{"gene":"SEMA6A","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"SEMA6A-1 (human and murine) directly binds EVL (Ena/VASP-like protein) via a novel carboxyl-terminal zyxin-like domain, physically linking the semaphorin and Ena/VASP protein families and suggesting a role for transmembrane semaphorins in retrograde signaling.","method":"Yeast two-hybrid, co-localization, binding assays (pulldown/co-IP)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-localization and binding data; novel finding but limited orthogonal validation","pmids":["10993894"],"is_preprint":false},{"year":2005,"finding":"Sema6A controls cerebellar granule cell migration; in Sema6A-deficient mice, postmitotic granule cells fail to initiate radial migration and remain ectopic in the molecular layer, with chimera analysis indicating this function is primarily non-cell-autonomous.","method":"Knockout mouse analysis, chimera studies, cerebellar explant migration assay, neurite outgrowth assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO with defined cellular phenotype replicated with chimera and explant assays, published in high-impact journal","pmids":["16205717"],"is_preprint":false},{"year":2008,"finding":"Plexin-A2 is the functional receptor for Sema6A in migrating cerebellar granule cells; Sema6A binds Plexin-A2, and loss of either Sema6A or Plexin-A2 disrupts nucleus-centrosome coupling and coordinated motility during migration, demonstrating semaphorin-plexin signaling controls cell migration by modulating centrosome positioning.","method":"Plexin-A2 knockout mouse (homologous recombination), ENU mutagenesis point mutant (abolishes Sema6A binding), chimera analysis, time-lapse video microscopy, binding assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic and biochemical evidence (binding abolished by single AA substitution), live imaging, chimera; replicates and extends prior Sema6A KO findings","pmids":["18327254"],"is_preprint":false},{"year":2010,"finding":"Sema6A engages in a cis interaction with its receptor Plexin-A4 in sensory neurons, which inhibits binding of exogenous Sema6A ligand in trans and suppresses responsiveness to Sema6A, revealing that co-expression of a transmembrane semaphorin with its receptor acts as a guidance response modulator.","method":"Heterologous expression (cis vs trans binding assay), sensory/sympathetic neuron collapse assay, Sema6A knockout neurons, Plexin-A4 knockdown","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (neuron collapse assay, binding inhibition, KO neurons, knockdown), mechanistically resolves cis vs trans signaling","pmids":["20606624"],"is_preprint":false},{"year":2012,"finding":"Sema6A is highly expressed by myelinating oligodendrocytes; Sema6A-deficient mice show delayed oligodendrocyte differentiation, delayed node of Ranvier development, and impaired myelination in co-culture, establishing a role for Sema6A in oligodendrocyte differentiation.","method":"Sema6A knockout mouse, optic nerve and anterior commissure analysis, in vitro oligodendrocyte differentiation assay, dorsal root ganglion neuron/oligodendrocyte co-culture myelination assay","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 — KO with defined cellular phenotypes corroborated by in vitro differentiation and myelination co-culture assays","pmids":["22777942"],"is_preprint":false},{"year":2012,"finding":"PlexinA2 mediates the inhibitory effect of oligodendrocyte-derived Sema6A on adult sensory axon growth; PlexinA2 null mice show greater corticospinal axon sprouting and functional recovery after pyramidotomy, establishing a PlexinA2-Sema6A axis that limits adult CNS axon growth after injury.","method":"PlexinA2 knockout mouse, adult dorsal root ganglion neurite inhibition assay, unilateral pyramidotomy model, immunohistochemistry (synaptophysin), behavioral assays","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — KO with defined in vitro and in vivo phenotypes, functional behavioral readout; builds on established Sema6A/PlexinA2 ligand-receptor relationship","pmids":["22564823"],"is_preprint":false},{"year":2013,"finding":"Sema6A expressed in oligodendrocyte precursor cells (OPCs) promotes their autonomous migration through cis and trans ligand-receptor interactions with Plexin-A4; Sema6A knockdown in OPC-like