{"gene":"TENM2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"Cryo-EM structure of the human TEN2 extracellular region (ECR) at 3.1 Å resolution reveals a striking similarity to bacterial Tc-toxins, featuring a large β-barrel that partially encapsulates a C-terminal domain, an immunoglobulin-like domain sealing the barrel bottom, and a β-propeller in perpendicular orientation. An alternatively spliced region within the β-propeller acts as a switch: one splice variant activates trans-cellular signaling in a latrophilin (LPHN)-dependent manner, while the other induces inhibitory postsynaptic differentiation.","method":"Single-particle cryo-EM at 3.1 Å resolution; functional assays of splice variants in trans-cellular adhesion and postsynaptic differentiation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structure with functional validation of alternative splicing switch, published in top journal","pmids":["29677516"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of the TEN2–LPHN3 complex at 2.9 Å resolution shows that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site distant from the alternatively spliced region. Alternative splicing regulates TEN2–LPHN3 interaction by sterically hindering access to the LPHN-binding surface rather than altering it. A trimeric TEN2–LPHN3–FLRT3 complex was also described. Mutagenesis of the LPHN-binding surface of TEN2 abolished LPHN3 interaction and impaired excitatory but not inhibitory synapse formation.","method":"Single-particle cryo-EM at 2.9 Å; site-directed mutagenesis; synapse formation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution structure combined with mutagenesis and functional synapse assays in a single rigorous study","pmids":["32358586"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM data of TEN2 shows that canonical Latrophilin binding is sterically incompatible with TEN2 homodimerization, making these two interactions mutually exclusive. Engineered surface mutations that specifically disrupt TEN2–TEN2 or TEN2–Latrophilin interactions confirmed distinct binding interfaces, and these binding mechanisms are conserved in TEN4.","method":"Single-particle cryo-EM; surface mutagenesis; proteomics; super-resolution microscopy; in vivo gene editing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural data plus mutagenesis and multiple orthogonal in vivo methods in one peer-reviewed study","pmids":["41991904"],"is_preprint":false},{"year":2019,"finding":"TEN2/Lasso is proteolytically cleaved at multiple sites and its extracellular domain is partially released into the intercellular space, especially during neuronal development. The soluble fragment of Lasso (TEN2 ECR) can diffuse and bind to LPHN1 on axonal growth cones, triggering LPHN1 redistribution on the cell surface and intracellular signaling leading to local exocytosis, causing axons to turn toward spatio-temporal Lasso gradients. LPHN1 knockout blocks this guidance effect.","method":"Affinity chromatography (isolation of TEN2/Lasso as endogenous LPHN1 ligand); live imaging of growth cone turning; LPHN1 KO epistasis","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical isolation plus KO epistasis and live-cell functional assay, single lab review/summary paper citing original experimental findings","pmids":["30967757"],"is_preprint":false},{"year":2023,"finding":"TEN2 localizes preferentially to inhibitory postsynapses that recruit microtubule (MT) plus ends, and interacts physically with MT plus-end tracking proteins (EB proteins). This TEN2–EB interaction recruits MTs to inhibitory postsynapses and provides a platform for GABAA receptor exocytosis.","method":"Live imaging; co-immunoprecipitation (TEN2 with EB proteins); subcellular fractionation; GABAA receptor exocytosis assay","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus live imaging and functional receptor exocytosis readout, single lab","pmids":["37272607"],"is_preprint":false},{"year":2013,"finding":"Ten-m2 knockout (KO) mice show a specific decrease in ipsilateral retinal ganglion cell projections to the dorsal lateral geniculate nucleus and superior colliculus, most prominent in ventral retina. Reduction of EphB1 expression in ventral retina of KO mice suggests TEN-M2 interacts with the EphB1 molecular pathway downstream of Zic2 to establish ipsilateral projections required for binocular circuit formation. Visually evoked potential recordings confirmed reduced ipsilateral-to-contralateral response ratio in KOs.","method":"Ten-m2 KO mouse; anterograde/retrograde axonal tracing; immunohistochemistry (EphB1, Zic2, c-fos); visually evoked potential recordings; behavioral swim task","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal