{"gene":"SEMA3C","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2014,"finding":"SEMA3C promotes glioma stem cell (GSC) survival through an autocrine/paracrine loop: GSCs preferentially secrete SEMA3C and co-express PlexinA2/D1 receptors, activating Rac1/NF-κB signaling. Introduction of activated Rac1 rescued the SEMA3C knockdown phenotype in vivo, placing SEMA3C upstream of Rac1 in this pathway.","method":"Knockdown in orthotopic glioblastoma models, receptor co-expression analysis, Rac1 rescue experiment in vivo","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (Rac1 rescue), in vivo model with defined phenotypic readout, replicated across GSC lines","pmids":["25464848"],"is_preprint":false},{"year":2015,"finding":"Bcl11a is a direct negative transcriptional regulator of Sema3C in cortical neurons; loss of Bcl11a increases Sema3C expression, and Sema3C elevation causes failure of multipolar-to-bipolar polarity switch and impaired radial migration of upper-layer cortical neurons. In vivo gain-of-function and rescue experiments confirmed Sema3C as the major downstream effector of Bcl11a.","method":"In vivo gain-of-function and rescue experiments, ChIP (direct binding of Bcl11a to Sema3C promoter), conditional knockout mice","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — direct transcriptional regulation shown by ChIP, epistasis confirmed by in vivo rescue, replicated with multiple approaches","pmids":["26182416"],"is_preprint":false},{"year":2015,"finding":"Neural crest-derived SEMA3C activates NRP1 on outflow tract endothelium to promote endothelial-to-mesenchymal transition (EndMT), supplying cells to endocardial cushions and repositioning cardiac neural crest cells, both required for cardiac outflow tract septal bridge formation.","method":"Ligand-specific and tissue-specific mouse mutants, explant assays, gene-expression studies, lineage tracing","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — complementary mutant series, lineage tracing, explant functional assays, mechanistic pathway defined","pmids":["26053665"],"is_preprint":false},{"year":2018,"finding":"SEMA3C drives activation of multiple receptor tyrosine kinases (EGFR, ErbB2, MET) in a cognate ligand-independent manner via PlexinB1. Plexin B1 sema domain:Fc fusion proteins suppress RTK signaling and cell growth, and inhibit CRPC progression in vivo.","method":"Co-IP/pulldown, Plexin B1 Fc fusion inhibitor in vitro and in vivo xenograft model, RTK phosphorylation assays","journal":"EMBO Molecular Medicine","confidence":"High","confidence_rationale":"Tier 2 — receptor identification by Co-IP, functional inhibition with Fc fusion in vivo, multiple RTK readouts","pmids":["29348142"],"is_preprint":false},{"year":2018,"finding":"Ephrin-B1 upregulation in post-crossing corpus callosum axons inhibits Sema3C/Neuropilin-1 signaling to silence the attractant response to Sema3C. This silencing is independent of Eph receptors and requires N-glycosylation at N-139 in the Ephrin-B1 extracellular domain, which mediates physical interaction with Nrp1.","method":"In vivo axon guidance assays, epistasis experiments, co-immunoprecipitation of Ephrin-B1 with Nrp1, N-glycosylation site mutagenesis","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of interaction site, Co-IP, in vivo functional validation","pmids":["29779877"],"is_preprint":false},{"year":2017,"finding":"Foxc1/c2 transcription factors directly activate Sema3C transcription in the outflow tract, while Tbx1-driven Fgf8 inhibits Sema3C expression in cardiac neural crest cells via ERK1/2 signaling. Blocking FGF8 causes ectopic SEMA3C expression and cNCC migration defects.","method":"Promoter reporter assays, ChIP, FGF8 blocking experiments in chick, ERK1/2 signaling readout","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional activation shown, signaling pathway defined, but single-lab study","pmids":["28754980"],"is_preprint":false},{"year":2021,"finding":"MAOA promotes SEMA3C expression via Twist1-dependent transcriptional activation; SEMA3C in turn stimulates cMET to facilitate perineural invasion through autocrine/paracrine co-activation with PlexinA2 and NRP1 co-receptors.","method":"Knockdown/overexpression, co-culture PNI assay, in vivo orthotopic xenograft, signaling pathway analysis (cMET phosphorylation), ChIP for Twist1 on SEMA3C promoter","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — direct transcriptional mechanism, receptor complex defined, in vivo validation, multiple readouts","pmids":["33420365"],"is_preprint":false},{"year":2023,"finding":"Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process in glioma stem cells, leading to transcriptional activation of Wnt target genes independent of Wnt ligand binding. Combined depletion of Sema3C and TCF1 extended survival in a mouse glioblastoma model more than single inhibition.","method":"β-catenin localization assays, Rac1 dependency experiments, Wnt ligand secretion suppression, mouse glioblastoma model with combinatorial depletion","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — pathway placement by epistasis, β-catenin localization assay, in vivo survival data, multiple orthogonal methods","pmids":["37080989"],"is_preprint":false},{"year":2012,"finding":"Motoneuronal Sema3C expression regulates surface levels of Nrp1 and Nrp2 at the growth cone in opposing ways, thereby modulating responsiveness to exogenous Sema3A, Sema3F, and Sema3C repellents and determining stereotyped motor nerve trajectory positioning in chick forelimb.","method":"Targeted gain- and loss-of-function in chick neural tube, growth cone surface receptor quantification, in vivo motor nerve trajectory analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional manipulation, growth cone receptor quantification, but single-lab study in chick model","pmids":["22899844"],"is_preprint":false},{"year":2018,"finding":"The furin cleavage site 742RNRR745 in the basic domain of Sema3C is essential for its anti-angiogenic activity: point mutation R745A abrogates inhibition of microcapillary formation by human umbilical vein endothelial cells in vitro.","method":"Site-directed mutagenesis of furin cleavage site, in vitro angiogenesis assay (HUVEC tube formation)","journal":"Brazilian Journal of Medical and Biological Research","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with functional in vitro readout, but single lab, single paper","pmids":["30304095"],"is_preprint":false},{"year":2024,"finding":"SEMA3C binds NRP1 and ITGB1 receptors to activate AKT/Gli1/c-Myc signaling for HCC self-renewal. In hepatic stellate cells, SEMA3C interaction with NRP1 and ITGB1 activates NF-κB signaling, stimulating IL-6 release and HMGCR-mediated cholesterol synthesis. CAF-secreted TGF-β1 activates AP1 signaling to upregulate SEMA3C in HCC cells, forming a positive feedback loop.","method":"Co-IP (SEMA3C with NRP1 and ITGB1), signaling pathway analysis, in vivo tumor models, receptor knockdown","journal":"Signal