id: A8KB73 gene_symbol: olfm3a product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: olfm3a (olfactomedin 3a) is one of two zebrafish co-orthologs of vertebrate OLFM3 (optimedin, noelin-3), retained from the teleost-specific genome duplication; its paralog is olfm3b. It encodes a secreted glycoprotein with a signal peptide, an N-terminal coiled-coil region and a C-terminal olfactomedin (beta-propeller) domain, and belongs to the noelin subfamily with OLFM1 and OLFM2. In mammals OLFM3 is expressed in retina, brain and the anterior eye, forms homo- and hetero-oligomers with other noelins and binds myocilin, and the noelins together are extracellular constituents of AMPA-type glutamate receptor complexes that anchor the receptors at synapses. The zebrafish protein keeps the coiled coil, the olfactomedin domain and its cysteines. olfm3a is switched on during late pharyngula stages and is the predominant larval copy, expressed in brain (including tectal and hindbrain glutamatergic neurons) and retina. No functional study of this gene has been published. existing_annotations: - term: id: GO:0003674 label: molecular_function evidence_type: ND original_reference_id: GO_REF:0000015 qualifier: enables review: summary: Root-term ND placeholder recording that no molecular function has been curated for olfm3a. action: ACCEPT reason: Accurate. No molecular function has been measured for zebrafish olfm3a, and none is established specifically for OLFM3 in mammals beyond binding partners (myocilin, other noelins, AMPA receptor subunits). The paralog olfm3b lacks this ND row only because its record carries no MF row of any kind; the asymmetry is a bookkeeping artefact. supported_by: - reference_id: PMID:16115881 supporting_text: Although the function of optimedin is still not clear, it is suggested to be involved in cell-cell adhesion and cell attachment to the extracellular matrix. - term: id: GO:0005576 label: extracellular region evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:1202864 - MGI:MGI:1860437 - MGI:MGI:2387329 - MGI:MGI:2388361 - MGI:MGI:2443310 - MGI:MGI:2444741 - MGI:MGI:2685142 - PANTHER:PTN000573635 - RGD:727879 - UniProtKB:O95897 - UniProtKB:Q6UX06 - UniProtKB:Q99972 - UniProtKB:Q9IAK4 - UniProtKB:Q9XTA3 review: summary: Extracellular region (IBA) from the olfactomedin family node PTN000573635. action: ACCEPT reason: Olfactomedin-domain proteins are secreted, and OLFM3 is secreted in transfected cells. olfm3a has a predicted signal peptide and keeps the olfactomedin domain and cysteines of human OLFM3, so it is inside the secreted clade. supported_by: - reference_id: PMID:12019210 supporting_text: Both optimedin and myocilin are localized in Golgi and are secreted proteins. - reference_id: file:DANRE/olfm3a/olfm3a-bioinformatics/RESULTS.md supporting_text: Both copies keep the coiled coil, the olfactomedin domain, all six human cysteines and the calcium-site residues. - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0243 review: summary: Extracellular region from the UniProt 'Secreted' subcellular location (ARBA rule). action: ACCEPT reason: Consistent with the signal peptide and with secretion of mammalian OLFM3. supported_by: - reference_id: PMID:12019210 supporting_text: Both optimedin and myocilin are localized in Golgi and are secreted proteins. - term: id: GO:0007165 label: signal transduction evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1202864 - MGI:MGI:1860437 - PANTHER:PTN000573635 - UniProtKB:Q99972 review: summary: Signal transduction propagated from the olfactomedin family node, seeded by myocilin (mouse Myoc, human MYOC) and mouse Olfm1. action: MARK_AS_OVER_ANNOTATED reason: The node sits at the base of a large and functionally varied family (noelins, myocilin, gliomedin, OLFM4 and others), and its donors are myocilin and Olfm1, not an OLFM3. The best-supported mammalian role of the noelins, OLFM3 included, is extracellular organization of AMPA-receptor complexes, which is not signal transduction in the GO sense; OLFM3-specific data are limited to binding partners and overexpression effects on adhesion. For a secreted protein of unknown mechanism this very general process term says more than the evidence does. The same call is made for olfm3b. supported_by: - reference_id: PMID:37591201 supporting_text: Noelin tetramers tightly assemble with the extracellular domains of AMPARs and interconnect them in a network-like configuration with a variety of secreted and membrane-anchored proteins including Neurexin1, Neuritin1, and Seizure 6-like. - reference_id: PMID:16115881 supporting_text: Although the function of optimedin is still not clear, it is suggested to be involved in cell-cell adhesion and cell attachment to the extracellular matrix. - term: id: GO:0008150 label: biological_process evidence_type: ND original_reference_id: GO_REF:0000015 qualifier: involved_in review: summary: Root-term ND placeholder for biological process. action: ACCEPT reason: Accurate record that no process has been curated from zebrafish data. The only process row (signal transduction, IBA) is judged over-annotated, so the ND placeholder still reflects the state of