anatomical, molecular, electrophysiological, and behavioral readouts defining pathway position","pmids":["23884953"],"is_preprint":false},{"year":2019,"finding":"Ten-2 immunoreactivity is significantly upregulated in reactive astrocytes following mechanical brain injury, and reactive astrocytes also show intense immunoreactivity for LPHN-1 (latrophilin-1). TCAP-1 treatment of immortalized cerebellar astrocytes elicited a significant increase in intracellular calcium concentration.","method":"Immunohistochemistry; conventional RT-PCR; fluorescence microscopy with intracellular calcium indicator after TCAP-1 treatment","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemistry with functional calcium signaling assay, replicated across brain injury time points, single lab","pmids":["31316338"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated knockdown of TENM2 in human SGBS preadipocytes induces UCP1 mRNA and protein expression upon adipogenic differentiation without affecting mitochondrial mass. TENM2 knockdown also increased basal and leak mitochondrial respiration, indicating that TENM2 suppresses a brown adipocyte transcriptional program in white adipocyte precursors.","method":"siRNA knockdown; qRT-PCR; western blot (UCP1); Seahorse mitochondrial respiration assay","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal molecular and functional readouts in human cell model, single lab","pmids":["28088466"],"is_preprint":false},{"year":2026,"finding":"Following status epilepticus (SE) induction in rats, Ten-2, TCAP-2, and ADGRL1 (latrophilin-1) are significantly upregulated at both mRNA and protein levels in reactive astrocytes of the cerebral cortex and hippocampal CA3 region. Ten-2-LI and ADGRL1-LI colocalize in the same reactive astrocyte profiles positioned in regions of neuronal degeneration.","method":"Immunohistochemistry; quantitative RT-PCR; Fluoro-Jade C staining for neurodegeneration; LiCl-pilocarpine SE rat model","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO/injury model with orthogonal IHC and qPCR, colocalization data, single lab","pmids":["41930255"],"is_preprint":false}],"current_model":"TENM2 (TEN2/Lasso) is a type II transmembrane cell-adhesion protein whose extracellular region adopts a bacterial Tc-toxin-like β-barrel fold; an alternatively spliced insert within the β-propeller domain sterically gates access to a distant latrophilin (LPHN/ADGRL) binding surface, switching TEN2 function between excitatory synapse promotion (via the TEN2–LPHN3–FLRT3 trimeric complex) and inhibitory synapse induction, while TEN2 homodimerization and LPHN binding are mutually exclusive; at inhibitory synapses TEN2 recruits microtubule plus ends via EB proteins to facilitate GABAA receptor exocytosis; proteolytically shed soluble TEN2/Lasso acts as an axonal guidance cue by engaging LPHN1 on growth cones to trigger local exocytosis and axon turning; and in vivo, TEN2 is required for formation of ipsilateral retinal projections and binocular circuits, partly through regulation of EphB1 in ventral retina."},"narrative":{"mechanistic_narrative":"TENM2 (TEN2/Lasso) is a type II transmembrane cell-adhesion protein that organizes synaptic and axonal connectivity through ligand-gated trans-cellular signaling [PMID:29677516, PMID:23884953]. Its extracellular region adopts a Tc-toxin-like architecture in which a large β-barrel partially encapsulates a C-terminal domain, sealed by an immunoglobulin-like domain and apposed by a β-propeller; an alternatively spliced insert within the β-propeller acts as a molecular switch, with one variant driving latrophilin (LPHN)-dependent trans-cellular signaling and the other inducing inhibitory postsynaptic differentiation [PMID:29677516]. The N-terminal lectin domain of LPHN3 docks onto the TEN2 barrel at a site distant from the spliced region, and splicing controls this interaction by sterically occluding access to the LPHN-binding surface rather than altering it directly; mutation of this surface abolishes LPHN3 binding and selectively impairs excitatory but not inhibitory synapse formation, consistent with TEN2 acting within a trimeric TEN2–LPHN3–FLRT3 complex [PMID:32358586]. LPHN engagement and TEN2 homodimerization are mutually exclusive, occupying distinct conserved interfaces [PMID:41991904]. At inhibitory postsynapses, TEN2 binds microtubule plus-end tracking EB proteins to recruit microtubules and support GABAA receptor exocytosis [PMID:37272607], while proteolytically shed soluble TEN2 ECR diffuses to engage LPHN1 on growth cones, triggering local exocytosis and gradient-directed axon turning [PMID:30967757]. In vivo, TENM2 is required for ipsilateral retinal