipid rafts, and suppressing cytoplasmic gelsolin (cGSN)-dependent actin dynamics; it engages in homophilic trans-interactions (acting as both ligand and receptor) to inhibit OPC differentiation; it promotes apoptosis by binding and inhibiting WNK3 kinase activity; it negatively regulates TrkA/B/C and EGF receptor signaling by promoting lysosomal receptor degradation; it is predominantly intracellular in neurons where it associates with p75NTR in pre-Golgi compartments; it restricts hippocampal LTP through the ROCK2-Cofilin pathway downstream of Nogo-66/NgR1; it is a regulatory subunit of BK channels, inhibiting their surface expression via its extracellular domain and controlling inactivation kinetics via its intracellular tail; and its transcription is driven by SP1 after neural injury and repressed by the RA-RAR-β pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LINGO-1 is a CNS single-pass transmembrane LRR-Ig protein that acts as a multivalent negative regulator of neural repair, axonal outgrowth, and myelination [#0, #1]. It is an essential functional component of the NgR1/p75 receptor complex that confers responsiveness to myelin-associated inhibitors such as OMgp and signals through RhoA activation to restrict neurite extension [#0]. Its ectodomain adopts a bimodular kinked LRR-Ig fold that self-assembles into a ring-shaped tetramer, a quaternary arrangement that scaffolds receptor-complex assembly and whose disruption by the Li81 Fab abolishes biological activity [#2, #17]. In oligodendrocytes LINGO-1 suppresses differentiation and myelination by sustaining RhoA activity [#1], blocking ErbB2 translocation into lipid rafts and ErbB2 activation [#16], and repressing the actin-severing protein cytoplasmic gelsolin downstream of the receptor [#22]; it can act simultaneously as ligand and receptor through homophilic trans-interactions that activate RhoA in OPCs [#14]. Beyond myelin inhibition, LINGO-1 transduces neuronal RhoA signaling through the kinase WNK1, which controls RhoA activation via Rho-GDI1 [#8], and it couples to neuronal survival pathways by binding and inhibiting WNK3 to promote apoptosis [#15] and by negatively regulating neurotrophin and growth-factor receptors—it complexes with TrkB and EGFR to restrain their signaling and Akt activation [#5, #10] and drives lysosomal degradation of TrkA/B/C as a negative-feedback mechanism [#20]. At hippocampal synapses LINGO-1 serves as the NgR1 co-receptor that restricts LTP through the ROCK2-Cofilin pathway [#23]. LINGO1 also operates as a regulatory subunit of large-conductance Ca2+-activated (BK) channels, where its extracellular domain reduces channel surface expression and its intracellular tail confers current inactivation and Ca2+-dependent gating [#24, #27]. Loss of LINGO-1 function promotes remyelination, axonal survival, and functional recovery across spinal cord injury, EAE, Parkinsonian, and retinal injury models [#3, #6, #7, #5], and its transcription is induced by SP1 after injury [#25] and repressed by retinoic-acid signaling through RAR-β [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established LINGO-1 as the missing functional component of the myelin-inhibitory receptor complex, answering how NgR1/p75 transduces inhibitory signals.\",\n      \"evidence\": \"Co-IP/binding, RhoA activation reconstituted in non-neuronal cells, dominant-negative in primary neurons\",\n      \"pmids\": [\"14966521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the ternary complex unresolved\", \"Did not address localization of the complex\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended LINGO-1's role from neurons to oligodendrocytes, showing it cell-autonomously gates differentiation and myelination via RhoA.\",\n      \"evidence\": \"DN, RNAi, LINGO-1-Fc, KO mice, RhoA assay, coculture myelination\",\n      \"pmids\": [\"15895088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of RhoA in OPCs not defined\", \"Ligand on oligodendrocytes unidentified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural basis for LINGO-1 self-assembly, showing a tetrameric ectodomain that could scaffold receptor complex components.\",\n      \"evidence\": \"X-ray crystallography plus solution biophysics\",\n      \"pmids\": [\"17005555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tetramer relevance in vivo not demonstrated\", \"No structure of full receptor complex\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated therapeutic potential of LINGO-1 antagonism in spinal cord injury through the same RhoA mechanism.\",\n      \"evidence\": \"LINGO-1-Fc in rat spinal cord hemisection, RhoA assay, behavior\",\n      \"pmids\": [\"17011208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Contributions of neuronal vs glial LINGO-1 not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed LINGO-1 acts from both axon and oligodendrocyte and is regulated by NGF/TrkA, refining where the inhibitory signal originates.\",\n      \"evidence\": \"Synapsin-LINGO-1 transgenic mice, coculture, NGF/TrkA dose-response\",\n      \"pmids\": [\"17202489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans vs cis signaling not distinguished here\", \"Molecular link from TrkA to LINGO-1 transcription not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Broadened LINGO-1 function to neuronal survival, linking its inhibition to EGFR/Akt activation and neuroprotection in Parkinson's models.