FBD-102b cells represses migration, and co-culture segregation experiments confirm Sema6A/Plexin-A4 repulsive interaction.","method":"Sema6A siRNA knockdown in FBD-102b cells, in vitro migration assay, co-culture segregation assay, gradient exposure assay, Plexin-A4 knockdown","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple in vitro assays but cell line model; consistent with prior in vivo findings","pmids":["23376059"],"is_preprint":false},{"year":2014,"finding":"Sema6a and Plexin-A2 cooperate in a cell-autonomous, tissue-autonomous manner to keep zebrafish eye vesicle progenitor cells integrated within the epithelium; knockdown of either disrupts eye vesicle integrity with progenitors failing to enter or delaminating from the vesicle, as shown by time-lapse microscopy.","method":"Morpholino knockdown in zebrafish, time-lapse microscopy of eye progenitors, explant rescue experiments, double knockdown epistasis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with epistasis (double KD rescue), but morpholino-based; zebrafish ortholog consistent with mammalian Sema6A/PlexinA2","pmids":["24917502"],"is_preprint":false},{"year":2014,"finding":"Time-lapse analysis of Sema6A and PlexinA2 knockout cerebella reveals that lack of Sema6A preferentially perturbs later-born granule cells and that defects in tangential migration (bipolar cell stage) precede the failure to initiate radial migration, confirming that Sema6A/PlexinA2 regulate mode-switching in granule cell migration.","method":"Cerebellar slice electroporation, time-lapse video microscopy in Sema6A and PlexinA2 KO mice","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell imaging in KO mice, mechanistically pinpoints the tangential phase as the primary defect","pmids":["25284064"],"is_preprint":false},{"year":2015,"finding":"Sema6A silencing in BRAFV600E melanoma cells causes cytoskeletal remodeling, loss of stress fibers, cell death, and loss of anchorage-independent growth; forced Sema6A overexpression promotes invasiveness, establishing Sema6A as a regulator of actin cytoskeleton and cell viability in melanoma complexed with plexins.","method":"Sema6A siRNA knockdown, overexpression in NRASQ61R clones, cytoskeletal imaging, anchorage-independent growth assay, chemotaxis/invasion assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple functional readouts; mechanism (plexin complex, actin) inferred but not fully reconstituted","pmids":["25576923"],"is_preprint":false},{"year":2016,"finding":"Sema6A/PlexinA2 signaling participates in interkinetic nuclear migration of retinal progenitor cells (RPCs) around birth; loss of either Sema6A or PlexinA2 blocks RPC migration at the apical side of the neuroblastic layer.","method":"Sema6A and PlexinA2 knockout mouse retina analysis, time-lapse videomicroscopy","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — KO with live imaging, but single lab","pmids":["27301906"],"is_preprint":false},{"year":2017,"finding":"Shear stress-induced miR-27b promotes pericyte recruitment to endothelial cells partly by repressing SEMA6A and SEMA6D; silencing of SEMA6A rescues reduced pericyte adhesion caused by miR-27 inhibition, identifying SEMA6A as a repulsive cue that normally inhibits pericyte-endothelial interaction.","method":"miR-27b overexpression/inhibition in endothelial cells, SEMA6A/SEMA6D siRNA knockdown, pericyte adhesion assay, in vivo locked nucleic acid antisense oligonucleotide treatment, ex vivo femoral artery explant","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 — rescue experiment (SEMA6A KD rescues miR-27 inhibition phenotype), in vivo validation, multiple methods","pmids":["28453731"],"is_preprint":false},{"year":2018,"finding":"The extracellular SEMA domain of SEMA6A attenuates intracellular apoptotic signaling: truncation of the SEMA domain or the entire extracellular region causes increased apoptosis, and re-introduction of the SEMA domain rescues this. FADD binds the cytosolic region of truncated SEMA6A and mediates apoptosis induction, revealing a novel mechanism of SEMA6A intracellular signaling.","method":"Domain truncation transfection into lung cancer cells, co-immunoprecipitation (FADD–cytosolic SEMA6A), co-culture assay, gene silencing, in vivo tumor growth assay","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis