{"gene":"SEMA3F","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2008,"finding":"SEMA3F forms a complex with NRP2 (neuropilin-2) and plexin A1, triggering a signaling cascade in which ABL2/ARG tyrosine kinase directly binds plexin A1 (but not a plexin A1 mutant lacking the cytoplasmic domain), phosphorylates and activates p190RhoGAP, which inactivates RhoA (GTP to GDP), resulting in cytoskeletal collapse and inhibition of cell migration in glioma cells and endothelial cells.","method":"Co-immunoprecipitation, direct binding assay with plexin A1 cytoplasmic domain mutant, siRNA knockdown of ABL2 and p190RhoGAP, RhoA activity assays, cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including receptor complex identification, domain-specific mutant binding, kinase activity assays, siRNA epistasis, and functional readouts in two cell types","pmids":["18660502"],"is_preprint":false},{"year":2003,"finding":"SEMA3F inhibits cell attachment and spreading in breast cancer cells through neuropilin receptors (NRP1 in MCF7 cells, NRP2 in C100 cells), with antagonistic effects to VEGF; SEMA3F treatment caused redistribution of Rac1-GFP to the base of collapsing lamellipodia, indicating modulation of Rac1 localization rather than total GTP-bound Rac1 or RhoA levels.","method":"Cell attachment/spreading assays, blocking anti-NRP1/NRP2 antibodies, time-lapse microscopy with Rac1-GFP, GTPase pull-down assays (negative for total GTP-Rac1/RhoA changes)","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (receptor blocking, live imaging, GTPase assays) in single lab","pmids":["12659673"],"is_preprint":false},{"year":2005,"finding":"SEMA3F has a repulsive effect on motile breast cancer cells (C100) mediated through NRP2, and inhibits E-cadherin-mediated cell contacts in MCF7 cells expressing NRP1; SEMA3F suppresses cell spreading and proliferation.","method":"3D gradient migration assay, stripe assay, blocking anti-NRP1/NRP2 antibodies, loss of membrane-associated E-cadherin and beta-catenin assessed by imaging","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-blocking epistasis and functional assays, single lab, multiple readouts","pmids":["15802023"],"is_preprint":false},{"year":2007,"finding":"SEMA3F expression in lung cancer H157 cells decreases integrin-linked kinase (ILK) kinase activity, reduces activated αVβ3 integrin and adhesion to extracellular matrix, and down-regulates phospho-ERK1/2, phospho-AKT, and phospho-STAT3 signaling; downstream consequences include reduced HIF-1α protein (via inhibition of AKT-driven translation initiation, with no effect on HIF-1α mRNA or protein degradation) and reduced VEGF mRNA.","method":"Stable SEMA3F transfection (constitutive and inducible), ILK kinase activity assay, siRNA knockdown of ILK, phospho-protein analysis, conditioned medium experiments, nude mouse xenograft with microvessel density quantification","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assays, siRNA epistasis, multiple signaling readouts, and in vivo validation in single rigorous study","pmids":["17875711"],"is_preprint":false},{"year":2005,"finding":"SEMA3F selectively suppresses in vivo tumorigenicity in NCI-H157 lung cancer cells (which express NRP2) but not in NCI-H460 cells (which express NRP1 but not NRP2), establishing NRP2 as the functionally required receptor for SEMA3F antitumor activity; this is associated with loss of activated αVβ3 integrin and loss of p42/p44 MAPK phosphorylation.","method":"Orthotopic rat lung cancer model, retroviral stable transfection, receptor expression analysis, integrin activation assay, MAPK phosphorylation assay","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo epistasis using two cell lines with defined NRP1/NRP2 expression, combined with molecular signaling readouts","pmids":["15967098"],"is_preprint":false},{"year":2015,"finding":"SEMA3F acts predominantly through NRP2 to collapse lymphatic endothelial cells (LECs) and potently inhibit lymphangiogenesis in vivo; reconstitution of all plexin and neuropilin receptor combinations identified NRP2 as the principal signaling co-receptor in LECs; SEMA3F re-expression in HNSCC orthotopic mouse models diminishes lymphangiogenesis and lymph node metastasis.","method":"Recombinant SEMA3F protein treatment, reconstitution of plexin/neuropilin receptor combinations in LECs, in vivo lymphangiogenesis assays, orthotopic HNSCC mouse metastasis models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — receptor reconstitution experiments combined with in vivo genetic models and functional readouts","pmids":["25952650"],"is_preprint":false},{"year":2017,"finding":"Sema3F-Neuropilin-2/PlexinA3 signaling mediates homeostatic synaptic downscaling in cortical neurons in response to increased neuronal activity; NRP2 physically associates with AMPA-type glutamate receptor (AMPAR) subunit GluA1, and Sema3F regulates this interaction to control cell surface AMPAR levels.","method":"Co-immunoprecipitation of NRP2 with GluA1, genetic loss-of-function (Npn-2 and PlexA3 knockout mice), electrophysiology for homeostatic scaling, surface AMPAR quantification","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, multiple genetic knockouts, electrophysiological readout","pmids":["29154130"],"is_preprint":false},{"year":2020,"finding":"CRMP2 mediates Sema3F-dependent axon pruning in hippocampus and visual cortex and dendritic spine remodeling; crmp2-/- mice display defects consistent with impaired Sema3F (not Sema3A) signaling, and CRMP2 was shown to mediate Sema3F signaling in primary neurons.","method":"crmp2 knockout mice, in vitro primary neuron Sema3F signaling assay, histological analysis of axon pruning and spine remodeling, behavioral assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype, primary neuron functional assay, multiple orthogonal readouts","pmids":["31919978"],"is_preprint":false},{"year":2012,"finding":"RORα directly regulates transcription of SEMA3F, as established by chromatin immunoprecipitation and luciferase reporter assays; knockdown of SEMA3F in RORα-expressing cancer cells rescued aggressive 3D phenotypes and tumor invasion, placing SEMA3F downstream of RORα as the effector of its tumor-suppressive activity.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown of SEMA3F, 3D culture invasion assay, nude mouse tumor growth","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct transcription factor binding demonstrated by ChIP and reporter assay, rescue epistasis experiment confirms pathway placement","pmids":["22350413"],"is_preprint":false},{"year":2015,"finding":"SEMA3F inhibits invasion and metastasis of colorectal cancer cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis; the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion in vitro and in vivo, placing CXCR4 downstream of SEMA3F/PI3K-AKT/ASCL2.","method":"SEMA3F knockdown and overexpression in CRC cells, PI3K-AKT pathway inhibitors, CXCR4 antagonist (AMD3100) rescue experiments, in vitro invasion assay, in vivo metastasis model","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis and rescue experiments in vitro and in vivo, single lab","pmids":["25866254"],"is_preprint":false},{"year":2017,"finding":"In the extraembryonic yolk sac, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, which drives expression of the proangiogenic microRNA cluster 17/92 and suppresses Thrombospondin-1 (Thbs1); in Sema3f-null yolk sacs, miR-17/92 transcription is impaired, Thbs1 synthesis is increased, and Vegf signaling is inhibited