{"gene":"CLDN11","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1999,"finding":"OSP/claudin-11 null mice lack tight junction intramembranous strands in CNS myelin and between Sertoli cells, demonstrating that CLDN11 is the mediator of parallel-array tight junction strands in these tissues, and is required for paracellular barrier formation essential for spermatogenesis and normal CNS nerve conduction.","method":"Knockout mouse (Osp-null), freeze fracture electron microscopy, electrophysiology, behavioral phenotyping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic knockout with multiple orthogonal readouts (freeze fracture EM, nerve conduction, behavioral deficits, sterility), replicated across two labs in the same year","pmids":["10612400"],"is_preprint":false},{"year":1999,"finding":"OSP/claudin-11 forms tight junction strands in transfected fibroblasts, and immunoelectron microscopy localizes it specifically to interlamellar strands of oligodendrocyte myelin sheaths and to Sertoli cell TJ strands in testis, establishing that interlamellar strands are a variant of TJ strands sharing claudin-11 with Sertoli cell junctions.","method":"Transfection of fibroblasts (TJ strand formation assay), immunofluorescence microscopy, immunoelectron microscopy, Northern blot","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct reconstitution of TJ strand formation in fibroblasts plus immunoelectron microscopy localization, independent replication by second group (PMID 10612400)","pmids":["10225958"],"is_preprint":false},{"year":2001,"finding":"OSP/claudin-11 forms a ternary complex with OAP-1 (a novel tetraspanin) and β1 integrin; this complex regulates oligodendrocyte proliferation and migration. OAP-1 was identified by yeast two-hybrid screen, confirmed by co-immunoprecipitation and confocal immunocytochemistry. Overexpression of OSP/claudin-11 or OAP-1 induced proliferation, and antibodies against each component or loss of OSP/claudin-11 impaired primary oligodendrocyte migration.","method":"Yeast two-hybrid screen, co-immunoprecipitation, confocal immunocytochemistry, overexpression assays, antibody inhibition of migration, OSP-deficient primary oligodendrocyte migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus functional loss-of-function migration assay, multiple orthogonal methods in one study","pmids":["11309411"],"is_preprint":false},{"year":2005,"finding":"In OSP/claudin-11 and PLP/DM20 double-knockout mice, CNS myelin compaction is severely disrupted and axon diameters are markedly reduced, while single knockouts have mild phenotypes. Furthermore, loss of one protein leads to compensatory upregulation of the other, demonstrating functional redundancy and an essential structural role for both proteins in maintaining compact myelin.","method":"Double-knockout mouse generation, electron microscopy of myelin, Western blot (compensatory expression), neurological assessment","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double-KO with EM structural readout and compensatory expression analysis, multiple orthogonal methods","pmids":["15886014"],"is_preprint":false},{"year":2006,"finding":"K+ channel KV3.1 associates with OSP/claudin-11; this interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-immunohistochemistry. KV3.1-specific currents and OSP/claudin-11 cooperate to regulate oligodendrocyte progenitor cell proliferation and migration, and KV3.1 knockout mice show decreased axon diameter and thinner myelin.","method":"Yeast two-hybrid, co-immunoprecipitation, co-immunohistochemistry, Kv3.1 knockout mouse, patch-clamp electrophysiology, proliferation and migration assays","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus KO phenotype, multiple orthogonal methods in one study","pmids":["16624990"],"is_preprint":false},{"year":2000,"finding":"During prenatal development CLDN11 is expressed in meninges, cartilage-adjacent areas, and mesoderm; postnatally, expression is restricted to oligodendrocytes (from early progenitor through mature stages) and testis. Electron microscopic immunohistochemistry localizes OSP/claudin-11 to laminar myelin in adult CNS. Two developmentally regulated transcripts were detected by Western blot.","method":"In situ hybridization, immunohistochemistry, electron microscopic immunohistochemistry, Western blot","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by EM-IHC with developmental context, single lab, multiple methods but no functional perturbation","pmids":["10797530"],"is_preprint":false},{"year":1997,"finding":"OSP is the third most abundant protein in CNS myelin, comprising approximately 7% of total myelin protein, and is enriched >30-fold in purified myelin. It is not a glycoprotein based on negative reactivity with agglutinins and HNK1 antibody.","method":"Immunohistochemistry, biochemical fractionation/purification of myelin, Western blot with peptide antibody","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biochemical fractionation with quantification, single lab, single study","pmids":["9418959"],"is_preprint":false},{"year":2012,"finding":"A 5 kb promoter/enhancer region upstream of exon 1 of Cldn11 is sufficient to rescue azoospermia in Cldn11-null mice via transgenic complementation, and cis-regulatory elements sufficient for Sertoli cell-specific expression are located within 2 kb upstream of the Cldn11 transcription start site.","method":"Transgenic mouse rescue of Cldn11-null azoospermia, promoter-deletion transgenic analysis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transgenic rescue of null phenotype with promoter deletion mapping, single lab","pmids":["22378758"],"is_preprint":false},{"year":2018,"finding":"CLDN11 is epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma (NPC); DNA methylation inhibits binding of the transcription activator GATA1 to the CLDN11 promoter region −62 to −53. Re-expression of CLDN11 reduces cell migration and invasion. Co-immunoprecipitation and LC-MS/MS identified tubulin alpha-1b (TUBA1B) and beta-3 (TUBB3) as CLDN11-interacting proteins; CLDN11 interacts through its intracellular loop and C-terminus and