ganglion cell projections and binocular circuit formation, acting downstream of Zic2 through regulation of EphB1 in ventral retina [PMID:23884953]. Beyond the nervous system, TENM2 suppresses a brown-adipocyte (UCP1) transcriptional program in human white adipocyte precursors [PMID:28088466].","teleology":[{"year":2013,"claim":"Established that TENM2 has a non-redundant in vivo role in wiring binocular visual circuits, placing it within a defined molecular pathway for ipsilateral retinal projections.","evidence":"Ten-m2 KO mouse with axonal tracing, immunohistochemistry, visually evoked potentials, and behavior","pmids":["23884953"],"confidence":"High","gaps":["Whether TEN-M2 regulates EphB1 directly or indirectly is not resolved","Molecular mechanism linking TEN-M2 to Zic2/EphB1 not biochemically defined"]},{"year":2017,"claim":"Extended TENM2 function beyond neurons by showing it represses a thermogenic transcriptional program in adipocyte precursors.","evidence":"siRNA knockdown in human SGBS preadipocytes with qRT-PCR, western blot, and Seahorse respirometry","pmids":["28088466"],"confidence":"Medium","gaps":["Mechanism by which TENM2 suppresses UCP1 is unknown","No link established between adipocyte role and the synaptic/adhesion functions"]},{"year":2018,"claim":"Solved the architecture of the TEN2 extracellular region and identified an alternatively spliced β-propeller insert as the switch toggling between LPHN-dependent excitatory signaling and inhibitory postsynaptic differentiation.","evidence":"3.1 Å single-particle cryo-EM with splice-variant functional assays","pmids":["29677516"],"confidence":"High","gaps":["Structural basis for how the splice switch is decoded into opposing synaptic outcomes not fully defined","No structure of TEN2 bound to a partner in this study"]},{"year":2019,"claim":"Defined a paracrine mode in which proteolytically shed soluble TEN2 acts as a diffusible LPHN1 ligand directing axon guidance, distinguishing it from membrane-tethered adhesion signaling.","evidence":"Affinity isolation of TEN2/Lasso as LPHN1 ligand, growth-cone turning imaging, and LPHN1 KO epistasis","pmids":["30967757"],"confidence":"Medium","gaps":["Identity of the protease(s) that shed TEN2 not established","Intracellular signaling cascade downstream of LPHN1 redistribution not detailed"]},{"year":2019,"claim":"Identified TEN2 and LPHN1 co-upregulation in reactive astrocytes after brain injury, with TCAP-1 eliciting calcium signaling, implicating the pathway in injury responses.","evidence":"Immunohistochemistry, RT-PCR, and intracellular calcium imaging after mechanical injury / TCAP-1 treatment","pmids":["31316338"],"confidence":"Medium","gaps":["Causal role of TEN2 in the astrocyte injury response not tested by loss-of-function","Relationship between TCAP-1 calcium signaling and full-length TEN2 function unclear"]},{"year":2020,"claim":"Resolved how alternative splicing controls LPHN3 binding — by sterically occluding a distant binding surface — and showed this interaction selectively drives excitatory synapse formation within a TEN2–LPHN3–FLRT3 trimer.","evidence":"2.9 Å cryo-EM of the TEN2–LPHN3 complex with mutagenesis and synapse formation assays","pmids":["32358586"],"confidence":"High","gaps":["Structural basis of the inhibitory-synapse branch not resolved","Stoichiometry and assembly dynamics of the trimeric complex in cells not defined"]},{"year":2023,"claim":"Provided a cytoplasmic effector mechanism for inhibitory synapse function by linking TEN2 to microtubule plus ends via EB proteins to support GABAA receptor delivery.","evidence":"Live imaging, reciprocal Co-IP with EB proteins, fractionation, and GABAA receptor exocytosis assay","pmids":["37272607"],"confidence":"Medium","gaps":["Whether the EB interaction is direct or bridged not established","Connection between the splice switch and EB recruitment not defined"]},{"year":2026,"claim":"Showed that LPHN binding and TEN2 homodimerization are mutually exclusive structural states, defining how distinct interfaces partition TEN2 into competing signaling modes.","evidence":"Cryo-EM with interface-specific surface mutagenesis, proteomics, super-resolution microscopy, and in vivo gene editing","pmids":["41991904"],"confidence":"High","gaps":["Cellular triggers that bias TEN2 toward homodimer versus LPHN complex unknown","Functional consequence of homodimerization in vivo not fully defined"]},{"year":2026,"claim":"Confirmed coordinated upregulation of Ten-2 and ADGRL1/latrophilin-1 in reactive astrocytes during seizure-induced neurodegeneration, generalizing the injury-response role across pathologies.","evidence":"Immunohistochemistry, qRT-PCR, Fluoro-Jade C staining in a