in yolk sac endothelial cells — establishing a proangiogenic (rather than antiangiogenic) role for Sema3F in extraembryonic tissue.","method":"Sema3f knockout mice, exogenous recombinant Sema3F treatment of differentiated F9 cells, Myc phosphorylation assays, miRNA expression analysis, Thbs1 protein quantification, in vivo vascular phenotyping","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic knockout with in vivo phenotype, recombinant protein rescue, multiple molecular readouts in single rigorous study","pmids":["28729362"],"is_preprint":false},{"year":2007,"finding":"SEMA3F directly binds to the cytoplasmic loop domain of connexin 43 (Cx43), as demonstrated by yeast two-hybrid assay; SEMA3F siRNA knockdown in IAR20 cells reduced Cx43 localization in the plasma membrane and gap junctional intercellular communication (GJIC), establishing SEMA3F as a regulator of Cx43 membrane localization and function.","method":"Yeast two-hybrid complementation and screening, immunolocalization, siRNA knockdown, GJIC functional assay","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid binding plus siRNA functional assay, single lab, two orthogonal methods","pmids":["17665084"],"is_preprint":false},{"year":2010,"finding":"Sema3F is secreted by early-arriving olfactory sensory neuron (OSN) axons and deposited at the anterodorsal olfactory bulb, where it repels Nrp2-positive axons arriving later; complementary graded expression of Nrp2 and Sema3F by OSNs and sequential axon arrival together establish topographic order along the dorsal-ventral axis of the olfactory bulb.","method":"Mouse genetic models with complementary Nrp2/Sema3F expression analysis, axon tracing, olfactory bulb topography mapping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic epistasis with defined ligand-receptor pair and quantitative topographic mapping","pmids":["20550939"],"is_preprint":false},{"year":2003,"finding":"Ectopic Sema3F expression in COS1 cell clusters placed on embryonic neocortical slices reduced migration of Nrp2-positive GABAergic neurons from the ganglionic eminence; combining Sema3A and Sema3F expression almost completely blocked migration, and ectopic Sema3F in vivo diverted Dlx2-positive cells to the upper intermediate zone — establishing Sema3F/Nrp2 as a regulator of cortical GABAergic interneuron migration.","method":"Slice culture assay with COS1 cell clusters expressing Sema3F, in vivo ectopic Sema3F expression, Dlx2 immunolabeling, neuropilin expression analysis","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo slice epistasis and in vivo ectopic expression with defined cellular phenotype, single lab","pmids":["12454988"],"is_preprint":false},{"year":2005,"finding":"SEMA3F promoter methylation at position −3850 to −3644 nt significantly correlates with loss of SEMA3F expression in lung cancer cell lines; however, histone deacetylase inhibition (Trichostatin A) was more effective than demethylation (5-aza-2'-deoxycytidine) in reactivating SEMA3F, indicating chromatin remodeling via HDAC inhibition is sufficient to activate SEMA3F transcription.","method":"Southern blot, methylation-specific PCR, Trichostatin A and 5-aza-2'-deoxycytidine treatment, transcriptional initiation site mapping","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal epigenetic methods with functional transcription readout, single lab","pmids":["16005989"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function variants in SEMA3F and its receptor PLXNA3 cause idiopathic hypogonadotropic hypogonadism (IHH); SEMA3F and PLXNA3 are expressed along the olfactory nerve and vomeronasal/terminal nerve during early human fetal development, and PLXNA1-A3 are expressed in early migratory GnRH neurons, establishing SEMA3F/PLXNA signaling as required for GnRH neuron guidance in humans.","method":"Exome sequencing of 216 IHH patients, functional assays in HEK293T cells with WT vs. variant plasmids, fluorescent IHC in human fetal nasal region and nasal/forebrain junction","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variants with in vitro functional validation and in situ expression in human fetal tissue, single study","pmids":["33495532"],"is_preprint":false},{"year":2025,"finding":"Missense variants in SEMA3F associated with human nonsyndromic hearing loss decreased furin-mediated processing of SEMA3F and abolished SEMA3F-induced collapse of filamentous actin cytoskeleton in endothelial cells; inner ear-specific Sema3f knockout mice exhibited hearing loss with abnormal spiral ganglion neuron projections into outer hair cell regions.","method":"Inner ear-specific Sema3f knockout mice, auditory brainstem response and DPOAE testing, spiral ganglion neuron tracing, in vitro furin cleavage assay, F-actin collapse assay in HUVECs with patient variants","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional knockout mouse with defined phenotype, in vitro biochemical processing assay, and cell-based functional assay with patient variants","pmids":["39909336"],"is_preprint":false},{"year":2012,"finding":"Sema3F down-regulates p53 expression in primary hippocampal neurons, contributing to growth cone collapse; p53 overexpression partially rescued Sema3F-induced growth cone collapse, while p53 inhibition or siRNA knockdown alone caused collapse, establishing p53 as a required downstream mediator of growth cone structure.","method":"Primary hippocampal neuron culture, Sema3F treatment, p53 siRNA and inhibitor, p53 overexpression rescue, growth cone morphology quantification","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single publication, limited methodological detail in abstract","pmids":["22977659"],"is_preprint":false},{"year":2025,"finding":"A bispecific antibody dimerizing NRP2 and PLXNA1 mimics SEMA3F-mediated NRP2-dependent signaling (receptor dimerization, phospho-AKT reduction, oncogene expression suppression, cell proliferation inhibition); structural studies showed the antibody binds PLXNA1/NRP2 at sites distinct from the SEMA3F-binding site but allows proper spacing for receptor complex formation and signaling.","method":"Cell-based receptor dimerization assay, phospho-AKT assay, cell proliferation assay, structural studies of antibody-receptor binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — structural characterization combined with multiple cell-based functional assays, single study","pmids":["41391772"],"is_preprint":false},{"year":2025,"finding":"In TIE2-mutant endothelial cells (venous malformation model), Sema3F (and Sema3A) are overexpressed and act as chemorepellents to inhibit wild-type endothelial cell sprouting and lumen formation; shRNA-mediated silencing of Sema3F (or Sema3A) in TIE2-mutant EC rescued the chemorepellent phenotype, restored wild-type EC migration and sprouting, and normalized vessel size in vivo.","method":"Xenograft murine VM model, 3D fibrin gel lumen formation assay, cell migration confrontation assay, RNA-sequencing, shRNA knockdown of Sema3F/Sema3A, in vivo vessel morphology analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA epistasis with in vitro and in vivo rescue, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"SEMA3F is a secreted class 3 semaphorin that signals through NRP2 (and NRP1) co-receptors complexed with plexin A1/A3, triggering ABL2/ARG-mediated phosphorylation of p190RhoGAP, inactivation of RhoA, and cytoskeletal collapse; it suppresses tumor cell adhesion, migration, and invasion by down-regulating ILK-ERK1/2, AKT-STAT3, and HIF-1α/VEGF signaling, acts as a repulsive axon guidance cue (via Nrp2) for olfactory map formation and GABAergic neuron migration, mediates homeostatic synaptic downscaling through NRP2/PlexA3-dependent regulation of AMPAR surface levels (requiring CRMP2 as an intracellular mediator), guides GnRH neurons via PLXNA signaling, is transcriptionally regulated by RORα (direct binding) and epigenetically silenced by promoter methylation/HDAC activity in cancer, and requires furin-mediated proteolytic processing for full activity."