{"gene":"OLFM1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"Noelin-1 (OLFM1) is a secreted glycoprotein expressed in a graded pattern in the closing neural tube and subsequently in dorsal neural folds and migrating neural crest. Overexpression via recombinant retroviruses in avian embryos caused excess neural crest emigration and extended the time the neural tube was competent to generate and regenerate neural crest cells, establishing OLFM1 as a secreted regulator of neural crest production.","method":"Retroviral overexpression in chick embryos, in situ hybridization, immunohistochemistry","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with defined cellular phenotype (excess neural crest emigration) in avian model, single lab but multiple readouts","pmids":["10783240"],"is_preprint":false},{"year":2001,"finding":"In Xenopus, Noelin-1 (OLFM1) is a secreted glycoprotein that likely forms large multiunit complexes. Only secreted forms of the protein (not intracellular forms) could activate sensory marker expression, while all forms could induce early neurogenesis, demonstrating that the secreted localization of OLFM1 is required for its sensory neurogenic function. Co-expression of secreted Noelin-1 with noggin amplified noggin-induced neural marker expression, and Noelin-1 caused premature expression of neuronal differentiation markers in animal caps.","method":"mRNA microinjection in Xenopus animal caps, overexpression of secreted vs. non-secreted forms, RT-PCR for neural markers","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparison of secreted vs. non-secreted forms provides mechanistic distinction, single lab, multiple orthogonal readouts","pmids":["11784068"],"is_preprint":false},{"year":2002,"finding":"Mouse Noelin-1/2 (OLFM1) is expressed in the neural plate, neural crest, and cranial ganglia at E8-10, and later prominently in brain tissue and in the zone of polarizing activity in the limb, confirming conserved neural expression across vertebrates.","method":"In situ hybridization, comparison across mouse, frog, and avian embryos","journal":"Mechanisms of development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data only, single lab, no functional consequence directly tested in this paper","pmids":["12385760"],"is_preprint":false},{"year":2023,"finding":"Noelin (OLFM1) tetramers tightly assemble with the extracellular domains of AMPA receptors (AMPARs) and interconnect them in a network-like configuration with secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knockout of Noelins 1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory interneurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity, establishing the Noelin-organized extracellular network as a determinant of constitutive and context-dependent AMPAR anchoring and synaptic plasticity.","method":"Co-immunoprecipitation, mass spectrometry interactome, Noelin1-3 triple knockout mice, electrophysiology, AMPAR density/clustering imaging, synaptic plasticity assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, MS interactome, clean KO with multiple defined cellular phenotypes (reduced synaptic AMPARs, abolished LTP), multiple orthogonal methods in one study","pmids":["37591201"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM of immunoaffinity-purified native calcium-permeable AMPARs from rat cerebella resolved the structure of the NOE1 (OLFM1)-GluA1-GluA4 complex, showing that NOE1 specifically binds to the GluA4 subunit at the B and D positions and stabilizes the amino-terminal domain (ATD) layer without affecting gating properties. NOE1 forms dimeric AMPAR assemblies likely to engage in extracellular networks, providing a structural mechanism for AMPAR clustering in synaptic environments.","method":"Cryo-electron microscopy of immunoaffinity-purified native CP-AMPARs, structural analysis of NOE1-AMPAR complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with defined subunit-binding specificity (GluA4 B/D positions) and functional characterization (ATD stabilization, no gating effect), rigorous structural study","pmids":["40550474"],"is_preprint":false},{"year":2014,"finding":"A chromosomal translocation t(3;9)(q25.1;q34.3) truncated the OLFM1 gene and produced fusion transcripts in carriers with Gilles de la Tourette syndrome, OCD, and ADHD. OLFM1 expression was found to be high in GTS-related human brain regions, and haploinsufficiency or dominant-negative fusion transcripts were identified as potential mechanisms contributing to the neuropsychiatric phenotype.","method":"Mate-pair sequencing of