blocks tubulin polymerization to inhibit cell migration.","method":"MBD-ChIP sequencing, bisulfite sequencing, promoter reporter assay, EMSA, CLDN11 overexpression + migration/invasion assays, Co-immunoprecipitation, LC-MS/MS proteomics, nocodazole treatment","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus LC-MS/MS for interaction, domain mapping, functional rescue; single lab with multiple orthogonal methods","pmids":["29747653"],"is_preprint":false},{"year":2021,"finding":"De novo stop-loss variants in CLDN11 (c.622T>C and c.622T>G) cause hypomyelinating leukodystrophy. The c.622T>C variant does not trigger nonsense-mediated decay in fibroblasts, indicating translation of an extended protein predicted to form an α-helix not incorporated into the cytoplasmic membrane, potentially perturbing CLDN11 interactions with intracellular proteins.","method":"Exome sequencing, RNA expression analysis in patient fibroblasts, protein structure prediction","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — patient genetic variants with RNA-level functional validation in fibroblasts; structural prediction is computational but RNA result is experimental","pmids":["33313762"],"is_preprint":false},{"year":2021,"finding":"MALAT1 sequesters miR-146b-5p to maintain CLDN11 expression in intestinal epithelial cells; MALAT1 knockout mice are hypersensitive to DSS-induced colitis and show loss of CLDN11 at apical junction complexes. The MALAT1–miR-146b-5p–CLDN11 axis regulates intestinal mucosal barrier integrity.","method":"MALAT1 knockout mouse colitis model, lentiviral transfection, miRNA mimic/inhibitor, dual-luciferase reporter assay, Ago2-RIP, monolayer permeability assay, Western blot","journal":"Journal of Crohn's & colitis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase and Ago2-RIP validate miRNA–target interaction; CLDN11 functional consequence shown in KO mouse and cell assays; single lab","pmids":["33677577"],"is_preprint":false},{"year":2025,"finding":"CLDN11 mRNA stability in intestinal epithelial cells is regulated by IGF2BP3, which binds CLDN11 mRNA directly (validated by RNA immunoprecipitation and RNA pull-down). TNF-α treatment downregulates IGF2BP3 and consequently destabilizes CLDN11 mRNA, increasing intestinal paracellular permeability; CLDN11 overexpression reduces Caco-2 monolayer permeability and knockdown increases it.","method":"RNA immunoprecipitation (RIP), RNA pull-down assay, IGF2BP3/CLDN11 knockdown and overexpression, Caco-2 permeability assay, adeno-associated virus-mediated CLDN11 overexpression in obesity-related SAP model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pull-down establish direct mRNA–protein interaction; functional permeability consequence shown in vitro and in vivo; single lab","pmids":["39856555"],"is_preprint":false},{"year":2024,"finding":"CLDN11 deficiency in breast cancer cells activates the hedgehog signaling pathway, leading to upregulation of FOXM1 and sustained tumor proliferation and migration; in vivo, hedgehog signaling blockade suppressed tumor progression caused by CLDN11 silencing.","method":"CLDN11 siRNA silencing in MCF-7 and MDA-MB-231 cells, hedgehog pathway inhibitor in vivo, proliferation and migration assays, Western blot","journal":"Journal of molecular histology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inference from KD + inhibitor rescue without direct biochemical interaction between CLDN11 and hedgehog components","pmids":["39438406"],"is_preprint":false},{"year":2025,"finding":"CLDN11 promotes granulosa cell proliferation via the PI3K/AKT signaling pathway, increasing expression of CCND1 and PCNA; CLDN11 knockdown inhibited viability and increased apoptosis of granulosa cells, while AAV-mediated CLDN11 overexpression reversed the PCOS-like phenotype in a rat model.","method":"CLDN11 siRNA knockdown and overexpression in rat granulosa cells, PI3K/AKT pathway analysis, AAV-mediated overexpression in rat PCOS model, Western blot, cell viability and apoptosis assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway attribution based on downstream marker changes without direct biochemical CLDN11–PI3K interaction","pmids":["39875531"],"is_preprint":false},{"year":2024,"finding":"CXCR7 activation of the AKT pathway in fibroblasts promotes CLDN11 expression; fibroblast-secreted CLDN11 promotes gastric cancer cell proliferation and peritoneal metastasis in vitro and in vivo.","method":"Single-cell RNA sequencing, Western blot, immunohistochemistry, in vitro proliferation/migration assays, in vivo peritoneal metastasis model","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, CLDN11 secretion mechanism and downstream receptor on cancer cells not directly characterized","pmids":["38335659"],"is_preprint":false},{"year":2026,"finding":"CLDN11 knockdown in rat chondrocytes transcriptionally suppresses Tspan5 expression, leading to attenuation of Notch signaling and acceleration of osteoarthritis cartilage degeneration; Notch pathway inhibitor intervention worsened OA, consistent with CLDN11→Tspan5→Notch as a protective axis.","method":"Cldn11 RNAi lentivirus intra-articular injection in rat OA model, Notch inhibitor treatment, qRT-PCR, Western blot, immunohistochemistry, von Frey pain threshold","journal":"Journal of orthopaedic surgery and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on knockdown plus inhibitor without direct biochemical CLDN11–Tspan5 interaction","pmids":["41485015"],"is_preprint":false},{"year":2024,"finding":"Cldn11 knockout in mice impairs Sertoli cell polarization and disrupts basal localization of stem cell factor (SCF), a key molecule for spermatogonial maintenance, resulting in impaired differentiating spermatogonial proliferation. Spermatogenesis defects in Cldn11-null mice were not rescued on a severely immunodeficient background, indicating the defect is not caused by autoimmune attack on spermatogenic cells. Autoantibodies against spermatocyte/spermatid antigens were detected in Cldn11-null sera, providing direct evidence that Sertoli cell TJs form an immunological barrier.","method":"Cldn11 knockout mouse, immunodeficient