},"narrative":{"mechanistic_narrative":"SEMA3F is a secreted class 3 semaphorin that signals through neuropilin co-receptors—principally NRP2—complexed with A-type plexins to reorganize the actin cytoskeleton and restrain cell adhesion, migration, and invasion [PMID:18660502, PMID:15967098]. Engagement of the NRP2/plexin A1 complex recruits the ABL2/ARG tyrosine kinase to the plexin A1 cytoplasmic domain, which phosphorylates and activates p190RhoGAP, inactivating RhoA and producing cytoskeletal collapse and loss of motility [PMID:18660502]; SEMA3F also redistributes Rac1 to the base of collapsing lamellipodia and disrupts E-cadherin-based contacts [PMID:12659673, PMID:15802023]. Through NRP2 it acts as a tumor suppressor, lowering integrin-linked kinase activity and αVβ3 integrin activation and damping ERK1/2, AKT, and STAT3 signaling, thereby reducing HIF-1α and VEGF output and suppressing tumorigenicity, lymphangiogenesis, and metastasis [PMID:17875711, PMID:15967098, PMID:25952650]; in colorectal cells this anti-invasive activity operates through PI3K-AKT-dependent down-regulation of the ASCL2–CXCR4 axis [PMID:25866254]. In the nervous system SEMA3F is a repulsive guidance cue acting via Nrp2/PlexA3: it patterns olfactory bulb topography and cortical GABAergic interneuron migration [PMID:20550939, PMID:12454988], drives CRMP2-dependent axon pruning and dendritic spine remodeling [PMID:31919978], and mediates homeostatic synaptic downscaling by controlling surface AMPAR levels through an NRP2–GluA1 association [PMID:29154130]. Its activity requires furin-mediated proteolytic processing, and loss-of-function or processing-impairing variants cause idiopathic hypogonadotropic hypogonadism via defective GnRH neuron guidance and nonsyndromic hearing loss via aberrant spiral ganglion neuron projections [PMID:33495532, PMID:39909336]. SEMA3F is itself a direct transcriptional target of RORα and is epigenetically silenced in cancer by promoter methylation and HDAC activity [PMID:22350413, PMID:16005989].","teleology":[{"year":2003,"claim":"Established that SEMA3F acts through neuropilin receptors to inhibit cell attachment and spreading, defining its anti-adhesive activity and antagonism with VEGF.","evidence":"Cell attachment/spreading assays with blocking anti-NRP1/NRP2 antibodies and Rac1-GFP live imaging in breast cancer cells","pmids":["12659673"],"confidence":"Medium","gaps":["Total GTP-Rac1/RhoA were unchanged, leaving the cytoskeletal mechanism unresolved at this stage","Did not identify intracellular signaling intermediates"]},{"year":2005,"claim":"Showed SEMA3F is repulsive to motile tumor cells and that NRP2 is the functionally required receptor for its in vivo antitumor activity, separating NRP2- from NRP1-dependent responses.","evidence":"3D gradient/stripe migration assays and orthotopic rat lung cancer models comparing NRP2+ vs NRP2- cell lines","pmids":["15802023","15967098"],"confidence":"High","gaps":["Downstream kinases linking NRP2 to integrin/MAPK changes not yet defined","Plexin co-receptor identity not established here"]},{"year":2007,"claim":"Defined a tumor-suppressive signaling output whereby SEMA3F lowers ILK activity and integrin activation to suppress ERK/AKT/STAT3, HIF-1α, and VEGF; separately linked SEMA3F to Cx43 membrane localization.","evidence":"ILK kinase assays, phospho-protein analysis, xenograft microvessel quantification; yeast two-hybrid and GJIC assays for Cx43","pmids":["17875711","17665084"],"confidence":"Medium","gaps":["Mechanistic connection between receptor engagement and ILK inhibition incomplete","Cx43 binding shown by Y2H without reciprocal in vivo validation"]},{"year":2008,"claim":"Resolved the proximal signaling mechanism: the NRP2/plexin A1 complex recruits ABL2/ARG to the plexin A1 cytoplasmic domain to activate p190RhoGAP and inactivate RhoA, driving cytoskeletal collapse.","evidence":"Co-IP, domain-deletion binding assays, ABL2/p190RhoGAP siRNA, RhoA activity and migration assays in glioma and endothelial cells","pmids":["18660502"],"confidence":"High","gaps":["How ligand binding triggers ABL2 recruitment structurally not defined","Relationship to the Rac1 redistribution seen earlier not reconciled"]},{"year":2010,"claim":"Demonstrated SEMA3F functions as a deposited repulsive cue establishing olfactory bulb topographic order, defining a developmental guidance role distinct from its tumor activity.","evidence":"Mouse genetic models with complementary Nrp2/Sema3F expression and axon tracing/topographic mapping","pmids":["20550939"],"confidence":"High","gaps":["Intracellular effectors in OSN axons not identified here","Quantitative gradient thresholds for repulsion not defined"]},{"year":2012,"claim":"Placed SEMA3F downstream of RORα as a transcriptional effector of tumor suppression and identified promoter methylation/HDAC silencing as its cancer inactivation route.","evidence":"ChIP, luciferase reporters, SEMA3F siRNA rescue of RORα phenotypes; methylation-specific PCR and TSA/5-aza treatment","pmids":["22350413","16005989"],"confidence":"Medium","gaps":["Other upstream regulators not surveyed","Relative contribution of methylation vs HDAC in vivo unresolved"]},{"year":2017,"claim":"Revealed two distinct in vivo roles: NRP2/PlexA3-dependent control of surface AMPAR levels for homeostatic synaptic downscaling, and a context-dependent proangiogenic function in extraembryonic yolk sac via Myc/miR-17-92/Thbs1.","evidence":"NRP2-GluA1 Co-IP with Npn-2/PlexA3 knockout electrophysiology; Sema3f-null yolk sac phenotyping with Myc/miRNA/Thbs1 readouts","pmids":["29154130","28729362"],"confidence":"High","gaps":["Mechanism by which NRP2 controls AMPAR trafficking not fully defined","Tissue determinants switching SEMA3F between pro- and anti-angiogenic outputs unclear"]},{"year":2020,"claim":"Identified CRMP2 as the intracellular mediator selectively coupling Sema3F (not Sema3A) signaling to axon pruning and spine remodeling.","evidence":"crmp2 knockout mice, primary neuron Sema3F signaling assays, histology and behavior","pmids":["31919978"],"confidence":"High","gaps":["Biochemical link between CRMP2 and receptor complex not detailed","Whether CRMP2 acts in non-neuronal SEMA3F responses untested"]},{"year":2021,"claim":"Connected SEMA3F/PLXNA signaling to human disease, showing loss-of-function variants in SEMA3F and PLXNA3 cause idiopathic hypogonadotropic hypogonadism via GnRH neuron guidance.","evidence":"Exome sequencing of IHH patients, HEK293T functional assays, fetal nasal/forebrain IHC","pmids":["33495532"],"confidence":"Medium","gaps":["Single cohort; penetrance and oligogenicity not resolved","In vivo guidance defect in human tissue inferred from expression"]},{"year":2025,"claim":"Established a furin-processing requirement for SEMA3F activity and a sensory disease link, and demonstrated that engineered NRP2/PLXNA1 dimerization can recapitulate SEMA3F signaling.","evidence":"Inner-ear Sema3f knockout mice with patient missense variants and furin/F-actin