translocation breakpoints, RT-PCR identification of fusion transcripts, expression analysis in human brain regions","journal":"Psychiatry research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case, breakpoint mapping and fusion transcript identification without functional validation of the proposed dominant-negative mechanism","pmids":["25595337"],"is_preprint":false}],"current_model":"OLFM1 (Noelin-1) is a secreted glycoprotein that forms tetrameric extracellular complexes; it promotes neural crest production and neurogenesis in vertebrate embryos (with activity requiring secretion), and in the mature nervous system it directly binds the extracellular/ATD domain of GluA4-containing AMPA receptors, organizing an extracellular protein network that anchors AMPARs at synapses and in dendrites and is required for activity-dependent synaptic plasticity."},"narrative":{"mechanistic_narrative":"OLFM1 (Noelin-1) is a secreted glycoprotein that acts across vertebrate neural development and mature synaptic organization, functioning through extracellular oligomeric assembly [PMID:10783240, PMID:37591201]. In the embryo it is expressed in a graded pattern in the closing neural tube, dorsal neural folds, and migrating neural crest, and gain-of-function expands neural crest emigration while prolonging neural tube competence to generate neural crest [PMID:10783240]; its sensory-neurogenic activity strictly requires secretion, as only secreted forms activate sensory marker expression and amplify noggin-induced neural induction [PMID:11784068]. In the mature nervous system, OLFM1 tetramers assemble with the extracellular domains of AMPA receptors and interconnect them into a network with Neurexin1, Neuritin1, and Seizure 6-like, and loss of Noelins 1-3 reduces synaptic and dendritic AMPARs and abolishes activity-dependent synaptic plasticity [PMID:37591201]. Cryo-EM of native calcium-permeable AMPARs shows OLFM1 binds specifically the GluA4 subunit at the B and D positions, stabilizing the amino-terminal domain layer and forming dimeric AMPAR assemblies without altering gating, providing a structural basis for AMPAR clustering [PMID:40550474].","teleology":[{"year":2000,"claim":"Established OLFM1 as a secreted regulator of neural crest production, answering whether the neural-tube-expressed glycoprotein actively controls neural crest output.","evidence":"Retroviral overexpression in chick embryos with in situ hybridization and immunohistochemistry","pmids":["10783240"],"confidence":"Medium","gaps":["No receptor or downstream effector identified","Loss-of-function not tested","Molecular mechanism of competence extension unknown"]},{"year":2001,"claim":"Demonstrated that secretion is required for the sensory-neurogenic function, distinguishing an extracellular mode of action from intracellular activity.","evidence":"mRNA microinjection of secreted vs. non-secreted forms in Xenopus animal caps with RT-PCR for neural markers","pmids":["11784068"],"confidence":"Medium","gaps":["Multiunit complex composition inferred, not resolved","No binding partner identified","Relationship to noggin amplification mechanism unresolved"]},{"year":2002,"claim":"Confirmed conserved neural and neural crest expression across vertebrates, supporting a generalizable developmental role.","evidence":"In situ hybridization across mouse, frog, and avian embryos","pmids":["12385760"],"confidence":"Low","gaps":["Localization only; no functional consequence tested in this study","Limb ZPA expression not functionally linked"]},{"year":2014,"claim":"Linked OLFM1 disruption to a neuropsychiatric phenotype, raising the question of dosage- or fusion-driven contributions.","evidence":"Mate-pair breakpoint sequencing and RT-PCR of fusion transcripts in a Tourette/OCD/ADHD carrier with brain-region expression analysis","pmids":["25595337"],"confidence":"Low","gaps":["Single case without functional validation","Haploinsufficiency vs. dominant-negative mechanism not distinguished","No causal model"]},{"year":2023,"claim":"Defined the mature-nervous-system function: OLFM1 tetramers organize an extracellular network that anchors AMPARs and is required for synaptic plasticity.","evidence":"Reciprocal Co-IP, mass spectrometry interactome, Noelin1-3 triple knockout mice, electrophysiology, AMPAR imaging, and plasticity assays","pmids":["37591201"],"confidence":"High","gaps":["Redundancy among Noelins 1-3 not separated to OLFM1 alone","How the network couples to plasticity signaling unresolved","Developmental vs. synaptic functions not mechanistically connected"]},{"year":2025,"claim":"Provided