Transduction and Targeted Therapy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP for receptor identification, multiple signaling readouts, in vivo validation, but single-lab study","pmids":["38956074"],"is_preprint":false},{"year":2019,"finding":"SEMA3C signals through NRP2 (not NRP1) in corneal epithelial cells to promote wound healing and sensory nerve regeneration. siRNA knockdown of SEMA3C or NRP2-neutralizing antibodies decreased wound healing and nerve regeneration; exogenous SEMA3C had opposing effects in diabetic corneas. NRP1 neutralization had a detrimental role in nerve regeneration.","method":"siRNA knockdown in vivo, NRP2 neutralizing antibodies, exogenous protein injection, wound healing assay, nerve fiber counting","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — receptor specificity defined in vivo with antibody and siRNA approaches, functional readouts for both healing and nerve regeneration","pmids":["30679185"],"is_preprint":false},{"year":2021,"finding":"FOXM1 binds the promoter region of SEMA3C to directly elevate its expression; SEMA3C then upregulates NRP2 and activates Hedgehog signaling (SMO-dependent) to promote M2 macrophage polarization and fibroblast proliferation/migration in diabetic wound healing.","method":"ChIP (FOXM1 binding to SEMA3C promoter), knockdown/overexpression, SMO antagonist epistasis, M2 polarization assay, wound healing model","journal":"Diabetes Research and Clinical Practice","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional regulation by ChIP, pathway placement by SMO epistasis, but single-lab study","pmids":["34742786"],"is_preprint":false},{"year":2021,"finding":"The lncRNA LETR1 regulates SEMA3C expression in lymphatic endothelial cells as a nuclear trans-acting lncRNA via epigenetic factors; knockdown of LETR1 reduces SEMA3C levels and impairs LEC migratory ability, which is rescued by SEMA3C restoration.","method":"Antisense oligonucleotide knockdown, transcriptomic profiling, RNA-DNA and RNA-protein interaction studies, phenotype rescue assay","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, phenotype rescue, but no direct SEMA3C mechanism downstream defined","pmids":["33568674"],"is_preprint":false},{"year":2025,"finding":"CAF-secreted SEMA3C binds NRP2 receptor on colorectal cancer liver metastasis-initiating cells, activating the MAPK pathway to promote liver metastasis.","method":"Co-culture experiments, receptor-ligand binding (SEMA3C-NRP2), in vivo and in vitro functional assays, MAPK pathway activation readout","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-ligand pair validated in vivo and in vitro, MAPK pathway activation defined, single-lab study","pmids":["40402249"],"is_preprint":false},{"year":2021,"finding":"SEMA3C overexpression in LNCaP prostate cancer cells promotes androgen synthesis in prostatic stromal cells through paracrine induction of Sonic Hedgehog (Shh) signaling (not direct SEMA3C action), as blocking Shh with a smoothened antagonist negated the steroidogenic effect.","method":"Conditioned media treatment, liquid chromatography-mass spectrometry for androgen quantification, SMO antagonist epistasis, qPCR for steroidogenic enzymes","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with Shh pathway, LC-MS for androgen quantification, but indirect effect (SEMA3C acts via intermediate)","pmids":["33503318"],"is_preprint":false},{"year":2024,"finding":"FOXA1 directly and negatively regulates SEMA3C transcription via intronic cis elements; FOXA1 forkhead domain mutations attenuate this inhibitory function (shown in reporter assays), leading to elevated SEMA3C levels in prostate cancer.","method":"Luciferase reporter assays, ChIP-seq analysis, analysis of prostate cancer specimens with FOXA1 mutations","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct regulatory element identified, mutagenesis in reporter assay, in vitro validation, single lab","pmids":["38528115"],"is_preprint":false},{"year":2025,"finding":"SEMA3C inhibits dendrite outgrowth in cortical neurons via PLXND1 and NRP2 receptors. Genetic reduction of astrocyte-secreted SEMA3C in female Rett Syndrome model mice enhances dendritic arborization, normalizes synaptic activity, visual acuity, and motor behavior.","method":"Astrocyte-neuron co-culture, receptor knockdown (PLXND1, NRP2), conditional genetic reduction in RTT mouse model, electrophysiology, behavioral assays","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — receptor specificity defined by knockdown, in vivo genetic model with behavioral and electrophysiological readouts; preprint not yet peer-reviewed","pmids":["41279175"],"is_preprint":true},{"year":2025,"finding":"A LINE-1 retrotransposon within Sema3c (Sema3c_L1Md_T) acts as a cis-regulatory enhancer, forming phase-separated nuclear condensates with BRD4 at H3K27ac-marked regions to drive SEMA3C transcription. SEMA3C sustains breast cancer stem cell survival via NRP1, PlexinA2, and PlexinD1 receptors. BRD4 PROTAC degradation reduces SEMA3C levels and decreases BCSC viability.","method":"Dual-luciferase reporter assay, CRISPRa (dCas9-based), RNA-seq, ChIP, BRD4 PROTAC treatment, receptor knockdown (NRP1, PlexinA2, PlexinD1), in vivo tumor models","journal":"Science China Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including CRISPRa, reporter assay, in vivo validation; single lab","pmids":["41984404"],"is_preprint":false},{"year":2025,"finding":"MALAT1 positively regulates SEMA3C expression in intracranial aneurysm vascular smooth muscle cells; SEMA3C mediates downstream Smad pathway activation, promoting VSMC phenotype switching from contractile to synthetic type and inflammatory cytokine release. SEMA3C overexpression reverses the effects of MALAT1 silencing.","method":"Lentiviral overexpression/knockdown, epistasis (SEMA3C OE reverting MALAT1 KD phenotype), Smad pathway activation assay, in vivo IA rat model","journal":"Frontiers in Cellular Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis, in vivo model, pathway (Smad) activation defined; single-lab study","pmids":["41890214"],"is_preprint":false},{"year":2023,"finding":"SEMA3C stimulation of ER+ breast cancer cells activates MAPK and AKT signaling in a dose-dependent manner. SEMA3C silencing inhibits ER expression, MAPK and AKT signaling, and induces apoptosis. The SEMA3C pathway inhibitor B1SP Fc fusion protein attenuates SEMA3C-induced signaling via PlexinB1.","method":"Recombinant SEMA3C stimulation assay, siRNA knockdown, flow cytometry (apoptosis), Western blot for pathway activation, B1SP Fc fusion protein inhibition","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — receptor identified (PlexinB1 via B1SP inhibitor), signaling readouts defined, but no direct receptor binding assay in this paper","pmids":["37443749"],"is_preprint":false},{"year":2025,"finding":"KLF6 recruits the PCAF-p300/CBP complex to the SEMA3C locus, increasing H3K23 succinylation and cooperating with FOSL2 to