assays; bispecific antibody dimerization with structural and phospho-AKT/proliferation assays","pmids":["39909336","41391772"],"confidence":"High","gaps":["Structural basis of full receptor assembly with native ligand not solved","Therapeutic durability of antibody mimicry untested"]},{"year":null,"claim":"How SEMA3F output is switched between repulsion, tumor suppression, synaptic regulation, and context-dependent proangiogenesis through shared NRP2/plexin machinery remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for receptor/effector selection across tissues","Limited structural data on the active ligand-receptor signaling complex","p53 as a growth-cone mediator rests on a single low-confidence study"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,5,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,10,12]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,13,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,7]}],"complexes":["NRP2/plexin A1 receptor complex","NRP2/PlexA3 receptor complex"],"partners":["NRP2","NRP1","PLXNA1","PLXNA3","ABL2","CRMP2","GLUA1","CX43"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13275","full_name":"Semaphorin-3F","aliases":["Sema III/F","Semaphorin IV","Sema IV"],"length_aa":785,"mass_kda":88.4,"function":"May play a role in cell motility and cell adhesion","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q13275/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA3F","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA3F","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"616165","title":"NEMALINE MYOPATHY 10; NEM10","url":"https://www.omim.org/entry/616165"},{"mim_id":"616112","title":"LEIOMODIN 3; LMOD3","url":"https://www.omim.org/entry/616112"},{"mim_id":"609907","title":"SEMAPHORIN 3D; SEMA3D","url":"https://www.omim.org/entry/609907"},{"mim_id":"604280","title":"PLEXIN A4; PLXNA4","url":"https://www.omim.org/entry/604280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":96.2}],"url":"https://www.proteinatlas.org/search/SEMA3F"},"hgnc":{"alias_symbol":["SEMAK","Sema4"],"prev_symbol":[]},"alphafold":{"accession":"Q13275","domains":[{"cath_id":"-","chopping":"58-151_185-205","consensus_level":"medium","plddt":92.6952,"start":58,"end":205},{"cath_id":"2.130.10.10","chopping":"209-460","consensus_level":"medium","plddt":94.5111,"start":209,"end":460},{"cath_id":"3.30.1680.10","chopping":"547-605","consensus_level":"high","plddt":85.2702,"start":547,"end":605},{"cath_id":"2.60.40.10","chopping":"611-707","consensus_level":"high","plddt":90.9802,"start":611,"end":707},{"cath_id":"2.60.40","chopping":"27-49_466-545","consensus_level":"medium","plddt":94.025,"start":27,"end":545}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13275","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13275-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13275-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA3F","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA3F"},"sequence":{"accession":"Q13275","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13275.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13275/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13275"}},"corpus_meta":[{"pmid":"8786119","id":"PMC_8786119","title":"Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8786119","citation_count":131,"is_preprint":false},{"pmid":"12845630","id":"PMC_12845630","title":"Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines.","date":"2003","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12845630","citation_count":122,"is_preprint":false},{"pmid":"20550939","id":"PMC_20550939","title":"Sequential arrival and graded secretion of Sema3F by olfactory neuron axons specify map topography at the bulb.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/20550939","citation_count":114,"is_preprint":false},{"pmid":"22350413","id":"PMC_22350413","title":"RORα suppresses breast tumor invasion by inducing SEMA3F expression.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22350413","citation_count":100,"is_preprint":false},{"pmid":"10702410","id":"PMC_10702410","title":"Semaphorin SEMA3F localization in malignant human lung and cell lines: A suggested role in cell adhesion and cell migration.","date":"2000","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10702410","citation_count":96,"is_preprint":false},{"pmid":"12659673","id":"PMC_12659673","title":"Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading.","date":"2003","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12659673","citation_count":93,"is_preprint":false},{"pmid":"18660502","id":"PMC_18660502","title":"ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18660502","citation_count":93,"is_preprint":false},{"pmid":"15802023","id":"PMC_15802023","title":"Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion.","date":"2005","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15802023","citation_count":91,"is_preprint":false},{"pmid":"12454988","id":"PMC_12454988","title":"Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex.","date":"2003","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12454988","citation_count":90,"is_preprint":false},{"pmid":"17875711","id":"PMC_17875711","title":"Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells.","date":"2007","source":"Cancer 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/17362911","citation_count":51,"is_preprint":false},{"pmid":"31919978","id":"PMC_31919978","title":"CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31919978","citation_count":41,"is_preprint":false},{"pmid":"25952650","id":"PMC_25952650","title":"Genetic Identification of SEMA3F as an Antilymphangiogenic Metastasis Suppressor Gene in Head and Neck Squamous Carcinoma.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25952650","citation_count":40,"is_preprint":false},{"pmid":"25866254","id":"PMC_25866254","title":"SEMA3F prevents metastasis of colorectal cancer by PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis.","date":"2015","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25866254","citation_count":38,"is_preprint":false},{"pmid":"36136913","id":"PMC_36136913","title":"The dual role of boron in vitro neurotoxication of glioblastoma cells via SEMA3F/NRP2 and ferroptosis signaling pathways.","date":"2022","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36136913","citation_count":27,"is_preprint":false},{"pmid":"16005989","id":"PMC_16005989","title":"Promoter characterization of Semaphorin SEMA3F, a tumor suppressor gene.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16005989","citation_count":25,"is_preprint":false},{"pmid":"33495532","id":"PMC_33495532","title":"Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33495532","citation_count":24,"is_preprint":false},{"pmid":"28373097","id":"PMC_28373097","title":"Sema3f Protects Against Subretinal Neovascularization In Vivo.","date":"2017","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/28373097","citation_count":22,"is_preprint":false},{"pmid":"17665084","id":"PMC_17665084","title":"Control of intracellular localization and function of Cx43 by SEMA3F.","date":"2007","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/17665084","citation_count":17,"is_preprint":false},{"pmid":"29299034","id":"PMC_29299034","title":"The crucial role of SEMA3F in suppressing the progression of oral squamous cell carcinoma.","date":"2017","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29299034","citation_count":17,"is_preprint":false},{"pmid":"28729362","id":"PMC_28729362","title":"Sema3F (Semaphorin 3F) Selectively Drives an Extraembryonic Proangiogenic Program.","date":"2017","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28729362","citation_count":16,"is_preprint":false},{"pmid":"33109776","id":"PMC_33109776","title":"The oncogenic role of LncRNA FAM83C-AS1 in colorectal cancer development by epigenetically inhibits SEMA3F via stabilizing EZH2.