background cross (genetic epistasis), serum autoantibody detection, SCF immunolocalization, spermatogonial proliferation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KO × immunodeficient background) plus direct SCF localization; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.07.16.602181"],"is_preprint":true}],"current_model":"CLDN11 (OSP) is a four-transmembrane claudin family protein that constitutes tight junction strands in CNS myelin sheaths and Sertoli cells; it forms a signaling complex with the tetraspanin OAP-1 and β1 integrin (and associates with KV3.1) to regulate oligodendrocyte progenitor proliferation and migration, interacts via its intracellular loop and C-terminus with tubulins TUBA1B/TUBB3 to suppress tubulin polymerization and cell migration, maintains intestinal paracellular barrier through IGF2BP3-stabilized mRNA regulated by TNF-α, creates a Sertoli cell microenvironment that polarizes SCF distribution to support spermatogonial proliferation, and is functionally redundant with PLP/DM20 in maintaining compact CNS myelin."},"narrative":{"mechanistic_narrative":"CLDN11 (oligodendrocyte-specific protein, OSP) is a claudin-family tight-junction protein that builds the parallel-array tight-junction strands of CNS myelin and Sertoli cell junctions, where it establishes the paracellular barriers required for normal nerve conduction and spermatogenesis [PMID:10612400, PMID:10225958]. It self-assembles into tight-junction strands when expressed in fibroblasts and localizes specifically to the interlamellar strands of oligodendrocyte myelin and to Sertoli cell junctions, making it one of the most abundant proteins of CNS myelin [PMID:10225958, PMID:9418959]. In myelin, CLDN11 acts redundantly with PLP/DM20 to maintain compact membrane wrapping and normal axon caliber, with each protein compensating for loss of the other [PMID:15886014]. Beyond its structural barrier role, CLDN11 functions in a signaling complex with the tetraspanin OAP-1 and β1 integrin, and associates with the K+ channel KV3.1, to regulate oligodendrocyte progenitor proliferation and migration [PMID:11309411, PMID:16624990]. In Sertoli cells, CLDN11-dependent junctions polarize the basal distribution of stem cell factor to support differentiating spermatogonia and form an immunological barrier that prevents autoimmune attack on germ cells [PMID:bio_10.1101_2024.07.16.602181]. In epithelial and cancer contexts, CLDN11 restrains cell migration and invasion by interacting through its intracellular loop and C-terminus with tubulins TUBA1B and TUBB3 to block tubulin polymerization, and its expression is controlled by promoter methylation, mRNA-stabilizing factors, and non-coding RNAs [PMID:29747653, PMID:39856555, PMID:33677577]. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy, consistent with its essential role in CNS myelin [PMID:33313762].","teleology":[{"year":1999,"claim":"Establishing whether a single claudin underlies the specialized tight-junction strands of myelin and Sertoli cells answered what molecule mediates these barriers and why their loss impairs conduction and fertility.","evidence":"Osp-null knockout mice analyzed by freeze-fracture EM, electrophysiology, and behavioral phenotyping; parallel reconstitution of TJ strands in transfected fibroblasts with immunoelectron microscopy localization","pmids":["10612400","10225958"],"confidence":"High","gaps":["Atomic/structural basis of strand formation not resolved","Partner claudins or accessory proteins in strands not defined here"]},{"year":2000,"claim":"Mapping CLDN11 expression across development clarified which lineages depend on it, refining the tissue scope of its barrier function.","evidence":"In situ hybridization, immunohistochemistry, EM-immunohistochemistry, and Western blot across prenatal and postnatal tissues","pmids":["10797530"],"confidence":"Medium","gaps":["Functional roles of prenatal meningeal/cartilage/mesoderm expression not tested","Identity and significance of the two developmental transcripts not resolved"]},{"year":2001,"claim":"Identifying CLDN11 binding partners showed that it is not merely structural but participates in a signaling complex governing oligodendrocyte progenitor behavior.","evidence":"Yeast two-hybrid screen identifying OAP-1, reciprocal co-IP, confocal immunocytochemistry, overexpression and antibody-inhibition migration assays, and OSP-deficient oligodendrocyte migration assays","pmids":["11309411"],"confidence":"High","gaps":["Downstream signaling output of the OSP–OAP-1–β1 integrin complex not defined","Stoichiometry of the ternary complex unknown"]},{"year":2005,"claim":"Double-knockout epistasis with PLP/DM20 resolved why single CLDN11 loss gives only mild myelin phenotypes, revealing functional redundancy in maintaining compact myelin.","evidence":"Cldn11/Plp double-knockout mice with EM of myelin, Western blot for compensatory expression, and neurological assessment","pmids":["15886014"],"confidence":"High","gaps":["Molecular basis of cross-compensation unknown","Whether CLDN11 and PLP physically interact not established"]},{"year":2006,"claim":"Linking CLDN11 to the KV3.1 K+ channel connected junctional protein function to ionic regulation of oligodendrocyte progenitor proliferation and migration.","evidence":"Yeast two-hybrid, reciprocal co-IP, co-immunohistochemistry, Kv3.1 knockout mouse, patch-clamp, and proliferation/migration assays","pmids":["16624990"],"confidence":"High","gaps":["Mechanism coupling channel activity to migration not defined","Whether KV3.1 binding modulates CLDN11 barrier function unknown"]},{"year":2012,"claim":"Defining the cis-regulatory region driving Sertoli-cell expression showed which DNA elements are sufficient to restore the fertility function of CLDN11.","evidence":"Transgenic rescue of Cldn11-null azoospermia with promoter-deletion mapping","pmids":["22378758"],"confidence":"Medium","gaps":["Specific transcription factors binding the Sertoli enhancer not identified","Regulation of oligodendrocyte expression not addressed here"]},{"year":2018,"claim":"Discovery of CLDN11–tubulin interaction and epigenetic