transcriptionally upregulate SEMA3C; SEMA3C in turn modulates the Wnt/β-catenin pathway (upregulating MYC and FOSL2) in 5-FU-resistant colon cancer cells.","method":"CUT&Tag, ATAC-seq, RNA-seq, ChIP assays for KLF6 and FOSL2 binding, knockdown of KLF6 and FOSL2","journal":"Experimental & Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple chromatin assays, direct TF binding shown, downstream pathway defined; single-lab study","pmids":["40082673"],"is_preprint":false}],"current_model":"SEMA3C is a secreted class 3 semaphorin that functions as an autocrine/paracrine ligand binding to receptor complexes (NRP1/NRP2, PlexinA2, PlexinB1, PlexinD1, ITGB1) to activate multiple intracellular pathways including Rac1/NF-κB, β-catenin/Wnt, MAPK, AKT, and Smad signaling; its transcription is directly regulated by Bcl11a, FOXA1, Foxc1/c2, Fgf8/ERK, FOXM1, KLF6/FOSL2/p300, and a LINE-1 enhancer/BRD4 axis, and it plays defined roles in cortical neuron migration, cardiac outflow tract septation (via EndMT downstream of NRP1), axon guidance, glioma stem cell survival, and cancer RTK transactivation via PlexinB1."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing that SEMA3C acts cell-autonomously in motor neurons to tune growth cone responsiveness by reciprocally modulating NRP1 and NRP2 surface levels, thereby determining motor nerve trajectory—revealing SEMA3C as an intrinsic regulator of semaphorin sensitivity, not merely an extrinsic cue.","evidence":"Targeted gain/loss-of-function in chick neural tube with growth cone surface receptor quantification and in vivo nerve trajectory analysis","pmids":["22899844"],"confidence":"Medium","gaps":["Single-lab study in chick; not replicated in mammalian model","Downstream signaling mediating NRP surface level changes undefined","Whether this mechanism operates in sensory or other axon types unknown"]},{"year":2014,"claim":"Demonstrating that SEMA3C functions as an autocrine survival factor for glioma stem cells through PlexinA2/D1 receptors and Rac1/NF-κB signaling—the first identification of a semaphorin autocrine loop in brain tumor maintenance, with Rac1 placed epistatically downstream.","evidence":"Knockdown in orthotopic glioblastoma models, receptor co-expression analysis, Rac1 constitutive-active rescue in vivo","pmids":["25464848"],"confidence":"High","gaps":["Direct physical interaction between SEMA3C and PlexinA2/D1 not shown by binding assay","Mechanism linking receptor activation to Rac1 unclear","Whether NRP co-receptors participate in GSC context not tested"]},{"year":2015,"claim":"Defining SEMA3C as a critical effector in two distinct developmental programs—cortical neuron migration (repressed by Bcl11a) and cardiac outflow tract septation (activating EndMT via NRP1)—establishing its dual developmental significance.","evidence":"ChIP for Bcl11a at Sema3c promoter, conditional knockout mice with in vivo rescue (cortex); ligand/tissue-specific mutants, lineage tracing, explant assays (heart)","pmids":["26182416","26053665"],"confidence":"High","gaps":["Downstream intracellular signaling mediating EndMT in outflow tract not fully resolved","Whether Bcl11a-SEMA3C axis operates outside upper-layer neurons untested","Identity of the SEMA3C receptor complex in cortical migration not defined"]},{"year":2017,"claim":"Revealing that SEMA3C transcription in the outflow tract is positively controlled by Foxc1/c2 and negatively regulated by Tbx1-driven Fgf8/ERK signaling in cardiac neural crest cells—providing the upstream transcriptional logic for spatially restricted SEMA3C expression during heart development.","evidence":"Promoter reporter assays, ChIP for Foxc1/c2, FGF8 blocking experiments in chick with ERK readout","pmids":["28754980"],"confidence":"Medium","gaps":["Single-lab study","Whether Foxc1/c2 and Fgf8/ERK converge on the same promoter elements unknown","Mammalian validation of FGF8-ERK repression incomplete"]},{"year":2018,"claim":"Identifying PlexinB1 as the receptor through which SEMA3C transactivates RTKs (EGFR, ErbB2, MET) in a cognate ligand-independent manner, and demonstrating that Ephrin-B1 silences SEMA3C/NRP1 attraction in commissural axons via direct glycosylation-dependent NRP1 binding—together resolving two distinct receptor-level regulatory mechanisms.","evidence":"Co-IP/pulldown and PlexinB1-Fc fusion inhibition in xenograft (prostate cancer); Co-IP of Ephrin-B1–NRP1, N-glycosylation mutagenesis, in vivo axon guidance assays (corpus callosum)","pmids":["29348142","29779877"],"confidence":"High","gaps":["Structural basis of PlexinB1-mediated RTK transactivation unknown","Whether Ephrin-B1 silencing mechanism applies to non-callosal axon systems untested","Furin cleavage requirement for RTK transactivation not addressed"]},{"year":2018,"claim":"Establishing that furin processing at the 742RNRR745 basic domain cleavage site is required for SEMA3C anti-angiogenic activity, indicating post-translational processing regulates functional output.","evidence":"Site-directed mutagenesis of furin site (R745A), HUVEC tube formation assay","pmids":["30304095"],"confidence":"Medium","gaps":["Single-lab, in vitro only","Whether furin cleavage regulates SEMA3C activities beyond angiogenesis unknown","No in vivo validation"]},{"year":2019,"claim":"Demonstrating NRP2-selective signaling for SEMA3C in corneal epithelium, where it promotes wound healing and sensory nerve regeneration—showing that receptor choice (NRP2 vs. NRP1) dictates tissue-specific outcomes.","evidence":"siRNA knockdown, NRP2 neutralizing antibodies, exogenous SEMA3C in diabetic cornea model in vivo","pmids":["30679185"],"confidence":"Medium","gaps":["Downstream intracellular signaling in corneal cells not defined","Single-lab study","Whether PlexinD1 participates as a co-receptor in cornea untested"]},{"year":2021,"claim":"Expanding the transcriptional regulation network: MAOA/Twist1 directly activates SEMA3C to drive cMET-mediated perineural invasion; FOXM1 activates SEMA3C to induce NRP2/Hedgehog-dependent M2 macrophage polarization; and the lncRNA LETR1 epigenetically maintains SEMA3C in lymphatic endothelial cells—demonstrating pervasive transcriptional control across tissues.","evidence":"ChIP for Twist1 and FOXM1 at SEMA3C promoter, SMO antagonist epistasis, lncRNA knockdown/rescue, in vivo models (pancreatic cancer, wound healing, lymphatics)","pmids":["33420365","34742786","33568674"],"confidence":"Medium","gaps":["How LETR1 mechanistically controls SEMA3C chromatin state undefined","Whether FOXM1-SEMA3C-Hedgehog axis operates outside wound context unknown","Twist1 binding specificity at SEMA3C promoter relative to other Twist1 targets not characterized"]},{"year":2023,"claim":"Resolving that SEMA3C drives Wnt-independent β-catenin nuclear accumulation via Rac1 in glioma stem cells, activating TCF/LEF targets—explaining how SEMA3C sustains stemness without canonical Wnt ligands and establishing combinatorial therapeutic vulnerability with