LiCl-pilocarpine status epilepticus rat model","pmids":["41930255"],"confidence":"Medium","gaps":["Functional role of astrocytic TEN2–ADGRL1 in neurodegeneration not tested by perturbation","Whether upregulation is protective or pathogenic unknown"]},{"year":null,"claim":"How a single extracellular splice/dimerization switch is decoded into the opposing outcomes of excitatory versus inhibitory synapse formation, and how this integrates with cytoplasmic EB-microtubule signaling, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the inhibitory-synapse signaling state","Mechanism coupling extracellular conformational state to intracellular GABAA receptor trafficking unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1]}],"complexes":["TEN2-LPHN3-FLRT3 trimeric complex"],"partners":["ADGRL3","ADGRL1","FLRT3","EPHB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NT68","full_name":"Teneurin-2","aliases":["Protein Odd Oz/ten-m homolog 2","Tenascin-M2","Ten-m2","Teneurin transmembrane protein 2"],"length_aa":2774,"mass_kda":307.8,"function":"Involved in neural development, regulating the establishment of proper connectivity within the nervous system (PubMed:21724987). Acts as a ligand of the ADGRL1 and ADGRL3 receptors that are expressed at the surface of adjacent cells (PubMed:21724987). Promotes the formation of filopodia and enlarged growth cone in neuronal cells (PubMed:21724987). Mediates axon guidance and homophilic and heterophilic cell-cell adhesion (PubMed:21724987). May function as a cellular signal transducer (PubMed:21724987) Acts as a ligand of the ADGRL1 receptor. Mediates axon guidance and heterophilic cell-cell adhesion Induces gene transcription inhibition","subcellular_location":"Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/Q9NT68/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TENM2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":77,"dependency_fraction":0.012987012987012988},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TENM2","total_profiled":1310},"omim":[{"mim_id":"616417","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3","url":"https://www.omim.org/entry/616417"},{"mim_id":"616416","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L1; ADGRL1","url":"https://www.omim.org/entry/616416"},{"mim_id":"610119","title":"TENEURIN TRANSMEMBRANE PROTEIN 2; TENM2","url":"https://www.omim.org/entry/610119"},{"mim_id":"610084","title":"TENEURIN TRANSMEMBRANE PROTEIN 4; TENM4","url":"https://www.omim.org/entry/610084"},{"mim_id":"610083","title":"TENEURIN TRANSMEMBRANE PROTEIN 3; TENM3","url":"https://www.omim.org/entry/610083"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":32.8}],"url":"https://www.proteinatlas.org/search/TENM2"},"hgnc":{"alias_symbol":["KIAA1127","Ten-M2","TEN2"],"prev_symbol":["ODZ2"]},"alphafold":{"accession":"Q9NT68","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NT68","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NT68-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NT68-2-F1-predicted_aligned_error_v6.png","plddt_mean":81.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TENM2","jax_strain_url":"https://www.jax.org/strain/search?query=TENM2"},"sequence":{"accession":"Q9NT68","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NT68.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NT68/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NT68"}},"corpus_meta":[{"pmid":"29677516","id":"PMC_29677516","title":"Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the 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An alternatively spliced region within the β-propeller acts as a switch: one splice variant activates trans-cellular signaling in a latrophilin (LPHN)-dependent manner, while the other induces inhibitory postsynaptic differentiation.\",\n      \"method\": \"Single-particle cryo-EM at 3.1 Å resolution; functional assays of splice variants in trans-cellular adhesion and postsynaptic differentiation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structure with functional validation of alternative splicing switch, published in top journal\",\n      \"pmids\": [\"29677516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of the TEN2–LPHN3 complex at 2.9 Å resolution shows that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site distant from the alternatively spliced region. Alternative splicing regulates TEN2–LPHN3 interaction by sterically hindering access to the LPHN-binding surface rather than altering it. A trimeric TEN2–LPHN3–FLRT3 complex was also described. Mutagenesis of the LPHN-binding surface of TEN2 abolished LPHN3 interaction and impaired excitatory but not inhibitory synapse formation.