the structural mechanism: OLFM1 binds the GluA4 subunit at defined positions to stabilize the ATD layer and bridge AMPARs into dimeric assemblies.","evidence":"Cryo-EM of immunoaffinity-purified native calcium-permeable AMPARs from rat cerebella","pmids":["40550474"],"confidence":"High","gaps":["Network with Neurexin1/Neuritin1/Sez6l not structurally resolved","Functional consequence of GluA4 selectivity in vivo not addressed","Gating shown unaffected but trafficking effects not structurally defined"]},{"year":null,"claim":"How the embryonic neural-crest/neurogenic activity and the mature AMPAR-anchoring function share a common molecular mechanism, and what cell-surface receptors mediate the developmental signal, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No developmental receptor identified","Unified mechanism across life stages uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]}],"complexes":["AMPA receptor complex (OLFM1-GluA1-GluA4)"],"partners":["GRIA4","GRIA1","NRXN1","NRN1","SEZ6L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99784","full_name":"Noelin","aliases":["Neuronal olfactomedin-related ER localized protein","Olfactomedin-1"],"length_aa":485,"mass_kda":55.3,"function":"Contributes to the regulation of axonal growth in the embryonic and adult central nervous system by inhibiting interactions between RTN4R and LINGO1. Inhibits RTN4R-mediated axon growth cone collapse (By similarity). May play an important role in regulating the production of neural crest cells by the neural tube (By similarity). May be required for normal responses to olfactory stimuli (By similarity)","subcellular_location":"Secreted; Synapse; Endoplasmic reticulum; Cell projection, axon; Perikaryon","url":"https://www.uniprot.org/uniprotkb/Q99784/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OLFM1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OLFM1","total_profiled":1310},"omim":[{"mim_id":"617492","title":"OLFACTOMEDIN 2; OLFM2","url":"https://www.omim.org/entry/617492"},{"mim_id":"617156","title":"MITOCHONDRIAL DNA DEPLETION SYNDROME 15 (HEPATOCEREBRAL TYPE); MTDPS15","url":"https://www.omim.org/entry/617156"},{"mim_id":"614061","title":"OLFACTOMEDIN 4; OLFM4","url":"https://www.omim.org/entry/614061"},{"mim_id":"610253","title":"KLEEFSTRA SYNDROME 1; KLEFS1","url":"https://www.omim.org/entry/610253"},{"mim_id":"610088","title":"OLFACTOMEDIN-LIKE 3; OLFML3","url":"https://www.omim.org/entry/610088"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":906.9}],"url":"https://www.proteinatlas.org/search/OLFM1"},"hgnc":{"alias_symbol":["NOE1","OlfA","AMY","NOELIN"],"prev_symbol":[]},"alphafold":{"accession":"Q99784","domains":[{"cath_id":"-","chopping":"187-226","consensus_level":"medium","plddt":62.7937,"start":187,"end":226},{"cath_id":"2.120.10","chopping":"231-483","consensus_level":"high","plddt":95.0768,"start":231,"end":483}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99784","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99784-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99784-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OLFM1","jax_strain_url":"https://www.jax.org/strain/search?query=OLFM1"},"sequence":{"accession":"Q99784","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99784.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99784/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99784"}},"corpus_meta":[{"pmid":"6190572","id":"PMC_6190572","title":"Two 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24177569","citation_count":9,"is_preprint":false},{"pmid":"39437308","id":"PMC_39437308","title":"Echocardiographic phenotype in severe aortic stenosis with and without transthyretin cardiac amyloidosis: the AMY-TAVI study.","date":"2025","source":"European heart journal. Cardiovascular Imaging","url":"https://pubmed.ncbi.nlm.nih.gov/39437308","citation_count":8,"is_preprint":false},{"pmid":"12620400","id":"PMC_12620400","title":"Molecular cloning of the mouse AMY-1 gene and identification of the synergistic activation of the AMY-1 promoter by GATA-1 and Sp1.