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33109776","citation_count":16,"is_preprint":false},{"pmid":"31968181","id":"PMC_31968181","title":"SEMA3F Promotes Liver Hepatocellular Carcinoma Metastasis by Activating Focal Adhesion Pathway.","date":"2020","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31968181","citation_count":15,"is_preprint":false},{"pmid":"16261621","id":"PMC_16261621","title":"Sema3D, Sema3F, and Sema5A are expressed in overlapping and distinct patterns in chick embryonic heart.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/16261621","citation_count":15,"is_preprint":false},{"pmid":"21815834","id":"PMC_21815834","title":"Expression patterns of Sema3F, PlexinA4, -A3, Neuropilin1 and -2 in the postnatal mouse molar suggest roles in tooth innervation and organogenesis.","date":"2011","source":"Acta odontologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/21815834","citation_count":12,"is_preprint":false},{"pmid":"39909336","id":"PMC_39909336","title":"Biallelic variants of SEMA3F are associated with nonsyndromic hearing loss.","date":"2025","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/39909336","citation_count":7,"is_preprint":false},{"pmid":"22977659","id":"PMC_22977659","title":"Sema3F downregulates p53 expression leading to axonal growth cone collapse in primary hippocampal neurons.","date":"2012","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22977659","citation_count":5,"is_preprint":false},{"pmid":"31215376","id":"PMC_31215376","title":"Changes in Expression Pattern of SEMA3F Depending on Endometrial Cancer Grade - Pilot Study.","date":"2019","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31215376","citation_count":4,"is_preprint":false},{"pmid":"39352623","id":"PMC_39352623","title":"A genome-wide CRISPR/Cas9 knockout screen identifies SEMA3F gene for resistance to cyclin-dependent kinase 4 and 6 inhibitors in breast cancer.","date":"2024","source":"Breast cancer (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/39352623","citation_count":3,"is_preprint":false},{"pmid":"39138514","id":"PMC_39138514","title":"The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma.","date":"2024","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/39138514","citation_count":2,"is_preprint":false},{"pmid":"32297576","id":"PMC_32297576","title":"Differences in the Expression Pattern of mRNA Protein SEMA3F in Endometrial Cancer in vitro under Cisplatin Treatment.","date":"2020","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32297576","citation_count":2,"is_preprint":false},{"pmid":"39232098","id":"PMC_39232098","title":"Semaphorin 3F (SEMA3F) influences patient survival in esophageal adenocarcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39232098","citation_count":1,"is_preprint":false},{"pmid":"37599522","id":"PMC_37599522","title":"Advances in SEMA3F regulation of clinically high-incidence cancers.","date":"2023","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/37599522","citation_count":1,"is_preprint":false},{"pmid":"40319865","id":"PMC_40319865","title":"Effect of SEMA3F on Proliferation, Migration, and Ferroptosis of Endometrial Stromal Cells in Patients with Endometriosis.","date":"2025","source":"Gynecologic and obstetric investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40319865","citation_count":1,"is_preprint":false},{"pmid":"12561429","id":"PMC_12561429","title":"[Mutation and expression of SEMA3B and SEMA3F gene in nasopharyngeal carcinoma].","date":"2003","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12561429","citation_count":1,"is_preprint":false},{"pmid":"41391772","id":"PMC_41391772","title":"A bispecific antibody designed to act as a NRP2/PLXNA1 agonist mimics anticancer activity of SEMA3F.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41391772","citation_count":0,"is_preprint":false},{"pmid":"41029010","id":"PMC_41029010","title":"Effect of Sema3F on VEGF in Primary Rat Hippocampal Neurons In vitro.","date":"2025","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41029010","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.18.665640","title":"Semaphorin 3A and 3F overexpression in TIE2 hyperactive endothelial cells contribute to the pathological lumen expansion in venous malformation","date":"2025-07-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.18.665640","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.12.612713","title":"Gene identification for ocular congenital cranial motor neuron disorders using human sequencing, zebrafish screening, and protein binding microarrays","date":"2024-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.12.612713","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.16.618445","title":"Microglia attenuate regenerative neurogenesis via  <i>sema4ab</i>  after spinal cord injury in zebrafish","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.16.618445","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24303,"output_tokens":5598,"usd":0.078439,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14063,"output_tokens":3868,"usd":0.083507,"stage2_stop_reason":"end_turn"},"total_usd":0.161946,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"SEMA3F forms a complex with NRP2 (neuropilin-2) and plexin A1, triggering a signaling cascade in which ABL2/ARG tyrosine kinase directly binds plexin A1 (but not a plexin A1 mutant lacking the cytoplasmic domain), phosphorylates and activates p190RhoGAP, which inactivates RhoA (GTP to GDP), resulting in cytoskeletal collapse and inhibition of cell migration in glioma cells and endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay with plexin A1 cytoplasmic domain mutant, siRNA knockdown of ABL2 and p190RhoGAP, RhoA activity assays, cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including receptor complex identification, domain-specific mutant binding, kinase activity assays, siRNA epistasis, and functional readouts in two cell types\",\n      \"pmids\": [\"18660502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SEMA3F inhibits cell attachment and spreading in breast cancer cells through neuropilin receptors (NRP1 in MCF7 cells, NRP2 in C100 cells), with antagonistic effects to VEGF; SEMA3F treatment caused redistribution of Rac1-GFP to the base of collapsing lamellipodia, indicating modulation of Rac1 localization rather than total GTP-bound Rac1 or RhoA levels.\",\n      \"method\": \"Cell attachment/spreading assays, blocking anti-NRP1/NRP2 antibodies, time-lapse microscopy with Rac1-GFP, GTPase pull-down assays (negative for total GTP-Rac1/RhoA changes)\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (receptor blocking, live imaging, GTPase assays) in single lab\",\n      \"pmids\": [\"12659673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SEMA3F has a repulsive effect on motile breast cancer cells (C100) mediated through NRP2, and inhibits E-cadherin-mediated cell contacts in MCF7 cells expressing NRP1; SEMA3F suppresses cell spreading and proliferation.