\",\n      \"evidence\": \"KO mice, MPTP/6-OHDA, antagonists, p-Akt blot, EGFR binding assay\",\n      \"pmids\": [\"17726113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of EGFR inhibition not structurally resolved\", \"Relationship to RhoA pathway unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established LINGO-1 as a negative regulator of remyelination in vivo, validating it as a demyelinating-disease target.\",\n      \"evidence\": \"Lingo1 KO and anti-LINGO-1 antibody in EAE, MR DTI, electron microscopy\",\n      \"pmids\": [\"17906634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of relevant LINGO-1 in EAE not pinpointed\", \"Antibody mechanism of action not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the neuroprotective signaling logic in retinal ganglion cells, placing LINGO-1 upstream of a RhoA/JNK vs PI3K/Akt switch.\",\n      \"evidence\": \"Ocular hypertension model, LINGO-1-Fc/mAb, RhoA/JNK/Akt blots, kinase inhibitors\",\n      \"pmids\": [\"18326721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LINGO-1 bifurcates RhoA and Akt arms unclear\", \"Receptor partner in RGCs not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified WNK1 as an intracellular effector linking LINGO-1 to RhoA activation via Rho-GDI1.\",\n      \"evidence\": \"Yeast two-hybrid, FRET, co-IP, RNAi, DN, RhoA and neurite assays\",\n      \"pmids\": [\"19363035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical contact between LINGO-1 tail and WNK1 not mapped\", \"Kinase substrate landscape unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed N-glycosylation on the LRR concave surface is required for LINGO-1 surface trafficking.\",\n      \"evidence\": \"High-throughput mammalian expression, mutagenesis, surface expression assay\",\n      \"pmids\": [\"19254717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Functional consequence beyond surface expression untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified LINGO-1/TrkB complex as a brake on BDNF-dependent RGC survival, extending negative regulation to neurotrophin receptors.\",\n      \"evidence\": \"Co-IP, p-TrkB blot, anti-BDNF blockade, ocular hypertension model\",\n      \"pmids\": [\"20377621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect TrkB binding unresolved\", \"Single lab in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the molecular determinants of NgR1-LINGO-1 association, implicating gangliosides and the NgR1 stalk.\",\n      \"evidence\": \"Cell-free solid-phase binding with ganglioside manipulation\",\n      \"pmids\": [\"21872576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-free system only\", \"Physiological relevance of ganglioside bridging untested in neurons\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified RA-RAR-β as a transcriptional repressor of Lingo-1, explaining how retinoic acid overcomes myelin inhibition.\",\n      \"evidence\": \"RAR-β gain/loss, promoter reporter, neurite assay, dorsal column injury\",\n      \"pmids\": [\"21690307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAR-β binding site on promoter not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped self- and APP-interaction to ectodomain regions outside the LRR and TM/cytoplasmic domains.\",\n      \"evidence\": \"Deletional mutagenesis and binding assays\",\n      \"pmids\": [\"22133804\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab deletion-mapping with limited follow-up\", \"Functional significance of APP binding untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established LINGO-1 as a homophilic trans-acting ligand/receptor that activates RhoA in OPCs.\",\n      \"evidence\": \"Recombinant ectodomain binding, surface-bound LINGO-1 coculture, RhoA assay\",\n      \"pmids\": [\"22514275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-interaction interface not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed LINGO-1 promotes neuronal apoptosis by binding and inhibiting WNK3 through its intracellular domain.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, shRNA, DN WNK3, serum-deprivation apoptosis\",\n      \"pmids\": [\"23482566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"WNK3 anti-apoptotic substrates unidentified\", \"Relationship to WNK1/RhoA arm unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated LINGO-1 gates oligodendrocyte differentiation by blocking ErbB2 entry into lipid rafts.\",\n      \"evidence\": \"Co-IP, lipid raft fractionation, p-ErbB2 blot, KO oligodendrocytes, pharmacology\",\n      \"pmids\": [\"24583087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of raft exclusion unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how a therapeutic antibody works structurally, showing Li81 disrupts LINGO-1 oligomerization to block function.\",\n      \"evidence\": \"LINGO-1-Fab co-crystal, binding studies, oligodendrocyte differentiation assay\",\n      \"pmids\": [\"24756303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo correlation of quaternary rearrangement not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established constitutive cis-dimerization of LINGO-1 and that conformational modulators can tune EGFR-inhibitory activity.\",\n      \"evidence\": \"Co-IP, BRET saturation, small-molecule screen, EGFR/Erk blots\",\n      \"pmids\": [\"25257685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of cis-dimer with tetramer model unaddressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Challenged the surface ternary-complex model by showing LINGO-1 is predominantly intracellular and competes with NgR for p75NTR.