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12620400","citation_count":8,"is_preprint":false},{"pmid":"2987507","id":"PMC_2987507","title":"Members of the Amy-2 alpha-amylase gene family of mouse strain CE/J contain duplicated 5' termini.","date":"1985","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2987507","citation_count":8,"is_preprint":false},{"pmid":"10636133","id":"PMC_10636133","title":"AMY plaques in familial AD: comparison with sporadic Alzheimer's disease.","date":"2000","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10636133","citation_count":8,"is_preprint":false},{"pmid":"2496682","id":"PMC_2496682","title":"Molecular cloning of alpha-amylase genes from Drosophila melanogaster. III. An inversion at the Amy locus in an amylase-null strain.","date":"1989","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2496682","citation_count":7,"is_preprint":false},{"pmid":"15800131","id":"PMC_15800131","title":"Genetic coadaptation of the amylase gene system in Drosophila melanogaster: evidence for the selective advantage of the lowest AMY activity and of its epistatic genetic background.","date":"2005","source":"The Journal of heredity","url":"https://pubmed.ncbi.nlm.nih.gov/15800131","citation_count":6,"is_preprint":false},{"pmid":"1697417","id":"PMC_1697417","title":"Molecular genetics of a three-gene cluster in the Amy region of Drosophila.","date":"1990","source":"Progress in clinical and biological research","url":"https://pubmed.ncbi.nlm.nih.gov/1697417","citation_count":5,"is_preprint":false},{"pmid":"10604747","id":"PMC_10604747","title":"Spatial relationship of AMY protein deposits and different species of Abeta peptides in amyloid plaques of the Alzheimer disease brain.","date":"1999","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10604747","citation_count":5,"is_preprint":false},{"pmid":"2451911","id":"PMC_2451911","title":"Analysis of the mouse Amy locus in recombinant inbred mouse strains.","date":"1987","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2451911","citation_count":5,"is_preprint":false},{"pmid":"21874240","id":"PMC_21874240","title":"Molecular cloning and tissue distribution of a Schistosoma japonicum gene encoding AMY-1.","date":"2011","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/21874240","citation_count":4,"is_preprint":false},{"pmid":"39550021","id":"PMC_39550021","title":"Ab-Amy 2.0: Predicting light chain amyloidogenic risk of therapeutic antibodies based on antibody language model.","date":"2024","source":"Methods (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/39550021","citation_count":4,"is_preprint":false},{"pmid":"37199315","id":"PMC_37199315","title":"Long Non-Coding RNA LPP-AS2 Plays an Anti-Tumor Role in Thyroid Carcinoma by Regulating the miR-132-3p/OLFM1 Axis.","date":"2023","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/37199315","citation_count":2,"is_preprint":false},{"pmid":"38927729","id":"PMC_38927729","title":"Genome-Wide Identification and Expression Profiling of the α-Amylase (AMY) Gene Family in Potato.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38927729","citation_count":2,"is_preprint":false},{"pmid":"10564786","id":"PMC_10564786","title":"Regulation of the expression of amy TO1 encoding a thermostable alpha-amylase from Streptomyces sp. TO1, in its original host and in Streptomyces lividans TK24.","date":"1999","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/10564786","citation_count":2,"is_preprint":false},{"pmid":"38242278","id":"PMC_38242278","title":"Discovery and characterization of the α-amylases cDNAs from Enchytraeus albidus shed light on the evolution of \"Enchytraeus-Eisenia type\" Amy homologs in Annelida.","date":"2024","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/38242278","citation_count":1,"is_preprint":false},{"pmid":"41847734","id":"PMC_41847734","title":"Roles of try and amy in feeding, digestion, growth, and development of the Japanese medaka (Oryzias latipes): insight from a comparative gene knockout study.","date":"2025","source":"Journal of Zhejiang University. Science. B","url":"https://pubmed.ncbi.nlm.nih.gov/41847734","citation_count":1,"is_preprint":false},{"pmid":"7525409","id":"PMC_7525409","title":"Adaptive significance of amylase polymorphism in Drosophila. VIII. Effect of carbohydrate dietary components on alpha-amylase activity and Amy-electromorph frequency in Drosophila busckii.","date":"1994","source":"Genetica","url":"https://pubmed.ncbi.nlm.nih.gov/7525409","citation_count":1,"is_preprint":false},{"pmid":"11712442","id":"PMC_11712442","title":"Comparison of different sperm detection methods: amplification of fragment 3 of amelogenin gene (AMY 3), acid phosphatase detection, microcristalline choline assay and microscopic examination.","date":"2000","source":"Roczniki Akademii Medycznej w Bialymstoku (1995)","url":"https://pubmed.ncbi.nlm.nih.gov/11712442","citation_count":1,"is_preprint":false},{"pmid":"40325879","id":"PMC_40325879","title":"Amy and Friends: improving the lives of individuals affected by DNA repair disorders.","date":"2025","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/40325879","citation_count":0,"is_preprint":false},{"pmid":"41259663","id":"PMC_41259663","title":"Low OLFM1 and BMP6 Expression Predicts Recurrence in Early-Stage Nonsquamous NSCLC with Pure Solid Tumor Appearance.","date":"2025","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41259663","citation_count":0,"is_preprint":false},{"pmid":"37738960","id":"PMC_37738960","title":"Meet the authors: Amy Lee, Shaoni Mukhopadhyay, and Maria Amodeo.