TCF1.","evidence":"β-catenin localization assays, Rac1 dependency experiments, Wnt ligand secretion suppression, combinatorial depletion in mouse GBM model","pmids":["37080989"],"confidence":"High","gaps":["How Rac1 mechanistically promotes β-catenin nuclear import unresolved","Whether this Wnt-independent mechanism operates in non-glioma stem cells unknown","Identity of critical TCF/LEF target genes downstream not defined"]},{"year":2024,"claim":"Identifying ITGB1 as an additional SEMA3C co-receptor (alongside NRP1) that mediates AKT/Gli1/c-Myc signaling for HCC self-renewal and NF-κB-dependent IL-6/cholesterol synthesis in hepatic stellate cells, and defining FOXA1 as a direct transcriptional repressor of SEMA3C through intronic elements whose cancer-associated mutations de-repress expression.","evidence":"Co-IP of SEMA3C–NRP1–ITGB1, receptor knockdown, in vivo tumor models (HCC); ChIP-seq and luciferase reporters with FOXA1 forkhead domain mutants (prostate cancer)","pmids":["38956074","38528115"],"confidence":"Medium","gaps":["Whether ITGB1 directly contacts SEMA3C or is bridged by NRP1 unknown","FOXA1 intronic regulatory mechanism not structurally characterized","Single-lab studies for both findings"]},{"year":2025,"claim":"Revealing a LINE-1 retrotransposon-derived cis-enhancer within the Sema3c locus that forms BRD4/H3K27ac phase-separated condensates to drive SEMA3C transcription in breast cancer stem cells, and defining KLF6/FOSL2/p300-mediated H3K23 succinylation as an epigenetic activation mechanism in chemoresistant colon cancer—providing two novel chromatin-level regulatory paradigms.","evidence":"CRISPRa, dual-luciferase reporter, BRD4 PROTAC degradation, receptor knockdown (breast cancer); CUT&Tag, ATAC-seq, ChIP for KLF6/FOSL2, knockdown (colon cancer)","pmids":["41984404","40082673"],"confidence":"Medium","gaps":["Whether LINE-1 enhancer mechanism is generalizable across SEMA3C-expressing tissues unknown","H3K23 succinylation role awaits independent confirmation","Single-lab studies"]},{"year":2025,"claim":"Extending SEMA3C receptor biology to NRP2/MAPK in colorectal cancer liver metastasis initiation (CAF-secreted) and to PlexinD1/NRP2 in astrocyte-mediated dendrite growth inhibition relevant to Rett syndrome pathology.","evidence":"Co-culture and in vivo metastasis models with SEMA3C–NRP2 binding (CRC); astrocyte-neuron co-culture, conditional genetic reduction in RTT mouse model with behavioral rescue (preprint)","pmids":["40402249","41279175"],"confidence":"Medium","gaps":["RTT finding is a preprint, not yet peer-reviewed","Whether SEMA3C reduction is a viable therapeutic strategy for Rett syndrome untested clinically","Downstream MAPK effectors in liver metastasis initiation not identified"]},{"year":null,"claim":"Major open questions include: the structural basis for SEMA3C's engagement of distinct receptor complexes in different tissues; the mechanism by which Rac1 promotes β-catenin nuclear accumulation downstream of plexin/neuropilin activation; whether the multiple transcriptional regulators of SEMA3C operate through shared or independent chromatin domains; and the in vivo relevance of furin processing across SEMA3C's biological functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SEMA3C–receptor complex exists","Rac1-to-β-catenin mechanism molecularly undefined","Integrated chromatin map of SEMA3C regulatory elements across cell types lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,3,7,10,11,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3,10,14,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,7,10,14,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,5,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,18,21]}],"complexes":[],"partners":["NRP1","NRP2","PLXNA2","PLXNB1","PLXND1","ITGB1","EFNB1","BRD4"],"other_free_text":[]},"mechanistic_narrative":"SEMA3C is a secreted class 3 semaphorin that acts as an autocrine and paracrine signaling ligand through context-dependent engagement of neuropilin (NRP1, NRP2) and plexin (PlexinA2, PlexinB1, PlexinD1) co-receptor complexes, as well as ITGB1, to activate Rac1/NF-κB, Wnt/β-catenin, MAPK, AKT, and Hedgehog signaling cascades [PMID:25464848, PMID:37080989, PMID:29348142, PMID:38956074, PMID:34742786]. In development, neural crest–derived SEMA3C activates NRP1-dependent endothelial-to-mesenchymal transition required for cardiac outflow tract septation, regulates cortical neuron polarity and radial migration downstream of Bcl11a-mediated transcriptional repression, and modulates motor axon guidance by differentially controlling NRP1/NRP2 surface levels at growth cones [PMID:26053665, PMID:26182416, PMID:22899844]. SEMA3C transcription is directly controlled by multiple transcription factors—repressed by Bcl11a and FOXA1, and activated by Foxc1/c2, FOXM1, Twist1, KLF6/FOSL2/p300, and a LINE-1 enhancer/BRD4 condensate axis—enabling tissue- and disease-specific expression [PMID:26182416, PMID:38528115, PMID:28754980, PMID:34742786, PMID:33420365, PMID:40082673, PMID:41984404]. In cancer, SEMA3C sustains glioma and breast cancer stem cell survival via Rac1-dependent β-catenin nuclear accumulation and Wnt target gene activation, and drives ligand-independent transactivation of EGFR, ErbB2, and MET through PlexinB1 [PMID:37080989, PMID:25464848, PMID:29348142, PMID:41984404]."},"prefetch_data":{"uniprot":{"accession":"Q99985","full_name":"Semaphorin-3C","aliases":["Semaphorin-E","Sema E"],"length_aa":751,"mass_kda":85.2,"function":"Binds to plexin family members and plays an important role in the regulation of developmental processes. Required for normal cardiovascular development during embryogenesis. Functions as attractant for growing axons, and thereby plays an important role in axon growth and axon guidance (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q99985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA3C","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA3C","total_profiled":1310},"omim":[{"mim_id":"621297","title":"LYMPHATIC ENDOTHELIAL TRANSCRIPTIONAL REGULATOR lncRNA 1; LETR1","url":"https://www.omim.org/entry/621297"},{"mim_id":"609297","title":"SEMAPHORIN 5A; SEMA5A","url":"https://www.omim.org/entry/609297"},{"mim_id":"606557","title":"BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A","url":"https://www.omim.org/entry/606557"},{"mim_id":"604282","title":"PLEXIN D1; PLXND1","url":"https://www.omim.org/entry/604282"},{"mim_id":"602645","title":"SEMAPHORIN 3C; SEMA3C","url":"https://www.omim.org/entry/602645"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEMA3C"},"hgnc":{"alias_symbol":["SemE"],"prev_symbol":["SEMAE"]},"alphafold":{"accession":"Q99985","domains":[{"cath_id":"-","chopping":"25-53_442-510","consensus_level":"medium","plddt":93.7821,"start":25,"end":510},{"cath_id":"-","chopping":"55-170","consensus_level":"medium","plddt":95.5703,"start":55,"end":170},{"cath_id":"2.130.10.10","chopping":"177-288_353-409","consensus_level":"medium","plddt":92.8979,"start":177,"end":409},{"cath_id":"3.30.1680.10","chopping":"513-571","consensus_level":"high","plddt":84.2456,"start":513,"end":571},{"cath_id":"2.60.40.10","chopping":"575-674","consensus_level":"high","plddt":87.2507,"start":575,"end":674}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99985","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99985-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA3C","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA3C"},"sequence":{"accession":"Q99985","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99985"}},"corpus_meta":[{"pmid":"25464848","id":"PMC_25464848","title":"Sema3C 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Introduction of activated Rac1 rescued the SEMA3C knockdown phenotype in vivo, placing SEMA3C upstream of Rac1 in this pathway.