knowledge. supported_by: - reference_id: PMID:16115881 supporting_text: Although the function of optimedin is still not clear, it is suggested to be involved in cell-cell adhesion and cell attachment to the extracellular matrix. - term: id: GO:0045202 label: synapse evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0258 review: summary: Synapse from the UniProt subcellular-location mapping (ARBA rule). action: ACCEPT reason: Noelins 1-3, including noelin-3 (OLFM3), co-purify with AMPA receptor complexes from all mouse brain regions, and OLFM3 co-immunoprecipitates with GluA1 and GluA2. olfm3a is expressed in larval brain glutamatergic neurons. The location is a family-level inference but well supported for the subfamily. supported_by: - reference_id: PMID:37591201 supporting_text: Both, Noe1-3 and Nrn1, were effectively co-purified with the AMPAR complexes in all brain regions (even under high stringency conditions) and correlated well with each other - reference_id: PMID:32850838 supporting_text: We found that OLFM3 co-immunoprecipitation with GluA1 and GluA2. core_functions: - description: Secreted noelin-family olfactomedin glycoprotein of larval brain and retina; by homology an extracellular component of synaptic AMPA-receptor complexes. No molecular activity has been measured for the zebrafish protein; protein features are shared with olfm3b. locations: - id: GO:0005576 label: extracellular region - id: GO:0045202 label: synapse supported_by: - reference_id: PMID:37591201 supporting_text: Knock out of Noelins1-3 profoundly reduced AMPARs in synapses onto excitatory and inhibitory (inter)neurons, decreased their density and clustering in dendrites, and abolished activity-dependent synaptic plasticity. - reference_id: PMID:34895465 supporting_text: tectal glutamatergic Cluster 1 and hindbrain glutamatergic Cluster 31 shared effector gene profiles including camk2n1a/stmn4/cbln2b/olfm3a/cd63 - reference_id: file:DANRE/olfm3a/olfm3a-bioinformatics/RESULTS.md supporting_text: olfm3a is the predominant larval copy; olfm3b is barely detected in whole embryos and larvae. references: - id: GO_REF:0000015 title: Use of the ND evidence code for Gene Ontology (GO) terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:12019210 title: 'Optimedin: a novel olfactomedin-related protein that interacts with myocilin.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only; identification of human/rat OLFM3 (optimedin), secretion, myocilin binding. - id: PMID:16115881 title: The Optimedin gene is a downstream target of Pax6. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only; two promoters/splice variants; Pax6 regulation; states function unclear. - id: PMID:17054946 title: Optimedin induces expression of N-cadherin and stimulates aggregation of NGF-stimulated PC12 cells. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Overexpression in PC12 cells; indirect evidence on adhesion. - id: PMID:21228389 title: 'Olfactomedin 2: expression in the eye and interaction with other olfactomedin domain-containing proteins.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Olfm1-3 heteromerization in transfected cells. - id: PMID:32850838 title: Olfactomedin-3 Enhances Seizure Activity by Interacting With AMPA Receptors in Epilepsy Models. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse; OLFM3 co-IP with GluA1/GluA2; lentiviral over- and knock-down. - id: PMID:37591201 title: A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Mouse Olfm1-3 knockouts; noelins as extracellular AMPAR-complex constituents; Olfm3 single KO mild. - id: PMID:34895465 title: The landscape of regulatory genes in brain-wide neuronal phenotypes of a vertebrate brain. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Zebrafish larval brain scRNA-seq; only zebrafish paper naming olfm3a. - id: file:DANRE/olfm3a/olfm3a-bioinformatics/RESULTS.md title: olfm3a / olfm3b protein, expression and synteny comparison reference_review: relevance: HIGH correctness: VERIFIED review_notes: Manual audit verified the sidecar supports both OLFM3 copies retaining coiled-coil and olfactomedin features; the expression differences are suggestive of partitioning but not definitive. findings: [] suggested_questions: - question: Where exactly are olfm3a and olfm3b expressed in larval and adult retina and brain (double in situ or single-cell data), and do they overlap in any cell type? - question: Do zebrafish noelins (olfm1a/b, olfm2a/b, olfm3a/b) co-purify with AMPA receptor complexes, and which olfm3 copy contributes? suggested_experiments: - hypothesis: olfm3a and olfm3b have complementary expression domains inherited from an ancestral brain/eye/ovary pattern. description: Paralog-specific in situ hybridization (or HCR) for olfm3a and olfm3b in larval and adult brain, retina, intestine and ovary, with gar OLFM3 in situ as outgroup. experiment_type: expression analysis - hypothesis: olfm3a is dispensable alone, as Olfm3 is in mouse, and acts together with other noelins. description: Generate olfm3a mutants alone and combined with olfm3b and olfm1a/b; measure AMPA receptor clustering and mEPSCs in larval tectal neurons. experiment_type: genetic interaction