silencing in cancer revealed a non-junctional, cytoskeleton-directed mechanism by which CLDN11 suppresses cell migration.","evidence":"MBD-ChIP-seq, bisulfite sequencing, promoter reporter/EMSA for GATA1, co-IP plus LC-MS/MS identifying TUBA1B/TUBB3, domain mapping, and migration/invasion assays with nocodazole","pmids":["29747653"],"confidence":"Medium","gaps":["Whether tubulin binding occurs in normal myelin/Sertoli contexts not tested","Structural basis of tubulin-polymerization blockade not resolved"]},{"year":2021,"claim":"Identification of de novo stop-loss variants tied CLDN11 directly to a human Mendelian myelin disease, establishing its non-redundant requirement in human CNS myelination.","evidence":"Exome sequencing of leukodystrophy patients, RNA expression analysis in patient fibroblasts, and structural prediction of the extended protein","pmids":["33313762"],"confidence":"Medium","gaps":["Functional consequence of the C-terminal extension on junction assembly not experimentally shown","Effect on intracellular partner interactions predicted but not demonstrated"]},{"year":2021,"claim":"Defining a MALAT1–miR-146b-5p–CLDN11 axis explained how CLDN11 levels are post-transcriptionally tuned to maintain the intestinal mucosal barrier.","evidence":"MALAT1 knockout colitis model, dual-luciferase reporter, Ago2-RIP, miRNA mimic/inhibitor, and monolayer permeability assays","pmids":["33677577"],"confidence":"Medium","gaps":["Direct CLDN11 junctional role in gut versus indirect effects not fully separated","Single-lab finding"]},{"year":2025,"claim":"Identifying IGF2BP3 as a CLDN11 mRNA stabilizer downstream of TNF-α linked inflammatory signaling to control of intestinal paracellular permeability through CLDN11.","evidence":"RNA immunoprecipitation and RNA pull-down, IGF2BP3/CLDN11 knockdown/overexpression, Caco-2 permeability assays, and AAV-mediated overexpression in an in vivo model","pmids":["39856555"],"confidence":"Medium","gaps":["Whether IGF2BP3 regulates CLDN11 in CNS or testis unknown","Single-lab finding"]},{"year":2024,"claim":"Sertoli-cell knockout work resolved whether spermatogenesis failure is barrier-driven or autoimmune, showing CLDN11 polarizes SCF distribution and forms an immunological barrier.","evidence":"Cldn11 knockout crossed to immunodeficient background (genetic epistasis), serum autoantibody detection, SCF immunolocalization, and spermatogonial proliferation assays (preprint)","pmids":["bio_10.1101_2024.07.16.602181"],"confidence":"Medium","gaps":["Mechanism by which CLDN11 junctions polarize SCF not defined","Preprint, not yet peer-reviewed"]},{"year":2024,"claim":"Cancer studies placed CLDN11 in growth-signaling contexts (hedgehog/FOXM1 in breast cancer; fibroblast-secreted CLDN11 in gastric cancer), implicating altered CLDN11 in tumor proliferation and metastasis.","evidence":"siRNA silencing with hedgehog inhibitor in breast cancer cells and in vivo; single-cell RNA-seq and metastasis models implicating CXCR7/AKT-driven fibroblast CLDN11 in gastric cancer","pmids":["39438406","38335659"],"confidence":"Low","gaps":["No direct biochemical interaction between CLDN11 and hedgehog or secretion machinery shown","Context-dependent and possibly opposing roles not reconciled"]},{"year":null,"claim":"How CLDN11's structural barrier activity, cytoskeletal tubulin engagement, and the various signaling outputs (PI3K/AKT, hedgehog, Notch) mechanistically integrate within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CLDN11 strands or partner complexes","Whether signaling roles are direct or secondary to barrier disruption unknown","Tissue-specific partner usage not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5]}],"complexes":["CNS myelin tight-junction (interlamellar) strands","Sertoli cell tight junction","OSP/CLDN11–OAP-1–β1 integrin complex"],"partners":["OAP-1","ITGB1","KCNC1","TUBA1B","TUBB3","PLP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75508","full_name":"Claudin-11","aliases":["Oligodendrocyte-specific protein"],"length_aa":207,"mass_kda":22.0,"function":"Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity","subcellular_location":"Cell junction, tight junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O75508/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLDN11","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/CLDN11","total_profiled":1310},"omim":[{"mim_id":"619328","title":"LEUKODYSTROPHY, HYPOMYELINATING, 22; HLD22","url":"https://www.omim.org/entry/619328"},{"mim_id":"602910","title":"CLAUDIN 3; CLDN3","url":"https://www.omim.org/entry/602910"},{"mim_id":"601326","title":"CLAUDIN 11; CLDN11","url":"https://www.omim.org/entry/601326"},{"mim_id":"312080","title":"PELIZAEUS-MERZBACHER DISEASE; PMD","url":"https://www.omim.org/entry/312080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Lipid droplets","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":119.5},{"tissue":"ovary","ntpm":46.0},{"tissue":"testis","ntpm":50.6}],"url":"https://www.proteinatlas.org/search/CLDN11"},"hgnc":{"alias_symbol":["OSP"],"prev_symbol":["OTM"]},"alphafold":{"accession":"O75508","domains":[{"cath_id":"1.20.140.150","chopping":"11-30_76-188","consensus_level":"high","plddt":90.8137,"start":11,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75508","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75508-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75508-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLDN11","jax_strain_url":"https://www.jax.org/strain/search?query=CLDN11"},"sequence":{"accession":"O75508","fasta_url":"https://rest.uniprot.org/uniprotkb/O75508.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75508/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75508"}},"corpus_meta":[{"pmid":"10612400","id":"PMC_10612400","title":"CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10612400","citation_count":587,"is_preprint":false},{"pmid":"10225958","id":"PMC_10225958","title":"Claudin-11/OSP-based tight junctions of myelin sheaths in brain and Sertoli cells in testis.