\",\n      \"method\": \"Knockdown in orthotopic glioblastoma models, receptor co-expression analysis, Rac1 rescue experiment in vivo\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (Rac1 rescue), in vivo model with defined phenotypic readout, replicated across GSC lines\",\n      \"pmids\": [\"25464848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bcl11a is a direct negative transcriptional regulator of Sema3C in cortical neurons; loss of Bcl11a increases Sema3C expression, and Sema3C elevation causes failure of multipolar-to-bipolar polarity switch and impaired radial migration of upper-layer cortical neurons. In vivo gain-of-function and rescue experiments confirmed Sema3C as the major downstream effector of Bcl11a.\",\n      \"method\": \"In vivo gain-of-function and rescue experiments, ChIP (direct binding of Bcl11a to Sema3C promoter), conditional knockout mice\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional regulation shown by ChIP, epistasis confirmed by in vivo rescue, replicated with multiple approaches\",\n      \"pmids\": [\"26182416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Neural crest-derived SEMA3C activates NRP1 on outflow tract endothelium to promote endothelial-to-mesenchymal transition (EndMT), supplying cells to endocardial cushions and repositioning cardiac neural crest cells, both required for cardiac outflow tract septal bridge formation.\",\n      \"method\": \"Ligand-specific and tissue-specific mouse mutants, explant assays, gene-expression studies, lineage tracing\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complementary mutant series, lineage tracing, explant functional assays, mechanistic pathway defined\",\n      \"pmids\": [\"26053665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEMA3C drives activation of multiple receptor tyrosine kinases (EGFR, ErbB2, MET) in a cognate ligand-independent manner via PlexinB1. Plexin B1 sema domain:Fc fusion proteins suppress RTK signaling and cell growth, and inhibit CRPC progression in vivo.\",\n      \"method\": \"Co-IP/pulldown, Plexin B1 Fc fusion inhibitor in vitro and in vivo xenograft model, RTK phosphorylation assays\",\n      \"journal\": \"EMBO Molecular Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor identification by Co-IP, functional inhibition with Fc fusion in vivo, multiple RTK readouts\",\n      \"pmids\": [\"29348142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ephrin-B1 upregulation in post-crossing corpus callosum axons inhibits Sema3C/Neuropilin-1 signaling to silence the attractant response to Sema3C. This silencing is independent of Eph receptors and requires N-glycosylation at N-139 in the Ephrin-B1 extracellular domain, which mediates physical interaction with Nrp1.\",\n      \"method\": \"In vivo axon guidance assays, epistasis experiments, co-immunoprecipitation of Ephrin-B1 with Nrp1, N-glycosylation site mutagenesis\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of interaction site, Co-IP, in vivo functional validation\",\n      \"pmids\": [\"29779877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Foxc1/c2 transcription factors directly activate Sema3C transcription in the outflow tract, while Tbx1-driven Fgf8 inhibits Sema3C expression in cardiac neural crest cells via ERK1/2 signaling. Blocking FGF8 causes ectopic SEMA3C expression and cNCC migration defects.\",\n      \"method\": \"Promoter reporter assays, ChIP, FGF8 blocking experiments in chick, ERK1/2 signaling readout\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional activation shown, signaling pathway defined, but single-lab study\",\n      \"pmids\": [\"28754980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAOA promotes SEMA3C expression via Twist1-dependent transcriptional activation; SEMA3C in turn stimulates cMET to facilitate perineural invasion through autocrine/paracrine co-activation with PlexinA2 and NRP1 co-receptors.\",\n      \"method\": \"Knockdown/overexpression, co-culture PNI assay, in vivo orthotopic xenograft, signaling pathway analysis (cMET phosphorylation), ChIP for Twist1 on SEMA3C promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional mechanism, receptor complex defined, in vivo validation, multiple readouts\",\n      \"pmids\": [\"33420365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process in glioma stem cells, leading to transcriptional activation of Wnt target genes independent of Wnt ligand binding. Combined depletion of Sema3C and TCF1 extended survival in a mouse glioblastoma model more than single inhibition.\",\n      \"method\": \"β-catenin localization assays, Rac1 dependency experiments, Wnt ligand secretion suppression, mouse glioblastoma model with combinatorial depletion\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement by epistasis, β-catenin localization assay, in vivo survival data, multiple orthogonal methods\",\n      \"pmids\": [\"37080989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Motoneuronal Sema3C expression regulates surface levels of Nrp1 and Nrp2 at the growth cone in opposing ways, thereby modulating responsiveness to exogenous Sema3A, Sema3F, and Sema3C repellents and determining stereotyped motor nerve trajectory positioning in chick forelimb.\",\n      \"method\": \"Targeted gain- and loss-of-function in chick neural tube, growth cone surface receptor quantification, in vivo motor nerve trajectory analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional manipulation, growth cone receptor quantification, but single-lab study in chick model\",\n      \"pmids\": [\"22899844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The furin cleavage site 742RNRR745 in the basic domain of Sema3C is essential for its anti-angiogenic activity: point mutation R745A abrogates inhibition of microcapillary formation by human umbilical vein endothelial cells in vitro.