\",\n      \"method\": \"Single-particle cryo-EM at 2.9 Å; site-directed mutagenesis; synapse formation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution structure combined with mutagenesis and functional synapse assays in a single rigorous study\",\n      \"pmids\": [\"32358586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM data of TEN2 shows that canonical Latrophilin binding is sterically incompatible with TEN2 homodimerization, making these two interactions mutually exclusive. Engineered surface mutations that specifically disrupt TEN2–TEN2 or TEN2–Latrophilin interactions confirmed distinct binding interfaces, and these binding mechanisms are conserved in TEN4.\",\n      \"method\": \"Single-particle cryo-EM; surface mutagenesis; proteomics; super-resolution microscopy; in vivo gene editing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural data plus mutagenesis and multiple orthogonal in vivo methods in one peer-reviewed study\",\n      \"pmids\": [\"41991904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEN2/Lasso is proteolytically cleaved at multiple sites and its extracellular domain is partially released into the intercellular space, especially during neuronal development. The soluble fragment of Lasso (TEN2 ECR) can diffuse and bind to LPHN1 on axonal growth cones, triggering LPHN1 redistribution on the cell surface and intracellular signaling leading to local exocytosis, causing axons to turn toward spatio-temporal Lasso gradients. LPHN1 knockout blocks this guidance effect.\",\n      \"method\": \"Affinity chromatography (isolation of TEN2/Lasso as endogenous LPHN1 ligand); live imaging of growth cone turning; LPHN1 KO epistasis\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical isolation plus KO epistasis and live-cell functional assay, single lab review/summary paper citing original experimental findings\",\n      \"pmids\": [\"30967757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TEN2 localizes preferentially to inhibitory postsynapses that recruit microtubule (MT) plus ends, and interacts physically with MT plus-end tracking proteins (EB proteins). This TEN2–EB interaction recruits MTs to inhibitory postsynapses and provides a platform for GABAA receptor exocytosis.\",\n      \"method\": \"Live imaging; co-immunoprecipitation (TEN2 with EB proteins); subcellular fractionation; GABAA receptor exocytosis assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus live imaging and functional receptor exocytosis readout, single lab\",\n      \"pmids\": [\"37272607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ten-m2 knockout (KO) mice show a specific decrease in ipsilateral retinal ganglion cell projections to the dorsal lateral geniculate nucleus and superior colliculus, most prominent in ventral retina. Reduction of EphB1 expression in ventral retina of KO mice suggests TEN-M2 interacts with the EphB1 molecular pathway downstream of Zic2 to establish ipsilateral projections required for binocular circuit formation. Visually evoked potential recordings confirmed reduced ipsilateral-to-contralateral response ratio in KOs.\",\n      \"method\": \"Ten-m2 KO mouse; anterograde/retrograde axonal tracing; immunohistochemistry (EphB1, Zic2, c-fos); visually evoked potential recordings; behavioral swim task\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal anatomical, molecular, electrophysiological, and behavioral readouts defining pathway position\",\n      \"pmids\": [\"23884953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ten-2 immunoreactivity is significantly upregulated in reactive astrocytes following mechanical brain injury, and reactive astrocytes also show intense immunoreactivity for LPHN-1 (latrophilin-1). TCAP-1 treatment of immortalized cerebellar astrocytes elicited a significant increase in intracellular calcium concentration.\",\n      \"method\": \"Immunohistochemistry; conventional RT-PCR; fluorescence microscopy with intracellular calcium indicator after TCAP-1 treatment\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemistry with functional calcium signaling assay, replicated across brain injury time points, single lab\",\n      \"pmids\": [\"31316338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated knockdown of TENM2 in human SGBS preadipocytes induces UCP1 mRNA and protein expression upon adipogenic differentiation without affecting mitochondrial mass. TENM2 knockdown also increased basal and leak mitochondrial respiration, indicating that TENM2 suppresses a brown adipocyte transcriptional program in white adipocyte precursors.