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37738960","citation_count":0,"is_preprint":false},{"pmid":"39095264","id":"PMC_39095264","title":"Connective tissue amyloidosis in patients referred for orthopedic surgery. CONNECT-AMY study.","date":"2024","source":"Medicina clinica","url":"https://pubmed.ncbi.nlm.nih.gov/39095264","citation_count":0,"is_preprint":false},{"pmid":"41319778","id":"PMC_41319778","title":"FA-Amy: An amyloid protein prediction model based on protein pre-trained large models and an attention-fusion strategy.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41319778","citation_count":0,"is_preprint":false},{"pmid":"40908935","id":"PMC_40908935","title":"Copy Number Variation in the Amylase Gene (AMY) in the Brown Bear (Ursus arctos), Based on Whole Genome Resequencing Data.","date":"2025","source":"Zoological science","url":"https://pubmed.ncbi.nlm.nih.gov/40908935","citation_count":0,"is_preprint":false},{"pmid":"34019784","id":"PMC_34019784","title":"Meet the author: Amy Tresenrider.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34019784","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32000,"output_tokens":2236,"usd":0.06477,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8586,"output_tokens":2242,"usd":0.04949,"stage2_stop_reason":"end_turn"},"total_usd":0.11426,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the canonical OLFM1/NOELIN/NOE1 protein (an olfactomedin-domain secreted glycoprotein involved in neural development). I'll classify each paper:\n\n- Papers 1, 3, 5-7, 9-11, 13-14, 19-23, 30, 33-34, 37, 40, 44-45, 47, 51, 53-55, 57, 61, 63-65, 72: About alpha-amylase (AMY) genes in various organisms → EXCLUDE (symbol collision)\n- Papers 4, 17, 18, 24-25, 27, 38, 46, 50, 58: About AMY-1 (Associate of Myc-1), an 11 kDa c-Myc binding protein → EXCLUDE (different gene, symbol collision)\n- Papers 8, 15, 36, 49, 52, 56, 59, 70-71: About amyloid/AMY-101/AMY protein in Alzheimer's → EXCLUDE\n- Papers 2, 6, 26, 28, 35, 43: About OLFM1/Noelin-1 → INCLUDE\n- Paper 60: About OLFM1 in thyroid carcinoma → mostly expression, but contains luciferase/RIP experiments about miR-132-3p targeting OLFM1 — this is about a lncRNA/miRNA axis, not the OLFM1 protein mechanism → EXCLUDE\n- Paper 68: Expression correlation for OLFM1 in NSCLC → EXCLUDE (prognostic biomarker)\n- Paper 12: About OLFM2 (noelin 2), not OLFM1 → EXCLUDE\n- Paper 35: About OLFM1 gene disruption/fusion transcripts in GTS → INCLUDE (identifies OLFM1 expression in brain regions)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Noelin-1 (OLFM1) is a secreted glycoprotein expressed in a graded pattern in the closing neural tube and subsequently in dorsal neural folds and migrating neural crest. Overexpression via recombinant retroviruses in avian embryos caused excess neural crest emigration and extended the time the neural tube was competent to generate and regenerate neural crest cells, establishing OLFM1 as a secreted regulator of neural crest production.\",\n      \"method\": \"Retroviral overexpression in chick embryos, in situ hybridization, immunohistochemistry\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with defined cellular phenotype (excess neural crest emigration) in avian model, single lab but multiple readouts\",\n      \"pmids\": [\"10783240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In Xenopus, Noelin-1 (OLFM1) is a secreted glycoprotein that likely forms large multiunit complexes. Only secreted forms of the protein (not intracellular forms) could activate sensory marker expression, while all forms could induce early neurogenesis, demonstrating that the secreted localization of OLFM1 is required for its sensory neurogenic function. Co-expression of secreted Noelin-1 with noggin amplified noggin-induced neural marker expression, and Noelin-1 caused premature expression of neuronal differentiation markers in animal caps.