\",\n      \"method\": \"3D gradient migration assay, stripe assay, blocking anti-NRP1/NRP2 antibodies, loss of membrane-associated E-cadherin and beta-catenin assessed by imaging\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-blocking epistasis and functional assays, single lab, multiple readouts\",\n      \"pmids\": [\"15802023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SEMA3F expression in lung cancer H157 cells decreases integrin-linked kinase (ILK) kinase activity, reduces activated αVβ3 integrin and adhesion to extracellular matrix, and down-regulates phospho-ERK1/2, phospho-AKT, and phospho-STAT3 signaling; downstream consequences include reduced HIF-1α protein (via inhibition of AKT-driven translation initiation, with no effect on HIF-1α mRNA or protein degradation) and reduced VEGF mRNA.\",\n      \"method\": \"Stable SEMA3F transfection (constitutive and inducible), ILK kinase activity assay, siRNA knockdown of ILK, phospho-protein analysis, conditioned medium experiments, nude mouse xenograft with microvessel density quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assays, siRNA epistasis, multiple signaling readouts, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"17875711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SEMA3F selectively suppresses in vivo tumorigenicity in NCI-H157 lung cancer cells (which express NRP2) but not in NCI-H460 cells (which express NRP1 but not NRP2), establishing NRP2 as the functionally required receptor for SEMA3F antitumor activity; this is associated with loss of activated αVβ3 integrin and loss of p42/p44 MAPK phosphorylation.\",\n      \"method\": \"Orthotopic rat lung cancer model, retroviral stable transfection, receptor expression analysis, integrin activation assay, MAPK phosphorylation assay\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo epistasis using two cell lines with defined NRP1/NRP2 expression, combined with molecular signaling readouts\",\n      \"pmids\": [\"15967098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEMA3F acts predominantly through NRP2 to collapse lymphatic endothelial cells (LECs) and potently inhibit lymphangiogenesis in vivo; reconstitution of all plexin and neuropilin receptor combinations identified NRP2 as the principal signaling co-receptor in LECs; SEMA3F re-expression in HNSCC orthotopic mouse models diminishes lymphangiogenesis and lymph node metastasis.\",\n      \"method\": \"Recombinant SEMA3F protein treatment, reconstitution of plexin/neuropilin receptor combinations in LECs, in vivo lymphangiogenesis assays, orthotopic HNSCC mouse metastasis models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — receptor reconstitution experiments combined with in vivo genetic models and functional readouts\",\n      \"pmids\": [\"25952650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sema3F-Neuropilin-2/PlexinA3 signaling mediates homeostatic synaptic downscaling in cortical neurons in response to increased neuronal activity; NRP2 physically associates with AMPA-type glutamate receptor (AMPAR) subunit GluA1, and Sema3F regulates this interaction to control cell surface AMPAR levels.\",\n      \"method\": \"Co-immunoprecipitation of NRP2 with GluA1, genetic loss-of-function (Npn-2 and PlexA3 knockout mice), electrophysiology for homeostatic scaling, surface AMPAR quantification\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, multiple genetic knockouts, electrophysiological readout\",\n      \"pmids\": [\"29154130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRMP2 mediates Sema3F-dependent axon pruning in hippocampus and visual cortex and dendritic spine remodeling; crmp2-/- mice display defects consistent with impaired Sema3F (not Sema3A) signaling, and CRMP2 was shown to mediate Sema3F signaling in primary neurons.\",\n      \"method\": \"crmp2 knockout mice, in vitro primary neuron Sema3F signaling assay, histological analysis of axon pruning and spine remodeling, behavioral assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype, primary neuron functional assay, multiple orthogonal readouts\",\n      \"pmids\": [\"31919978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RORα directly regulates transcription of SEMA3F, as established by chromatin immunoprecipitation and luciferase reporter assays; knockdown of SEMA3F in RORα-expressing cancer cells rescued aggressive 3D phenotypes and tumor invasion, placing SEMA3F downstream of RORα as the effector of its tumor-suppressive activity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown of SEMA3F, 3D culture invasion assay, nude mouse tumor growth\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct transcription factor binding demonstrated by ChIP and reporter assay, rescue epistasis experiment confirms pathway placement\",\n      \"pmids\": [\"22350413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEMA3F inhibits invasion and metastasis of colorectal cancer cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis; the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion in vitro and in vivo, placing CXCR4 downstream of SEMA3F/PI3K-AKT/ASCL2.\",\n      \"method\": \"SEMA3F knockdown and overexpression in CRC cells, PI3K-AKT pathway inhibitors, CXCR4 antagonist (AMD3100) rescue experiments, in vitro invasion assay, in vivo metastasis model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis and rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"25866254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the extraembryonic yolk sac, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, which drives expression of the proangiogenic microRNA cluster 17/92 and suppresses Thrombospondin-1 (Thbs1); in Sema3f-null yolk sacs, miR-17/92 transcription is impaired, Thbs1 synthesis is increased, and Vegf signaling is inhibited in yolk sac endothelial cells — establishing a proangiogenic (rather than antiangiogenic) role for Sema3F in extraembryonic tissue.\",\n      \"method\": \"Sema3f knockout mice, exogenous recombinant Sema3F treatment of differentiated F9 cells, Myc phosphorylation assays, miRNA expression analysis, Thbs1 protein quantification, in vivo vascular phenotyping\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic knockout with in vivo phenotype, recombinant protein rescue, multiple molecular readouts in single rigorous study\",\n      \"pmids\": [\"28729362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SEMA3F directly binds to the cytoplasmic loop domain of connexin 43 (Cx43), as demonstrated by yeast two-hybrid assay; SEMA3F siRNA knockdown in IAR20 cells reduced Cx43 localization in the plasma membrane and gap junctional intercellular communication (GJIC), establishing SEMA3F as a regulator of Cx43 membrane localization and function.\",\n      \"method\": \"Yeast two-hybrid complementation and screening, immunolocalization, siRNA knockdown, GJIC functional assay\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid binding plus siRNA functional assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"17665084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema3F is secreted by early-arriving olfactory sensory neuron (OSN) axons and deposited at the anterodorsal olfactory bulb, where it repels Nrp2-positive axons arriving later; complementary graded expression of Nrp2 and Sema3F by OSNs and sequential axon arrival together establish topographic order along the dorsal-ventral axis of the olfactory bulb.