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10225958","citation_count":363,"is_preprint":false},{"pmid":"11309411","id":"PMC_11309411","title":"OSP/claudin-11 forms a complex with a novel member of the tetraspanin super family and beta1 integrin and regulates proliferation and migration of oligodendrocytes.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11309411","citation_count":153,"is_preprint":false},{"pmid":"1563773","id":"PMC_1563773","title":"Heterogeneity of outer membrane proteins in Borrelia burgdorferi: comparison of osp operons of three isolates of different geographic origins.","date":"1992","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/1563773","citation_count":127,"is_preprint":false},{"pmid":"1842929","id":"PMC_1842929","title":"OSP: a computer program for choosing PCR and DNA sequencing primers.","date":"1991","source":"PCR methods and applications","url":"https://pubmed.ncbi.nlm.nih.gov/1842929","citation_count":112,"is_preprint":false},{"pmid":"10338494","id":"PMC_10338494","title":"Access of antibody or trypsin to an integral outer membrane protein (P66) of Borrelia burgdorferi is hindered by Osp lipoproteins.","date":"1999","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10338494","citation_count":108,"is_preprint":false},{"pmid":"9203661","id":"PMC_9203661","title":"Immunization with outer surface protein (Osp) A, but not OspC, provides cross-protection of mice challenged with North American isolates of Borrelia burgdorferi.","date":"1997","source":"The 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mice lack tight junction intramembranous strands in CNS myelin and between Sertoli cells, demonstrating that CLDN11 is the mediator of parallel-array tight junction strands in these tissues, and is required for paracellular barrier formation essential for spermatogenesis and normal CNS nerve conduction.\",\n      \"method\": \"Knockout mouse (Osp-null), freeze fracture electron microscopy, electrophysiology, behavioral phenotyping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic knockout with multiple orthogonal readouts (freeze fracture EM, nerve conduction, behavioral deficits, sterility), replicated across two labs in the same year\",\n      \"pmids\": [\"10612400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"OSP/claudin-11 forms tight junction strands in transfected fibroblasts, and immunoelectron microscopy localizes it specifically to interlamellar strands of oligodendrocyte myelin sheaths and to Sertoli cell TJ strands in testis, establishing that interlamellar strands are a variant of TJ strands sharing claudin-11 with Sertoli cell junctions.\",\n      \"method\": \"Transfection of fibroblasts (TJ strand formation assay), immunofluorescence microscopy, immunoelectron microscopy, Northern blot\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct reconstitution of TJ strand formation in fibroblasts plus immunoelectron microscopy localization, independent replication by second group (PMID 10612400)\",\n      \"pmids\": [\"10225958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"OSP/claudin-11 forms a ternary complex with OAP-1 (a novel tetraspanin) and β1 integrin; this complex regulates oligodendrocyte proliferation and migration. OAP-1 was identified by yeast two-hybrid screen, confirmed by co-immunoprecipitation and confocal immunocytochemistry. Overexpression of OSP/claudin-11 or OAP-1 induced proliferation, and antibodies against each component or loss of OSP/claudin-11 impaired primary oligodendrocyte migration.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, confocal immunocytochemistry, overexpression assays, antibody inhibition of migration, OSP-deficient primary oligodendrocyte migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus functional loss-of-function migration assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11309411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In OSP/claudin-11 and PLP/DM20 double-knockout mice, CNS myelin compaction is severely disrupted and axon diameters are markedly reduced, while single knockouts have mild phenotypes. Furthermore, loss of one protein leads to compensatory upregulation of the other, demonstrating functional redundancy and an essential structural role for both proteins in maintaining compact myelin.\",\n      \"method\": \"Double-knockout mouse generation, electron microscopy of myelin, Western blot (compensatory expression), neurological assessment\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double-KO with EM structural readout and compensatory expression analysis, multiple orthogonal methods\",\n      \"pmids\": [\"15886014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"K+ channel KV3.1 associates with OSP/claudin-11; this interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-immunohistochemistry. KV3.1-specific currents and OSP/claudin-11 cooperate to regulate oligodendrocyte progenitor cell proliferation and migration, and KV3.1 knockout mice show decreased axon diameter and thinner myelin.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-immunohistochemistry, Kv3.1 knockout mouse, patch-clamp electrophysiology, proliferation and migration assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus KO phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16624990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"During prenatal development CLDN11 is expressed in meninges, cartilage-adjacent areas, and mesoderm; postnatally, expression is restricted to oligodendrocytes (from early progenitor through mature stages) and testis. Electron microscopic immunohistochemistry localizes OSP/claudin-11 to laminar myelin in adult CNS. Two developmentally regulated transcripts were detected by Western blot.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, electron microscopic immunohistochemistry, Western blot\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by EM-IHC with developmental context, single lab, multiple methods but no functional perturbation\",\n      \"pmids\": [\"10797530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"OSP is the third most abundant protein in CNS myelin, comprising approximately 7% of total myelin protein, and is enriched >30-fold in purified myelin. It is not a glycoprotein based on negative reactivity with agglutinins and HNK1 antibody.