\",\n      \"method\": \"Site-directed mutagenesis of furin cleavage site, in vitro angiogenesis assay (HUVEC tube formation)\",\n      \"journal\": \"Brazilian Journal of Medical and Biological Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional in vitro readout, but single lab, single paper\",\n      \"pmids\": [\"30304095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEMA3C binds NRP1 and ITGB1 receptors to activate AKT/Gli1/c-Myc signaling for HCC self-renewal. In hepatic stellate cells, SEMA3C interaction with NRP1 and ITGB1 activates NF-κB signaling, stimulating IL-6 release and HMGCR-mediated cholesterol synthesis. CAF-secreted TGF-β1 activates AP1 signaling to upregulate SEMA3C in HCC cells, forming a positive feedback loop.\",\n      \"method\": \"Co-IP (SEMA3C with NRP1 and ITGB1), signaling pathway analysis, in vivo tumor models, receptor knockdown\",\n      \"journal\": \"Signal Transduction and Targeted Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for receptor identification, multiple signaling readouts, in vivo validation, but single-lab study\",\n      \"pmids\": [\"38956074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEMA3C signals through NRP2 (not NRP1) in corneal epithelial cells to promote wound healing and sensory nerve regeneration. siRNA knockdown of SEMA3C or NRP2-neutralizing antibodies decreased wound healing and nerve regeneration; exogenous SEMA3C had opposing effects in diabetic corneas. NRP1 neutralization had a detrimental role in nerve regeneration.\",\n      \"method\": \"siRNA knockdown in vivo, NRP2 neutralizing antibodies, exogenous protein injection, wound healing assay, nerve fiber counting\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor specificity defined in vivo with antibody and siRNA approaches, functional readouts for both healing and nerve regeneration\",\n      \"pmids\": [\"30679185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 binds the promoter region of SEMA3C to directly elevate its expression; SEMA3C then upregulates NRP2 and activates Hedgehog signaling (SMO-dependent) to promote M2 macrophage polarization and fibroblast proliferation/migration in diabetic wound healing.\",\n      \"method\": \"ChIP (FOXM1 binding to SEMA3C promoter), knockdown/overexpression, SMO antagonist epistasis, M2 polarization assay, wound healing model\",\n      \"journal\": \"Diabetes Research and Clinical Practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional regulation by ChIP, pathway placement by SMO epistasis, but single-lab study\",\n      \"pmids\": [\"34742786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA LETR1 regulates SEMA3C expression in lymphatic endothelial cells as a nuclear trans-acting lncRNA via epigenetic factors; knockdown of LETR1 reduces SEMA3C levels and impairs LEC migratory ability, which is rescued by SEMA3C restoration.\",\n      \"method\": \"Antisense oligonucleotide knockdown, transcriptomic profiling, RNA-DNA and RNA-protein interaction studies, phenotype rescue assay\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, phenotype rescue, but no direct SEMA3C mechanism downstream defined\",\n      \"pmids\": [\"33568674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-secreted SEMA3C binds NRP2 receptor on colorectal cancer liver metastasis-initiating cells, activating the MAPK pathway to promote liver metastasis.\",\n      \"method\": \"Co-culture experiments, receptor-ligand binding (SEMA3C-NRP2), in vivo and in vitro functional assays, MAPK pathway activation readout\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand pair validated in vivo and in vitro, MAPK pathway activation defined, single-lab study\",\n      \"pmids\": [\"40402249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEMA3C overexpression in LNCaP prostate cancer cells promotes androgen synthesis in prostatic stromal cells through paracrine induction of Sonic Hedgehog (Shh) signaling (not direct SEMA3C action), as blocking Shh with a smoothened antagonist negated the steroidogenic effect.\",\n      \"method\": \"Conditioned media treatment, liquid chromatography-mass spectrometry for androgen quantification, SMO antagonist epistasis, qPCR for steroidogenic enzymes\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with Shh pathway, LC-MS for androgen quantification, but indirect effect (SEMA3C acts via intermediate)\",\n      \"pmids\": [\"33503318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXA1 directly and negatively regulates SEMA3C transcription via intronic cis elements; FOXA1 forkhead domain mutations attenuate this inhibitory function (shown in reporter assays), leading to elevated SEMA3C levels in prostate cancer.\",\n      \"method\": \"Luciferase reporter assays, ChIP-seq analysis, analysis of prostate cancer specimens with FOXA1 mutations\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct regulatory element identified, mutagenesis in reporter assay, in vitro validation, single lab\",\n      \"pmids\": [\"38528115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEMA3C inhibits dendrite outgrowth in cortical neurons via PLXND1 and NRP2 receptors. Genetic reduction of astrocyte-secreted SEMA3C in female Rett Syndrome model mice enhances dendritic arborization, normalizes synaptic activity, visual acuity, and motor behavior.\",\n      \"method\": \"Astrocyte-neuron co-culture, receptor knockdown (PLXND1, NRP2), conditional genetic reduction in RTT mouse model, electrophysiology, behavioral assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor specificity defined by knockdown, in vivo genetic model with behavioral and electrophysiological readouts; preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279175\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A LINE-1 retrotransposon within Sema3c (Sema3c_L1Md_T) acts as a cis-regulatory enhancer, forming phase-separated nuclear condensates with BRD4 at H3K27ac-marked regions to drive SEMA3C transcription. SEMA3C sustains breast cancer stem cell survival via NRP1, PlexinA2, and PlexinD1 receptors. BRD4 PROTAC degradation reduces SEMA3C levels and decreases BCSC viability.\",\n      \"method\": \"Dual-luciferase reporter assay, CRISPRa (dCas9-based), RNA-seq, ChIP, BRD4 PROTAC treatment, receptor knockdown (NRP1, PlexinA2, PlexinD1), in vivo tumor models\",\n      \"journal\": \"Science China Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including CRISPRa, reporter assay, in vivo validation; single lab\",\n      \"pmids\": [\"41984404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MALAT1 positively regulates SEMA3C expression in intracranial aneurysm vascular smooth muscle cells; SEMA3C mediates downstream Smad pathway activation, promoting VSMC phenotype switching from contractile to synthetic type and inflammatory cytokine release. SEMA3C overexpression reverses the effects of MALAT1 silencing.\",\n      \"method\": \"Lentiviral overexpression/knockdown, epistasis (SEMA3C OE reverting MALAT1 KD phenotype), Smad pathway activation assay, in vivo IA rat model\",\n      \"journal\": \"Frontiers in Cellular Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, in vivo model, pathway (Smad) activation defined; single-lab study\",\n      \"pmids\": [\"41890214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEMA3C stimulation of ER+ breast cancer cells activates MAPK and AKT signaling in a dose-dependent manner. SEMA3C silencing inhibits ER expression, MAPK and AKT signaling, and induces apoptosis. The SEMA3C pathway inhibitor B1SP Fc fusion protein attenuates SEMA3C-induced signaling via PlexinB1.