\",\n      \"method\": \"siRNA knockdown; qRT-PCR; western blot (UCP1); Seahorse mitochondrial respiration assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal molecular and functional readouts in human cell model, single lab\",\n      \"pmids\": [\"28088466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Following status epilepticus (SE) induction in rats, Ten-2, TCAP-2, and ADGRL1 (latrophilin-1) are significantly upregulated at both mRNA and protein levels in reactive astrocytes of the cerebral cortex and hippocampal CA3 region. Ten-2-LI and ADGRL1-LI colocalize in the same reactive astrocyte profiles positioned in regions of neuronal degeneration.\",\n      \"method\": \"Immunohistochemistry; quantitative RT-PCR; Fluoro-Jade C staining for neurodegeneration; LiCl-pilocarpine SE rat model\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO/injury model with orthogonal IHC and qPCR, colocalization data, single lab\",\n      \"pmids\": [\"41930255\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TENM2 (TEN2/Lasso) is a type II transmembrane cell-adhesion protein whose extracellular region adopts a bacterial Tc-toxin-like β-barrel fold; an alternatively spliced insert within the β-propeller domain sterically gates access to a distant latrophilin (LPHN/ADGRL) binding surface, switching TEN2 function between excitatory synapse promotion (via the TEN2–LPHN3–FLRT3 trimeric complex) and inhibitory synapse induction, while TEN2 homodimerization and LPHN binding are mutually exclusive; at inhibitory synapses TEN2 recruits microtubule plus ends via EB proteins to facilitate GABAA receptor exocytosis; proteolytically shed soluble TEN2/Lasso acts as an axonal guidance cue by engaging LPHN1 on growth cones to trigger local exocytosis and axon turning; and in vivo, TEN2 is required for formation of ipsilateral retinal projections and binocular circuits, partly through regulation of EphB1 in ventral retina.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TENM2 (TEN2/Lasso) is a type II transmembrane cell-adhesion protein that organizes synaptic and axonal connectivity through ligand-gated trans-cellular signaling [#0, #5]. Its extracellular region adopts a Tc-toxin-like architecture in which a large β-barrel partially encapsulates a C-terminal domain, sealed by an immunoglobulin-like domain and apposed by a β-propeller; an alternatively spliced insert within the β-propeller acts as a molecular switch, with one variant driving latrophilin (LPHN)-dependent trans-cellular signaling and the other inducing inhibitory postsynaptic differentiation [#0]. The N-terminal lectin domain of LPHN3 docks onto the TEN2 barrel at a site distant from the spliced region, and splicing controls this interaction by sterically occluding access to the LPHN-binding surface rather than altering it directly; mutation of this surface abolishes LPHN3 binding and selectively impairs excitatory but not inhibitory synapse formation, consistent with TEN2 acting within a trimeric TEN2–LPHN3–FLRT3 complex [#1]. LPHN engagement and TEN2 homodimerization are mutually exclusive, occupying distinct conserved interfaces [#2]. At inhibitory postsynapses, TEN2 binds microtubule plus-end tracking EB proteins to recruit microtubules and support GABAA receptor exocytosis [#4], while proteolytically shed soluble TEN2 ECR diffuses to engage LPHN1 on growth cones, triggering local exocytosis and gradient-directed axon turning [#3]. In vivo, TENM2 is required for ipsilateral retinal ganglion cell projections and binocular circuit formation, acting downstream of Zic2 through regulation of EphB1 in ventral retina [#5]. Beyond the nervous system, TENM2 suppresses a brown-adipocyte (UCP1) transcriptional program in human white adipocyte precursors [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that TENM2 has a non-redundant in vivo role in wiring binocular visual circuits, placing it within a defined molecular pathway for ipsilateral retinal projections.\",\n      \"evidence\": \"Ten-m2 KO mouse with axonal tracing, immunohistochemistry, visually evoked potentials, and behavior\",\n      \"pmids\": [\"23884953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEN-M2 regulates EphB1 directly or indirectly is not resolved\", \"Molecular mechanism linking TEN-M2 to Zic2/EphB1 not biochemically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended TENM2 function beyond neurons by showing it represses a thermogenic transcriptional program in adipocyte precursors.\",\n      \"evidence\": \"siRNA knockdown in human SGBS preadipocytes with qRT-PCR, western blot, and Seahorse respirometry\",\n      \"pmids\": [\"28088466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TENM2 suppresses UCP1 is unknown\", \"No link established between adipocyte role and the synaptic/adhesion functions\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solved the architecture of the TEN2 extracellular region and identified an alternatively spliced β-propeller insert as the switch toggling between LPHN-dependent excitatory signaling and inhibitory postsynaptic differentiation.