\",\n      \"evidence\": \"Fractionation, immunofluorescence, C-terminus mutagenesis, co-IP competition, N-glycan analysis\",\n      \"pmids\": [\"25666623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological site of LINGO-1/p75 signaling unresolved\", \"Single lab contradicting prior model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified LINGO-1-driven lysosomal degradation of Trk receptors as a negative-feedback brake on neurotrophin signaling.\",\n      \"evidence\": \"Co-IP, lysosomal inhibitors, recycling endosome colocalization, deletion mutant in PC12\",\n      \"pmids\": [\"26546150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin/sorting machinery not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked LINGO-1 and paralogs to reduced amyloidogenic APP processing via lysosomal degradation.\",\n      \"evidence\": \"Cell-based APP processing assay, lysosomal pathway analysis\",\n      \"pmids\": [\"25758563\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic detail; abstract-level only\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed cytoplasmic gelsolin downstream of LINGO-1 as an actin-severing effector in OPC differentiation and remyelination.\",\n      \"evidence\": \"Anti-LINGO-1 antibody, cGSN siRNA/overexpression in vitro and in vivo, epistasis rescue\",\n      \"pmids\": [\"28193690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Connection from RhoA to cGSN regulation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined LINGO-1 as the NgR1 co-receptor restricting hippocampal LTP via ROCK2-Cofilin, excluding p75NTR involvement.\",\n      \"evidence\": \"Hippocampal slice electrophysiology, Lingo1 and p75NTR loss-of-function, pathway biochemistry\",\n      \"pmids\": [\"27166169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor partner replacing p75 in synaptic context unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an entirely distinct role for LINGO1 as a regulatory subunit of BK channels controlling inactivation and surface expression.\",\n      \"evidence\": \"Co-IP from human brain, patch-clamp of coexpressed channels, surface expression assay\",\n      \"pmids\": [\"31932443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native neuronal context of BK regulation not demonstrated\", \"Stoichiometry of LINGO1:BK unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified SP1 as the injury-induced transcription factor driving LINGO-1 expression in retinal ganglion cells.\",\n      \"evidence\": \"Promoter luciferase, SP1 overexpression qRT-PCR, in vivo SP1 shRNA, optic nerve crush\",\n      \"pmids\": [\"32562344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal activating SP1 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed LINGO-1 controls neural stem cell differentiation by modulating miR-15b-3p and Wnt5a translation.\",\n      \"evidence\": \"shRNA in NSPCs, miRNA-seq, Western/RT-qPCR, NSPC transplantation in SCI mice\",\n      \"pmids\": [\"34187584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LINGO-1 to miR-15b-3p levels unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected the BK-regulatory structure-function, attributing surface inhibition to the ectodomain and inactivation/gating to the intracellular tail.\",\n      \"evidence\": \"LINGO1/LINGO2 chimera domain swaps, patch-clamp, surface expression\",\n      \"pmids\": [\"40752573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic interface with BK channel unresolved\", \"LRR-independent mechanism not explained mechanistically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated LINGO1 into postoperative/aging cognitive decline via dual RhoA/ROCK1 activation and EGFR/PI3K/Akt suppression.\",\n      \"evidence\": \"AAV knockdown in aged mice, pathway Western blots, behavior\",\n      \"pmids\": [\"39781463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between tau phosphorylation and LINGO1 not directly tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed LINGO-1 negatively regulates CB1R/TrkB signaling and GABAergic interneuron integrity affecting spatial memory.\",\n      \"evidence\": \"AAV overexpression/silencing, CB1R pharmacology in HT22, Western blots, behavior\",\n      \"pmids\": [\"40441519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LINGO-1/CB1R binding not biochemically confirmed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LINGO-1's intracellular localization, cis-dimer/tetramer assembly, and competition with NgR for p75NTR are reconciled into a single coherent signaling topology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full NgR1/p75/LINGO-1 complex\", \"Native subcellular site of signaling disputed across studies\", \"Relationship between RhoA, WNK kinases, and BK-channel roles not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 24, 27]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 14, 23]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [24, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 18, 24]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 28]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [23, 24]}\n    ],\n    \"complexes\": [\n      \"NgR1/p75/LINGO-1 receptor complex\",\n      \"BK channel complex\"\n    ],\n    \"partners\": [\n      \"RTN4R\",\n      \"NGFR\",\n      \"WNK1\",\n      \"WNK3\",\n      \"ERBB2\",\n      \"NTRK2\",\n      \"EGFR\",\n      \"KCNMA1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":8,"faith_pct":87.5}}