\",\n      \"method\": \"Recombinant SEMA3C stimulation assay, siRNA knockdown, flow cytometry (apoptosis), Western blot for pathway activation, B1SP Fc fusion protein inhibition\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — receptor identified (PlexinB1 via B1SP inhibitor), signaling readouts defined, but no direct receptor binding assay in this paper\",\n      \"pmids\": [\"37443749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF6 recruits the PCAF-p300/CBP complex to the SEMA3C locus, increasing H3K23 succinylation and cooperating with FOSL2 to transcriptionally upregulate SEMA3C; SEMA3C in turn modulates the Wnt/β-catenin pathway (upregulating MYC and FOSL2) in 5-FU-resistant colon cancer cells.\",\n      \"method\": \"CUT&Tag, ATAC-seq, RNA-seq, ChIP assays for KLF6 and FOSL2 binding, knockdown of KLF6 and FOSL2\",\n      \"journal\": \"Experimental & Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple chromatin assays, direct TF binding shown, downstream pathway defined; single-lab study\",\n      \"pmids\": [\"40082673\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA3C is a secreted class 3 semaphorin that functions as an autocrine/paracrine ligand binding to receptor complexes (NRP1/NRP2, PlexinA2, PlexinB1, PlexinD1, ITGB1) to activate multiple intracellular pathways including Rac1/NF-κB, β-catenin/Wnt, MAPK, AKT, and Smad signaling; its transcription is directly regulated by Bcl11a, FOXA1, Foxc1/c2, Fgf8/ERK, FOXM1, KLF6/FOSL2/p300, and a LINE-1 enhancer/BRD4 axis, and it plays defined roles in cortical neuron migration, cardiac outflow tract septation (via EndMT downstream of NRP1), axon guidance, glioma stem cell survival, and cancer RTK transactivation via PlexinB1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEMA3C is a secreted class 3 semaphorin that acts as an autocrine and paracrine signaling ligand through context-dependent engagement of neuropilin (NRP1, NRP2) and plexin (PlexinA2, PlexinB1, PlexinD1) co-receptor complexes, as well as ITGB1, to activate Rac1/NF-κB, Wnt/β-catenin, MAPK, AKT, and Hedgehog signaling cascades [PMID:25464848, PMID:37080989, PMID:29348142, PMID:38956074, PMID:34742786]. In development, neural crest–derived SEMA3C activates NRP1-dependent endothelial-to-mesenchymal transition required for cardiac outflow tract septation, regulates cortical neuron polarity and radial migration downstream of Bcl11a-mediated transcriptional repression, and modulates motor axon guidance by differentially controlling NRP1/NRP2 surface levels at growth cones [PMID:26053665, PMID:26182416, PMID:22899844]. SEMA3C transcription is directly controlled by multiple transcription factors—repressed by Bcl11a and FOXA1, and activated by Foxc1/c2, FOXM1, Twist1, KLF6/FOSL2/p300, and a LINE-1 enhancer/BRD4 condensate axis—enabling tissue- and disease-specific expression [PMID:26182416, PMID:38528115, PMID:28754980, PMID:34742786, PMID:33420365, PMID:40082673, PMID:41984404]. In cancer, SEMA3C sustains glioma and breast cancer stem cell survival via Rac1-dependent β-catenin nuclear accumulation and Wnt target gene activation, and drives ligand-independent transactivation of EGFR, ErbB2, and MET through PlexinB1 [PMID:37080989, PMID:25464848, PMID:29348142, PMID:41984404].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that SEMA3C acts cell-autonomously in motor neurons to tune growth cone responsiveness by reciprocally modulating NRP1 and NRP2 surface levels, thereby determining motor nerve trajectory—revealing SEMA3C as an intrinsic regulator of semaphorin sensitivity, not merely an extrinsic cue.\",\n      \"evidence\": \"Targeted gain/loss-of-function in chick neural tube with growth cone surface receptor quantification and in vivo nerve trajectory analysis\",\n      \"pmids\": [\"22899844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study in chick; not replicated in mammalian model\", \"Downstream signaling mediating NRP surface level changes undefined\", \"Whether this mechanism operates in sensory or other axon types unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that SEMA3C functions as an autocrine survival factor for glioma stem cells through PlexinA2/D1 receptors and Rac1/NF-κB signaling—the first identification of a semaphorin autocrine loop in brain tumor maintenance, with Rac1 placed epistatically downstream.\",\n      \"evidence\": \"Knockdown in orthotopic glioblastoma models, receptor co-expression analysis, Rac1 constitutive-active rescue in vivo\",\n      \"pmids\": [\"25464848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between SEMA3C and PlexinA2/D1 not shown by binding assay\", \"Mechanism linking receptor activation to Rac1 unclear\", \"Whether NRP co-receptors participate in GSC context not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining SEMA3C as a critical effector in two distinct developmental programs—cortical neuron migration (repressed by Bcl11a) and cardiac outflow tract septation (activating EndMT via NRP1)—establishing its dual developmental significance.\",\n      \"evidence\": \"ChIP for Bcl11a at Sema3c promoter, conditional knockout mice with in vivo rescue (cortex); ligand/tissue-specific mutants, lineage tracing, explant assays (heart)\",\n      \"pmids\": [\"26182416\", \"26053665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intracellular signaling mediating EndMT in outflow tract not fully resolved\", \"Whether Bcl11a-SEMA3C axis operates outside upper-layer neurons untested\", \"Identity of the SEMA3C receptor complex in cortical migration not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealing that SEMA3C transcription in the outflow tract is positively controlled by Foxc1/c2 and negatively regulated by Tbx1-driven Fgf8/ERK signaling in cardiac neural crest cells—providing the upstream transcriptional logic for spatially restricted SEMA3C expression during heart development.\",\n      \"evidence\": \"Promoter reporter assays, ChIP for Foxc1/c2, FGF8 blocking experiments in chick with ERK readout\",\n      \"pmids\": [\"28754980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether Foxc1/c2 and Fgf8/ERK converge on the same promoter elements unknown\", \"Mammalian validation of FGF8-ERK repression incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying PlexinB1 as the receptor through which SEMA3C transactivates RTKs (EGFR, ErbB2, MET) in a cognate ligand-independent manner, and demonstrating that Ephrin-B1 silences SEMA3C/NRP1 attraction in commissural axons via direct glycosylation-dependent NRP1 binding—together resolving two distinct receptor-level regulatory mechanisms.