\",\n      \"method\": \"mRNA microinjection in Xenopus animal caps, overexpression of secreted vs. non-secreted forms, RT-PCR for neural markers\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparison of secreted vs. non-secreted forms provides mechanistic distinction, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"11784068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Noelin-1/2 (OLFM1) is expressed in the neural plate, neural crest, and cranial ganglia at E8-10, and later prominently in brain tissue and in the zone of polarizing activity in the limb, confirming conserved neural expression across vertebrates.\",\n      \"method\": \"In situ hybridization, comparison across mouse, frog, and avian embryos\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data only, single lab, no functional consequence directly tested in this paper\",\n      \"pmids\": [\"12385760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Noelin (OLFM1) tetramers tightly assemble with the extracellular domains of AMPA receptors (AMPARs) and interconnect them in a network-like configuration with secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. Knockout of Noelins 1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory interneurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity, establishing the Noelin-organized extracellular network as a determinant of constitutive and context-dependent AMPAR anchoring and synaptic plasticity.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry interactome, Noelin1-3 triple knockout mice, electrophysiology, AMPAR density/clustering imaging, synaptic plasticity assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, MS interactome, clean KO with multiple defined cellular phenotypes (reduced synaptic AMPARs, abolished LTP), multiple orthogonal methods in one study\",\n      \"pmids\": [\"37591201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM of immunoaffinity-purified native calcium-permeable AMPARs from rat cerebella resolved the structure of the NOE1 (OLFM1)-GluA1-GluA4 complex, showing that NOE1 specifically binds to the GluA4 subunit at the B and D positions and stabilizes the amino-terminal domain (ATD) layer without affecting gating properties. NOE1 forms dimeric AMPAR assemblies likely to engage in extracellular networks, providing a structural mechanism for AMPAR clustering in synaptic environments.\",\n      \"method\": \"Cryo-electron microscopy of immunoaffinity-purified native CP-AMPARs, structural analysis of NOE1-AMPAR complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with defined subunit-binding specificity (GluA4 B/D positions) and functional characterization (ATD stabilization, no gating effect), rigorous structural study\",\n      \"pmids\": [\"40550474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A chromosomal translocation t(3;9)(q25.1;q34.3) truncated the OLFM1 gene and produced fusion transcripts in carriers with Gilles de la Tourette syndrome, OCD, and ADHD. OLFM1 expression was found to be high in GTS-related human brain regions, and haploinsufficiency or dominant-negative fusion transcripts were identified as potential mechanisms contributing to the neuropsychiatric phenotype.\",\n      \"method\": \"Mate-pair sequencing of translocation breakpoints, RT-PCR identification of fusion transcripts, expression analysis in human brain regions\",\n      \"journal\": \"Psychiatry research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case, breakpoint mapping and fusion transcript identification without functional validation of the proposed dominant-negative mechanism\",\n      \"pmids\": [\"25595337\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OLFM1 (Noelin-1) is a secreted glycoprotein that forms tetrameric extracellular complexes; it promotes neural crest production and neurogenesis in vertebrate embryos (with activity requiring secretion), and in the mature nervous system it directly binds the extracellular/ATD domain of GluA4-containing AMPA receptors, organizing an extracellular protein network that anchors AMPARs at synapses and in dendrites and is required for activity-dependent synaptic plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OLFM1 (Noelin-1) is a secreted glycoprotein that acts across vertebrate neural development and mature synaptic organization, functioning through extracellular oligomeric assembly [#0, #3]. In the embryo it is expressed in a graded pattern in the closing neural tube, dorsal neural folds, and migrating neural crest, and gain-of-function expands neural crest emigration while prolonging neural tube competence to generate neural crest [#0]; its sensory-neurogenic activity strictly requires secretion, as