\",\n      \"method\": \"Mouse genetic models with complementary Nrp2/Sema3F expression analysis, axon tracing, olfactory bulb topography mapping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetic epistasis with defined ligand-receptor pair and quantitative topographic mapping\",\n      \"pmids\": [\"20550939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ectopic Sema3F expression in COS1 cell clusters placed on embryonic neocortical slices reduced migration of Nrp2-positive GABAergic neurons from the ganglionic eminence; combining Sema3A and Sema3F expression almost completely blocked migration, and ectopic Sema3F in vivo diverted Dlx2-positive cells to the upper intermediate zone — establishing Sema3F/Nrp2 as a regulator of cortical GABAergic interneuron migration.\",\n      \"method\": \"Slice culture assay with COS1 cell clusters expressing Sema3F, in vivo ectopic Sema3F expression, Dlx2 immunolabeling, neuropilin expression analysis\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo slice epistasis and in vivo ectopic expression with defined cellular phenotype, single lab\",\n      \"pmids\": [\"12454988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SEMA3F promoter methylation at position −3850 to −3644 nt significantly correlates with loss of SEMA3F expression in lung cancer cell lines; however, histone deacetylase inhibition (Trichostatin A) was more effective than demethylation (5-aza-2'-deoxycytidine) in reactivating SEMA3F, indicating chromatin remodeling via HDAC inhibition is sufficient to activate SEMA3F transcription.\",\n      \"method\": \"Southern blot, methylation-specific PCR, Trichostatin A and 5-aza-2'-deoxycytidine treatment, transcriptional initiation site mapping\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal epigenetic methods with functional transcription readout, single lab\",\n      \"pmids\": [\"16005989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function variants in SEMA3F and its receptor PLXNA3 cause idiopathic hypogonadotropic hypogonadism (IHH); SEMA3F and PLXNA3 are expressed along the olfactory nerve and vomeronasal/terminal nerve during early human fetal development, and PLXNA1-A3 are expressed in early migratory GnRH neurons, establishing SEMA3F/PLXNA signaling as required for GnRH neuron guidance in humans.\",\n      \"method\": \"Exome sequencing of 216 IHH patients, functional assays in HEK293T cells with WT vs. variant plasmids, fluorescent IHC in human fetal nasal region and nasal/forebrain junction\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variants with in vitro functional validation and in situ expression in human fetal tissue, single study\",\n      \"pmids\": [\"33495532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Missense variants in SEMA3F associated with human nonsyndromic hearing loss decreased furin-mediated processing of SEMA3F and abolished SEMA3F-induced collapse of filamentous actin cytoskeleton in endothelial cells; inner ear-specific Sema3f knockout mice exhibited hearing loss with abnormal spiral ganglion neuron projections into outer hair cell regions.\",\n      \"method\": \"Inner ear-specific Sema3f knockout mice, auditory brainstem response and DPOAE testing, spiral ganglion neuron tracing, in vitro furin cleavage assay, F-actin collapse assay in HUVECs with patient variants\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional knockout mouse with defined phenotype, in vitro biochemical processing assay, and cell-based functional assay with patient variants\",\n      \"pmids\": [\"39909336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema3F down-regulates p53 expression in primary hippocampal neurons, contributing to growth cone collapse; p53 overexpression partially rescued Sema3F-induced growth cone collapse, while p53 inhibition or siRNA knockdown alone caused collapse, establishing p53 as a required downstream mediator of growth cone structure.\",\n      \"method\": \"Primary hippocampal neuron culture, Sema3F treatment, p53 siRNA and inhibitor, p53 overexpression rescue, growth cone morphology quantification\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single publication, limited methodological detail in abstract\",\n      \"pmids\": [\"22977659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A bispecific antibody dimerizing NRP2 and PLXNA1 mimics SEMA3F-mediated NRP2-dependent signaling (receptor dimerization, phospho-AKT reduction, oncogene expression suppression, cell proliferation inhibition); structural studies showed the antibody binds PLXNA1/NRP2 at sites distinct from the SEMA3F-binding site but allows proper spacing for receptor complex formation and signaling.\",\n      \"method\": \"Cell-based receptor dimerization assay, phospho-AKT assay, cell proliferation assay, structural studies of antibody-receptor binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural characterization combined with multiple cell-based functional assays, single study\",\n      \"pmids\": [\"41391772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In TIE2-mutant endothelial cells (venous malformation model), Sema3F (and Sema3A) are overexpressed and act as chemorepellents to inhibit wild-type endothelial cell sprouting and lumen formation; shRNA-mediated silencing of Sema3F (or Sema3A) in TIE2-mutant EC rescued the chemorepellent phenotype, restored wild-type EC migration and sprouting, and normalized vessel size in vivo.\",\n      \"method\": \"Xenograft murine VM model, 3D fibrin gel lumen formation assay, cell migration confrontation assay, RNA-sequencing, shRNA knockdown of Sema3F/Sema3A, in vivo vessel morphology analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA epistasis with in vitro and in vivo rescue, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEMA3F is a secreted class 3 semaphorin that signals through NRP2 (and NRP1) co-receptors complexed with plexin A1/A3, triggering ABL2/ARG-mediated phosphorylation of p190RhoGAP, inactivation of RhoA, and cytoskeletal collapse; it suppresses tumor cell adhesion, migration, and invasion by down-regulating ILK-ERK1/2, AKT-STAT3, and HIF-1α/VEGF signaling, acts as a repulsive axon guidance cue (via Nrp2) for olfactory map formation and GABAergic neuron migration, mediates homeostatic synaptic downscaling through NRP2/PlexA3-dependent regulation of AMPAR surface levels (requiring CRMP2 as an intracellular mediator), guides GnRH neurons via PLXNA signaling, is transcriptionally regulated by RORα (direct binding) and epigenetically silenced by promoter methylation/HDAC activity in cancer, and requires furin-mediated proteolytic processing for full activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA3F is a secreted class 3 semaphorin that signals through neuropilin co-receptors—principally NRP2—complexed with A-type plexins to reorganize the actin cytoskeleton and restrain cell adhesion, migration, and invasion [#0, #4]. Engagement of the NRP2/plexin A1 complex recruits the ABL2/ARG tyrosine kinase to the plexin A1 cytoplasmic domain, which phosphorylates and activates p190RhoGAP, inactivating RhoA and producing cytoskeletal collapse and loss of motility [#0]; SEMA3F also redistributes Rac1 to the base of collapsing lamellipodia and disrupts E-cadherin-based contacts [#1, #2]. Through NRP2 it acts as a tumor suppressor, lowering integrin-linked kinase activity and αVβ3 integrin activation and damping ERK1/2, AKT, and STAT3 signaling, thereby reducing HIF-1α and VEGF output and suppressing tumorigenicity, lymphangiogenesis, and metastasis [#3, #4, #5]; in colorectal cells this anti-invasive activity operates through PI3K-AKT-dependent down-regulation of the ASCL2–CXCR4 axis [#9]. In the nervous system SEMA3F is a repulsive guidance cue acting via Nrp2/PlexA3: it patterns olfactory bulb topography and cortical GABAergic interneuron migration [#12, #13], drives CRMP2-dependent axon pruning and dendritic spine remodeling [#7], and mediates homeostatic synaptic downscaling by controlling surface AMPAR levels through an NRP2–GluA1 association [#6]. Its activity requires furin-mediated proteolytic processing, and loss-of-function or processing-impairing variants cause idiopathic hypogonadotropic hypogonadism via defective GnRH neuron guidance and nonsyndromic hearing loss via aberrant spiral ganglion neuron projections [#15, #16]. SEMA3F is itself a direct transcriptional target of RORα and is epigenetically silenced in cancer by promoter methylation and HDAC activity [#8, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that SEMA3F acts through neuropilin receptors to inhibit cell attachment and spreading, defining its anti-adhesive activity and antagonism with VEGF.