\",\n      \"method\": \"Immunohistochemistry, biochemical fractionation/purification of myelin, Western blot with peptide antibody\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biochemical fractionation with quantification, single lab, single study\",\n      \"pmids\": [\"9418959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A 5 kb promoter/enhancer region upstream of exon 1 of Cldn11 is sufficient to rescue azoospermia in Cldn11-null mice via transgenic complementation, and cis-regulatory elements sufficient for Sertoli cell-specific expression are located within 2 kb upstream of the Cldn11 transcription start site.\",\n      \"method\": \"Transgenic mouse rescue of Cldn11-null azoospermia, promoter-deletion transgenic analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transgenic rescue of null phenotype with promoter deletion mapping, single lab\",\n      \"pmids\": [\"22378758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLDN11 is epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma (NPC); DNA methylation inhibits binding of the transcription activator GATA1 to the CLDN11 promoter region −62 to −53. Re-expression of CLDN11 reduces cell migration and invasion. Co-immunoprecipitation and LC-MS/MS identified tubulin alpha-1b (TUBA1B) and beta-3 (TUBB3) as CLDN11-interacting proteins; CLDN11 interacts through its intracellular loop and C-terminus and blocks tubulin polymerization to inhibit cell migration.\",\n      \"method\": \"MBD-ChIP sequencing, bisulfite sequencing, promoter reporter assay, EMSA, CLDN11 overexpression + migration/invasion assays, Co-immunoprecipitation, LC-MS/MS proteomics, nocodazole treatment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus LC-MS/MS for interaction, domain mapping, functional rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29747653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"De novo stop-loss variants in CLDN11 (c.622T>C and c.622T>G) cause hypomyelinating leukodystrophy. The c.622T>C variant does not trigger nonsense-mediated decay in fibroblasts, indicating translation of an extended protein predicted to form an α-helix not incorporated into the cytoplasmic membrane, potentially perturbing CLDN11 interactions with intracellular proteins.\",\n      \"method\": \"Exome sequencing, RNA expression analysis in patient fibroblasts, protein structure prediction\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — patient genetic variants with RNA-level functional validation in fibroblasts; structural prediction is computational but RNA result is experimental\",\n      \"pmids\": [\"33313762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MALAT1 sequesters miR-146b-5p to maintain CLDN11 expression in intestinal epithelial cells; MALAT1 knockout mice are hypersensitive to DSS-induced colitis and show loss of CLDN11 at apical junction complexes. The MALAT1–miR-146b-5p–CLDN11 axis regulates intestinal mucosal barrier integrity.\",\n      \"method\": \"MALAT1 knockout mouse colitis model, lentiviral transfection, miRNA mimic/inhibitor, dual-luciferase reporter assay, Ago2-RIP, monolayer permeability assay, Western blot\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase and Ago2-RIP validate miRNA–target interaction; CLDN11 functional consequence shown in KO mouse and cell assays; single lab\",\n      \"pmids\": [\"33677577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLDN11 mRNA stability in intestinal epithelial cells is regulated by IGF2BP3, which binds CLDN11 mRNA directly (validated by RNA immunoprecipitation and RNA pull-down). TNF-α treatment downregulates IGF2BP3 and consequently destabilizes CLDN11 mRNA, increasing intestinal paracellular permeability; CLDN11 overexpression reduces Caco-2 monolayer permeability and knockdown increases it.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down assay, IGF2BP3/CLDN11 knockdown and overexpression, Caco-2 permeability assay, adeno-associated virus-mediated CLDN11 overexpression in obesity-related SAP model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pull-down establish direct mRNA–protein interaction; functional permeability consequence shown in vitro and in vivo; single lab\",\n      \"pmids\": [\"39856555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLDN11 deficiency in breast cancer cells activates the hedgehog signaling pathway, leading to upregulation of FOXM1 and sustained tumor proliferation and migration; in vivo, hedgehog signaling blockade suppressed tumor progression caused by CLDN11 silencing.\",\n      \"method\": \"CLDN11 siRNA silencing in MCF-7 and MDA-MB-231 cells, hedgehog pathway inhibitor in vivo, proliferation and migration assays, Western blot\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inference from KD + inhibitor rescue without direct biochemical interaction between CLDN11 and hedgehog components\",\n      \"pmids\": [\"39438406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLDN11 promotes granulosa cell proliferation via the PI3K/AKT signaling pathway, increasing expression of CCND1 and PCNA; CLDN11 knockdown inhibited viability and increased apoptosis of granulosa cells, while AAV-mediated CLDN11 overexpression reversed the PCOS-like phenotype in a rat model.\",\n      \"method\": \"CLDN11 siRNA knockdown and overexpression in rat granulosa cells, PI3K/AKT pathway analysis, AAV-mediated overexpression in rat PCOS model, Western blot, cell viability and apoptosis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway attribution based on downstream marker changes without direct biochemical CLDN11–PI3K interaction\",\n      \"pmids\": [\"39875531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CXCR7 activation of the AKT pathway in fibroblasts promotes CLDN11 expression; fibroblast-secreted CLDN11 promotes gastric cancer cell proliferation and peritoneal metastasis in vitro and in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, Western blot, immunohistochemistry, in vitro proliferation/migration assays, in vivo peritoneal metastasis model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, CLDN11 secretion mechanism and downstream receptor on cancer cells not directly characterized\",\n      \"pmids\": [\"38335659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CLDN11 knockdown in rat chondrocytes transcriptionally suppresses Tspan5 expression, leading to attenuation of Notch signaling and acceleration of osteoarthritis cartilage degeneration; Notch pathway inhibitor intervention worsened OA, consistent with CLDN11→Tspan5→Notch as a protective axis.