\",\n      \"evidence\": \"3.1 Å single-particle cryo-EM with splice-variant functional assays\",\n      \"pmids\": [\"29677516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how the splice switch is decoded into opposing synaptic outcomes not fully defined\", \"No structure of TEN2 bound to a partner in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a paracrine mode in which proteolytically shed soluble TEN2 acts as a diffusible LPHN1 ligand directing axon guidance, distinguishing it from membrane-tethered adhesion signaling.\",\n      \"evidence\": \"Affinity isolation of TEN2/Lasso as LPHN1 ligand, growth-cone turning imaging, and LPHN1 KO epistasis\",\n      \"pmids\": [\"30967757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the protease(s) that shed TEN2 not established\", \"Intracellular signaling cascade downstream of LPHN1 redistribution not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified TEN2 and LPHN1 co-upregulation in reactive astrocytes after brain injury, with TCAP-1 eliciting calcium signaling, implicating the pathway in injury responses.\",\n      \"evidence\": \"Immunohistochemistry, RT-PCR, and intracellular calcium imaging after mechanical injury / TCAP-1 treatment\",\n      \"pmids\": [\"31316338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of TEN2 in the astrocyte injury response not tested by loss-of-function\", \"Relationship between TCAP-1 calcium signaling and full-length TEN2 function unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how alternative splicing controls LPHN3 binding — by sterically occluding a distant binding surface — and showed this interaction selectively drives excitatory synapse formation within a TEN2–LPHN3–FLRT3 trimer.\",\n      \"evidence\": \"2.9 Å cryo-EM of the TEN2–LPHN3 complex with mutagenesis and synapse formation assays\",\n      \"pmids\": [\"32358586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the inhibitory-synapse branch not resolved\", \"Stoichiometry and assembly dynamics of the trimeric complex in cells not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a cytoplasmic effector mechanism for inhibitory synapse function by linking TEN2 to microtubule plus ends via EB proteins to support GABAA receptor delivery.\",\n      \"evidence\": \"Live imaging, reciprocal Co-IP with EB proteins, fractionation, and GABAA receptor exocytosis assay\",\n      \"pmids\": [\"37272607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the EB interaction is direct or bridged not established\", \"Connection between the splice switch and EB recruitment not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that LPHN binding and TEN2 homodimerization are mutually exclusive structural states, defining how distinct interfaces partition TEN2 into competing signaling modes.\",\n      \"evidence\": \"Cryo-EM with interface-specific surface mutagenesis, proteomics, super-resolution microscopy, and in vivo gene editing\",\n      \"pmids\": [\"41991904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular triggers that bias TEN2 toward homodimer versus LPHN complex unknown\", \"Functional consequence of homodimerization in vivo not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed coordinated upregulation of Ten-2 and ADGRL1/latrophilin-1 in reactive astrocytes during seizure-induced neurodegeneration, generalizing the injury-response role across pathologies.\",\n      \"evidence\": \"Immunohistochemistry, qRT-PCR, Fluoro-Jade C staining in a LiCl-pilocarpine status epilepticus rat model\",\n      \"pmids\": [\"41930255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of astrocytic TEN2–ADGRL1 in neurodegeneration not tested by perturbation\", \"Whether upregulation is protective or pathogenic unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single extracellular splice/dimerization switch is decoded into the opposing outcomes of excitatory versus inhibitory synapse formation, and how this integrates with cytoplasmic EB-microtubule signaling, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the inhibitory-synapse signaling state\", \"Mechanism coupling extracellular conformational state to intracellular GABAA receptor trafficking unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"TEN2-LPHN3-FLRT3 trimeric complex\"\n    ],\n    \"partners\": [\n      \"ADGRL3\",\n      \"ADGRL1\",\n      \"FLRT3\",\n      \"EphB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}