\",\n      \"evidence\": \"Cell attachment/spreading assays with blocking anti-NRP1/NRP2 antibodies and Rac1-GFP live imaging in breast cancer cells\",\n      \"pmids\": [\"12659673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Total GTP-Rac1/RhoA were unchanged, leaving the cytoskeletal mechanism unresolved at this stage\", \"Did not identify intracellular signaling intermediates\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed SEMA3F is repulsive to motile tumor cells and that NRP2 is the functionally required receptor for its in vivo antitumor activity, separating NRP2- from NRP1-dependent responses.\",\n      \"evidence\": \"3D gradient/stripe migration assays and orthotopic rat lung cancer models comparing NRP2+ vs NRP2- cell lines\",\n      \"pmids\": [\"15802023\", \"15967098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream kinases linking NRP2 to integrin/MAPK changes not yet defined\", \"Plexin co-receptor identity not established here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined a tumor-suppressive signaling output whereby SEMA3F lowers ILK activity and integrin activation to suppress ERK/AKT/STAT3, HIF-1α, and VEGF; separately linked SEMA3F to Cx43 membrane localization.\",\n      \"evidence\": \"ILK kinase assays, phospho-protein analysis, xenograft microvessel quantification; yeast two-hybrid and GJIC assays for Cx43\",\n      \"pmids\": [\"17875711\", \"17665084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic connection between receptor engagement and ILK inhibition incomplete\", \"Cx43 binding shown by Y2H without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the proximal signaling mechanism: the NRP2/plexin A1 complex recruits ABL2/ARG to the plexin A1 cytoplasmic domain to activate p190RhoGAP and inactivate RhoA, driving cytoskeletal collapse.\",\n      \"evidence\": \"Co-IP, domain-deletion binding assays, ABL2/p190RhoGAP siRNA, RhoA activity and migration assays in glioma and endothelial cells\",\n      \"pmids\": [\"18660502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ligand binding triggers ABL2 recruitment structurally not defined\", \"Relationship to the Rac1 redistribution seen earlier not reconciled\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated SEMA3F functions as a deposited repulsive cue establishing olfactory bulb topographic order, defining a developmental guidance role distinct from its tumor activity.\",\n      \"evidence\": \"Mouse genetic models with complementary Nrp2/Sema3F expression and axon tracing/topographic mapping\",\n      \"pmids\": [\"20550939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular effectors in OSN axons not identified here\", \"Quantitative gradient thresholds for repulsion not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed SEMA3F downstream of RORα as a transcriptional effector of tumor suppression and identified promoter methylation/HDAC silencing as its cancer inactivation route.\",\n      \"evidence\": \"ChIP, luciferase reporters, SEMA3F siRNA rescue of RORα phenotypes; methylation-specific PCR and TSA/5-aza treatment\",\n      \"pmids\": [\"22350413\", \"16005989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other upstream regulators not surveyed\", \"Relative contribution of methylation vs HDAC in vivo unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed two distinct in vivo roles: NRP2/PlexA3-dependent control of surface AMPAR levels for homeostatic synaptic downscaling, and a context-dependent proangiogenic function in extraembryonic yolk sac via Myc/miR-17-92/Thbs1.\",\n      \"evidence\": \"NRP2-GluA1 Co-IP with Npn-2/PlexA3 knockout electrophysiology; Sema3f-null yolk sac phenotyping with Myc/miRNA/Thbs1 readouts\",\n      \"pmids\": [\"29154130\", \"28729362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NRP2 controls AMPAR trafficking not fully defined\", \"Tissue determinants switching SEMA3F between pro- and anti-angiogenic outputs unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CRMP2 as the intracellular mediator selectively coupling Sema3F (not Sema3A) signaling to axon pruning and spine remodeling.\",\n      \"evidence\": \"crmp2 knockout mice, primary neuron Sema3F signaling assays, histology and behavior\",\n      \"pmids\": [\"31919978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between CRMP2 and receptor complex not detailed\", \"Whether CRMP2 acts in non-neuronal SEMA3F responses untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SEMA3F/PLXNA signaling to human disease, showing loss-of-function variants in SEMA3F and PLXNA3 cause idiopathic hypogonadotropic hypogonadism via GnRH neuron guidance.\",\n      \"evidence\": \"Exome sequencing of IHH patients, HEK293T functional assays, fetal nasal/forebrain IHC\",\n      \"pmids\": [\"33495532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cohort; penetrance and oligogenicity not resolved\", \"In vivo guidance defect in human tissue inferred from expression\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a furin-processing requirement for SEMA3F activity and a sensory disease link, and demonstrated that engineered NRP2/PLXNA1 dimerization can recapitulate SEMA3F signaling.\",\n      \"evidence\": \"Inner-ear Sema3f knockout mice with patient missense variants and furin/F-actin assays; bispecific antibody dimerization with structural and phospho-AKT/proliferation assays\",\n      \"pmids\": [\"39909336\", \"41391772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of full receptor assembly with native ligand not solved\", \"Therapeutic durability of antibody mimicry untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEMA3F output is switched between repulsion, tumor suppression, synaptic regulation, and context-dependent proangiogenesis through shared NRP2/plexin machinery remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for receptor/effector selection across tissues\", \"Limited structural data on the active ligand-receptor signaling complex\", \"p53 as a growth-cone mediator rests on a single low-confidence study\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 5, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 10, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 13, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"NRP2/plexin A1 receptor complex\", \"NRP2/PlexA3 receptor complex\"],\n    \"partners\": [\"NRP2\", \"NRP1\", \"PLXNA1\", \"PLXNA3\", \"ABL2\", \"CRMP2\", \"GluA1\", \"Cx43\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}