\",\n      \"method\": \"Cldn11 RNAi lentivirus intra-articular injection in rat OA model, Notch inhibitor treatment, qRT-PCR, Western blot, immunohistochemistry, von Frey pain threshold\",\n      \"journal\": \"Journal of orthopaedic surgery and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on knockdown plus inhibitor without direct biochemical CLDN11–Tspan5 interaction\",\n      \"pmids\": [\"41485015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cldn11 knockout in mice impairs Sertoli cell polarization and disrupts basal localization of stem cell factor (SCF), a key molecule for spermatogonial maintenance, resulting in impaired differentiating spermatogonial proliferation. Spermatogenesis defects in Cldn11-null mice were not rescued on a severely immunodeficient background, indicating the defect is not caused by autoimmune attack on spermatogenic cells. Autoantibodies against spermatocyte/spermatid antigens were detected in Cldn11-null sera, providing direct evidence that Sertoli cell TJs form an immunological barrier.\",\n      \"method\": \"Cldn11 knockout mouse, immunodeficient background cross (genetic epistasis), serum autoantibody detection, SCF immunolocalization, spermatogonial proliferation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KO × immunodeficient background) plus direct SCF localization; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.16.602181\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CLDN11 (OSP) is a four-transmembrane claudin family protein that constitutes tight junction strands in CNS myelin sheaths and Sertoli cells; it forms a signaling complex with the tetraspanin OAP-1 and β1 integrin (and associates with KV3.1) to regulate oligodendrocyte progenitor proliferation and migration, interacts via its intracellular loop and C-terminus with tubulins TUBA1B/TUBB3 to suppress tubulin polymerization and cell migration, maintains intestinal paracellular barrier through IGF2BP3-stabilized mRNA regulated by TNF-α, creates a Sertoli cell microenvironment that polarizes SCF distribution to support spermatogonial proliferation, and is functionally redundant with PLP/DM20 in maintaining compact CNS myelin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLDN11 (oligodendrocyte-specific protein, OSP) is a claudin-family tight-junction protein that builds the parallel-array tight-junction strands of CNS myelin and Sertoli cell junctions, where it establishes the paracellular barriers required for normal nerve conduction and spermatogenesis [#0, #1]. It self-assembles into tight-junction strands when expressed in fibroblasts and localizes specifically to the interlamellar strands of oligodendrocyte myelin and to Sertoli cell junctions, making it one of the most abundant proteins of CNS myelin [#1, #6]. In myelin, CLDN11 acts redundantly with PLP/DM20 to maintain compact membrane wrapping and normal axon caliber, with each protein compensating for loss of the other [#3]. Beyond its structural barrier role, CLDN11 functions in a signaling complex with the tetraspanin OAP-1 and \\u03b21 integrin, and associates with the K+ channel KV3.1, to regulate oligodendrocyte progenitor proliferation and migration [#2, #4]. In Sertoli cells, CLDN11-dependent junctions polarize the basal distribution of stem cell factor to support differentiating spermatogonia and form an immunological barrier that prevents autoimmune attack on germ cells [#16]. In epithelial and cancer contexts, CLDN11 restrains cell migration and invasion by interacting through its intracellular loop and C-terminus with tubulins TUBA1B and TUBB3 to block tubulin polymerization, and its expression is controlled by promoter methylation, mRNA-stabilizing factors, and non-coding RNAs [#8, #11, #10]. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy, consistent with its essential role in CNS myelin [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing whether a single claudin underlies the specialized tight-junction strands of myelin and Sertoli cells answered what molecule mediates these barriers and why their loss impairs conduction and fertility.\",\n      \"evidence\": \"Osp-null knockout mice analyzed by freeze-fracture EM, electrophysiology, and behavioral phenotyping; parallel reconstitution of TJ strands in transfected fibroblasts with immunoelectron microscopy localization\",\n      \"pmids\": [\"10612400\", \"10225958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic/structural basis of strand formation not resolved\", \"Partner claudins or accessory proteins in strands not defined here\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping CLDN11 expression across development clarified which lineages depend on it, refining the tissue scope of its barrier function.\",\n      \"evidence\": \"In situ hybridization, immunohistochemistry, EM-immunohistochemistry, and Western blot across prenatal and postnatal tissues\",\n      \"pmids\": [\"10797530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of prenatal meningeal/cartilage/mesoderm expression not tested\", \"Identity and significance of the two developmental transcripts not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying CLDN11 binding partners showed that it is not merely structural but participates in a signaling complex governing oligodendrocyte progenitor behavior.