\",\n      \"evidence\": \"Co-IP/pulldown and PlexinB1-Fc fusion inhibition in xenograft (prostate cancer); Co-IP of Ephrin-B1–NRP1, N-glycosylation mutagenesis, in vivo axon guidance assays (corpus callosum)\",\n      \"pmids\": [\"29348142\", \"29779877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PlexinB1-mediated RTK transactivation unknown\", \"Whether Ephrin-B1 silencing mechanism applies to non-callosal axon systems untested\", \"Furin cleavage requirement for RTK transactivation not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that furin processing at the 742RNRR745 basic domain cleavage site is required for SEMA3C anti-angiogenic activity, indicating post-translational processing regulates functional output.\",\n      \"evidence\": \"Site-directed mutagenesis of furin site (R745A), HUVEC tube formation assay\",\n      \"pmids\": [\"30304095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, in vitro only\", \"Whether furin cleavage regulates SEMA3C activities beyond angiogenesis unknown\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating NRP2-selective signaling for SEMA3C in corneal epithelium, where it promotes wound healing and sensory nerve regeneration—showing that receptor choice (NRP2 vs. NRP1) dictates tissue-specific outcomes.\",\n      \"evidence\": \"siRNA knockdown, NRP2 neutralizing antibodies, exogenous SEMA3C in diabetic cornea model in vivo\",\n      \"pmids\": [\"30679185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream intracellular signaling in corneal cells not defined\", \"Single-lab study\", \"Whether PlexinD1 participates as a co-receptor in cornea untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanding the transcriptional regulation network: MAOA/Twist1 directly activates SEMA3C to drive cMET-mediated perineural invasion; FOXM1 activates SEMA3C to induce NRP2/Hedgehog-dependent M2 macrophage polarization; and the lncRNA LETR1 epigenetically maintains SEMA3C in lymphatic endothelial cells—demonstrating pervasive transcriptional control across tissues.\",\n      \"evidence\": \"ChIP for Twist1 and FOXM1 at SEMA3C promoter, SMO antagonist epistasis, lncRNA knockdown/rescue, in vivo models (pancreatic cancer, wound healing, lymphatics)\",\n      \"pmids\": [\"33420365\", \"34742786\", \"33568674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LETR1 mechanistically controls SEMA3C chromatin state undefined\", \"Whether FOXM1-SEMA3C-Hedgehog axis operates outside wound context unknown\", \"Twist1 binding specificity at SEMA3C promoter relative to other Twist1 targets not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolving that SEMA3C drives Wnt-independent β-catenin nuclear accumulation via Rac1 in glioma stem cells, activating TCF/LEF targets—explaining how SEMA3C sustains stemness without canonical Wnt ligands and establishing combinatorial therapeutic vulnerability with TCF1.\",\n      \"evidence\": \"β-catenin localization assays, Rac1 dependency experiments, Wnt ligand secretion suppression, combinatorial depletion in mouse GBM model\",\n      \"pmids\": [\"37080989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rac1 mechanistically promotes β-catenin nuclear import unresolved\", \"Whether this Wnt-independent mechanism operates in non-glioma stem cells unknown\", \"Identity of critical TCF/LEF target genes downstream not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying ITGB1 as an additional SEMA3C co-receptor (alongside NRP1) that mediates AKT/Gli1/c-Myc signaling for HCC self-renewal and NF-κB-dependent IL-6/cholesterol synthesis in hepatic stellate cells, and defining FOXA1 as a direct transcriptional repressor of SEMA3C through intronic elements whose cancer-associated mutations de-repress expression.\",\n      \"evidence\": \"Co-IP of SEMA3C–NRP1–ITGB1, receptor knockdown, in vivo tumor models (HCC); ChIP-seq and luciferase reporters with FOXA1 forkhead domain mutants (prostate cancer)\",\n      \"pmids\": [\"38956074\", \"38528115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ITGB1 directly contacts SEMA3C or is bridged by NRP1 unknown\", \"FOXA1 intronic regulatory mechanism not structurally characterized\", \"Single-lab studies for both findings\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing a LINE-1 retrotransposon-derived cis-enhancer within the Sema3c locus that forms BRD4/H3K27ac phase-separated condensates to drive SEMA3C transcription in breast cancer stem cells, and defining KLF6/FOSL2/p300-mediated H3K23 succinylation as an epigenetic activation mechanism in chemoresistant colon cancer—providing two novel chromatin-level regulatory paradigms.\",\n      \"evidence\": \"CRISPRa, dual-luciferase reporter, BRD4 PROTAC degradation, receptor knockdown (breast cancer); CUT&Tag, ATAC-seq, ChIP for KLF6/FOSL2, knockdown (colon cancer)\",\n      \"pmids\": [\"41984404\", \"40082673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LINE-1 enhancer mechanism is generalizable across SEMA3C-expressing tissues unknown\", \"H3K23 succinylation role awaits independent confirmation\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending SEMA3C receptor biology to NRP2/MAPK in colorectal cancer liver metastasis initiation (CAF-secreted) and to PlexinD1/NRP2 in astrocyte-mediated dendrite growth inhibition relevant to Rett syndrome pathology.\",\n      \"evidence\": \"Co-culture and in vivo metastasis models with SEMA3C–NRP2 binding (CRC); astrocyte-neuron co-culture, conditional genetic reduction in RTT mouse model with behavioral rescue (preprint)\",\n      \"pmids\": [\"40402249\", \"41279175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RTT finding is a preprint, not yet peer-reviewed\", \"Whether SEMA3C reduction is a viable therapeutic strategy for Rett syndrome untested clinically\", \"Downstream MAPK effectors in liver metastasis initiation not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the structural basis for SEMA3C's engagement of distinct receptor complexes in different tissues; the mechanism by which Rac1 promotes β-catenin nuclear accumulation downstream of plexin/neuropilin activation; whether the multiple transcriptional regulators of SEMA3C operate through shared or independent chromatin domains; and the in vivo relevance of furin processing across SEMA3C's biological functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SEMA3C–receptor complex exists\", \"Rac1-to-β-catenin mechanism molecularly undefined\", \"Integrated chromatin map of SEMA3C regulatory elements across cell types lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 3, 7, 10, 11, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3, 10, 14, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 7, 10, 14, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 5, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 18, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NRP1\", \"NRP2\", \"PLXNA2\", \"PLXNB1\", \"PLXND1\", \"ITGB1\", \"EFNB1\", \"BRD4\"],\n    \"other_free_text\": []\n  }\n}\n```"}