only secreted forms activate sensory marker expression and amplify noggin-induced neural induction [#1]. In the mature nervous system, OLFM1 tetramers assemble with the extracellular domains of AMPA receptors and interconnect them into a network with Neurexin1, Neuritin1, and Seizure 6-like, and loss of Noelins 1-3 reduces synaptic and dendritic AMPARs and abolishes activity-dependent synaptic plasticity [#3]. Cryo-EM of native calcium-permeable AMPARs shows OLFM1 binds specifically the GluA4 subunit at the B and D positions, stabilizing the amino-terminal domain layer and forming dimeric AMPAR assemblies without altering gating, providing a structural basis for AMPAR clustering [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established OLFM1 as a secreted regulator of neural crest production, answering whether the neural-tube-expressed glycoprotein actively controls neural crest output.\",\n      \"evidence\": \"Retroviral overexpression in chick embryos with in situ hybridization and immunohistochemistry\",\n      \"pmids\": [\"10783240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or downstream effector identified\", \"Loss-of-function not tested\", \"Molecular mechanism of competence extension unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that secretion is required for the sensory-neurogenic function, distinguishing an extracellular mode of action from intracellular activity.\",\n      \"evidence\": \"mRNA microinjection of secreted vs. non-secreted forms in Xenopus animal caps with RT-PCR for neural markers\",\n      \"pmids\": [\"11784068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multiunit complex composition inferred, not resolved\", \"No binding partner identified\", \"Relationship to noggin amplification mechanism unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Confirmed conserved neural and neural crest expression across vertebrates, supporting a generalizable developmental role.\",\n      \"evidence\": \"In situ hybridization across mouse, frog, and avian embryos\",\n      \"pmids\": [\"12385760\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization only; no functional consequence tested in this study\", \"Limb ZPA expression not functionally linked\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked OLFM1 disruption to a neuropsychiatric phenotype, raising the question of dosage- or fusion-driven contributions.\",\n      \"evidence\": \"Mate-pair breakpoint sequencing and RT-PCR of fusion transcripts in a Tourette/OCD/ADHD carrier with brain-region expression analysis\",\n      \"pmids\": [\"25595337\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single case without functional validation\", \"Haploinsufficiency vs. dominant-negative mechanism not distinguished\", \"No causal model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the mature-nervous-system function: OLFM1 tetramers organize an extracellular network that anchors AMPARs and is required for synaptic plasticity.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry interactome, Noelin1-3 triple knockout mice, electrophysiology, AMPAR imaging, and plasticity assays\",\n      \"pmids\": [\"37591201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy among Noelins 1-3 not separated to OLFM1 alone\", \"How the network couples to plasticity signaling unresolved\", \"Developmental vs. synaptic functions not mechanistically connected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural mechanism: OLFM1 binds the GluA4 subunit at defined positions to stabilize the ATD layer and bridge AMPARs into dimeric assemblies.\",\n      \"evidence\": \"Cryo-EM of immunoaffinity-purified native calcium-permeable AMPARs from rat cerebella\",\n      \"pmids\": [\"40550474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Network with Neurexin1/Neuritin1/Sez6l not structurally resolved\", \"Functional consequence of GluA4 selectivity in vivo not addressed\", \"Gating shown unaffected but trafficking effects not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the embryonic neural-crest/neurogenic activity and the mature AMPAR-anchoring function share a common molecular mechanism, and what cell-surface receptors mediate the developmental signal, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No developmental receptor identified\", \"Unified mechanism across life stages uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"AMPA receptor complex (OLFM1-GluA1-GluA4)\"],\n    \"partners\": [\"GRIA4\", \"GRIA1\", \"NRXN1\", \"NRN1\", \"SEZ6L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}