\",\n      \"evidence\": \"Yeast two-hybrid screen identifying OAP-1, reciprocal co-IP, confocal immunocytochemistry, overexpression and antibody-inhibition migration assays, and OSP-deficient oligodendrocyte migration assays\",\n      \"pmids\": [\"11309411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling output of the OSP\\u2013OAP-1\\u2013\\u03b21 integrin complex not defined\", \"Stoichiometry of the ternary complex unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Double-knockout epistasis with PLP/DM20 resolved why single CLDN11 loss gives only mild myelin phenotypes, revealing functional redundancy in maintaining compact myelin.\",\n      \"evidence\": \"Cldn11/Plp double-knockout mice with EM of myelin, Western blot for compensatory expression, and neurological assessment\",\n      \"pmids\": [\"15886014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cross-compensation unknown\", \"Whether CLDN11 and PLP physically interact not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking CLDN11 to the KV3.1 K+ channel connected junctional protein function to ionic regulation of oligodendrocyte progenitor proliferation and migration.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, co-immunohistochemistry, Kv3.1 knockout mouse, patch-clamp, and proliferation/migration assays\",\n      \"pmids\": [\"16624990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling channel activity to migration not defined\", \"Whether KV3.1 binding modulates CLDN11 barrier function unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining the cis-regulatory region driving Sertoli-cell expression showed which DNA elements are sufficient to restore the fertility function of CLDN11.\",\n      \"evidence\": \"Transgenic rescue of Cldn11-null azoospermia with promoter-deletion mapping\",\n      \"pmids\": [\"22378758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific transcription factors binding the Sertoli enhancer not identified\", \"Regulation of oligodendrocyte expression not addressed here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of CLDN11\\u2013tubulin interaction and epigenetic silencing in cancer revealed a non-junctional, cytoskeleton-directed mechanism by which CLDN11 suppresses cell migration.\",\n      \"evidence\": \"MBD-ChIP-seq, bisulfite sequencing, promoter reporter/EMSA for GATA1, co-IP plus LC-MS/MS identifying TUBA1B/TUBB3, domain mapping, and migration/invasion assays with nocodazole\",\n      \"pmids\": [\"29747653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tubulin binding occurs in normal myelin/Sertoli contexts not tested\", \"Structural basis of tubulin-polymerization blockade not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of de novo stop-loss variants tied CLDN11 directly to a human Mendelian myelin disease, establishing its non-redundant requirement in human CNS myelination.\",\n      \"evidence\": \"Exome sequencing of leukodystrophy patients, RNA expression analysis in patient fibroblasts, and structural prediction of the extended protein\",\n      \"pmids\": [\"33313762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the C-terminal extension on junction assembly not experimentally shown\", \"Effect on intracellular partner interactions predicted but not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a MALAT1\\u2013miR-146b-5p\\u2013CLDN11 axis explained how CLDN11 levels are post-transcriptionally tuned to maintain the intestinal mucosal barrier.\",\n      \"evidence\": \"MALAT1 knockout colitis model, dual-luciferase reporter, Ago2-RIP, miRNA mimic/inhibitor, and monolayer permeability assays\",\n      \"pmids\": [\"33677577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CLDN11 junctional role in gut versus indirect effects not fully separated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying IGF2BP3 as a CLDN11 mRNA stabilizer downstream of TNF-\\u03b1 linked inflammatory signaling to control of intestinal paracellular permeability through CLDN11.\",\n      \"evidence\": \"RNA immunoprecipitation and RNA pull-down, IGF2BP3/CLDN11 knockdown/overexpression, Caco-2 permeability assays, and AAV-mediated overexpression in an in vivo model\",\n      \"pmids\": [\"39856555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IGF2BP3 regulates CLDN11 in CNS or testis unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Sertoli-cell knockout work resolved whether spermatogenesis failure is barrier-driven or autoimmune, showing CLDN11 polarizes SCF distribution and forms an immunological barrier.\",\n      \"evidence\": \"Cldn11 knockout crossed to immunodeficient background (genetic epistasis), serum autoantibody detection, SCF immunolocalization, and spermatogonial proliferation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.16.602181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CLDN11 junctions polarize SCF not defined\", \"Preprint, not yet peer-reviewed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cancer studies placed CLDN11 in growth-signaling contexts (hedgehog/FOXM1 in breast cancer; fibroblast-secreted CLDN11 in gastric cancer), implicating altered CLDN11 in tumor proliferation and metastasis.\",\n      \"evidence\": \"siRNA silencing with hedgehog inhibitor in breast cancer cells and in vivo; single-cell RNA-seq and metastasis models implicating CXCR7/AKT-driven fibroblast CLDN11 in gastric cancer\",\n      \"pmids\": [\"39438406\", \"38335659\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction between CLDN11 and hedgehog or secretion machinery shown\", \"Context-dependent and possibly opposing roles not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CLDN11's structural barrier activity, cytoskeletal tubulin engagement, and the various signaling outputs (PI3K/AKT, hedgehog, Notch) mechanistically integrate within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CLDN11 strands or partner complexes\", \"Whether signaling roles are direct or secondary to barrier disruption unknown\", \"Tissue-specific partner usage not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\"CNS myelin tight-junction (interlamellar) strands\", \"Sertoli cell tight junction\", \"OSP/CLDN11\\u2013OAP-1\\u2013\\u03b21 integrin complex\"],\n    \"partners\": [\"OAP-1\", \"ITGB1\", \"KCNC1\", \"TUBA1B\", \"TUBB3\", \"PLP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}