plus Co-IP identifying FADD as binding partner; single lab but multiple orthogonal methods","pmids":["30518871"],"is_preprint":false},{"year":2018,"finding":"Sema6A is required for the formation of axonal projections from the medial terminal nucleus (MTN) to the nucleus of the optic tract (NOT) in the accessory optic system, demonstrating a role for Sema6A in establishing midbrain circuits mediating motion perception.","method":"Genetic characterization using Cre-driver lines, Sema6A null mouse analysis, axonal tracing","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined axonal projection phenotype in a specific circuit; single lab","pmids":["30076594"],"is_preprint":false},{"year":2019,"finding":"Sema6A-plexin-A2 signaling stimulates RANKL-induced osteoclastogenesis through PLCγ-mediated NFATc1 activation; soluble Fc-Sema6A binds plexin-A2 from osteoclast lysates, and pharmacological inhibition of PLCγ abrogates Sema6A-stimulated NFATc1 activation.","method":"Co-immunoprecipitation (Fc-Sema6A + plexin-A2), plexin-A2 neutralization, PLCγ inhibitor (U73122), NFATc1 activation assay, osteoclastogenesis assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — binding confirmed by Co-IP, pathway dissected by inhibitor and neutralization; single lab","pmids":["30826495"],"is_preprint":false},{"year":2019,"finding":"Multiple genes including Sema6a are hyperexpressed when C11orf46 is knocked down in neurons; in vivo epigenetic editing of the Sema6a promoter using dCas9-SunTag with C11orf46 (recruiting SETDB1 repressor complex) normalizes SEMA6A expression and rescues transcallosal dysconnectivity, placing Sema6a downstream of C11orf46/SETDB1-mediated chromatin regulation in corpus callosum axon guidance.","method":"C11orf46 shRNA knockdown, RNA-guided epigenetic editing (dCas9-SunTag-C11orf46/SETDB1), in vivo transcallosal axon tracing, rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — epistasis established by targeted chromatin editing in vivo with rescue; multiple orthogonal methods","pmids":["31511512"],"is_preprint":false},{"year":2022,"finding":"In BRAF-mutant melanoma, SEMA6A coordinates actin cytoskeleton remodeling via RhoA-dependent YAP activation (SEMA6A/RhoA/YAP axis); SEMA6A depletion abrogates fibroblast-mediated protection from dual BRAF/MEK inhibition, identifying SEMA6A as a mediator of tumor-stroma interactions conferring targeted therapy resistance.","method":"Inducible SEMA6A silencing, fibroblast co-culture model, RhoA and YAP activity assays, pharmacological BRAF/MEK inhibition (dabrafenib+trametinib)","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with inducible KD and co-culture model; single lab but multiple readouts","pmids":["35440004"],"is_preprint":false},{"year":2023,"finding":"Semaphorin-6A expressed by median eminence-resident oligodendrocytes controls GnRH neuron innervation and puberty onset via its receptor Plexin-A2 by regulating vascular permeability of fenestrated capillaries in the median eminence; in vitro and in vivo experiments establish a role in neuroendocrine homeostasis.","method":"Sema6A knockout mouse, in vivo GnRH neuron tracing, vascular permeability assays (in vitro and in vivo), Plexin-A2 receptor identification, human patient variant identification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO with mechanistic in vitro and in vivo assays, receptor identified (PlexinA2), human genetics supporting pathogenicity; multiple methods","pmids":["38062045"],"is_preprint":false},{"year":2023,"finding":"SEMA6A is a direct transcriptional target of HIF-2α in hypoxic ccRCC cells (VHL-HIF-2α axis); SEMA6A physically interacts with SEC62 to promote β-catenin stabilization and Wnt/β-catenin pathway activation, driving ccRCC progression.","method":"Chromatin immunoprecipitation (HIF-2α binding to SEMA6A promoter), luciferase reporter assay, co-immunoprecipitation (SEMA6A–SEC62), SEC62 knockdown, in vitro and in vivo proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + Co-IP + functional rescue; single lab","pmids":["36739418"],"is_preprint":false},{"year":2024,"finding":"The intracellular domain of Sema6A (reverse signaling) is required for retinal integrity, Müller glia end-feet strength, and protection against retinal cell death in zebrafish, but not for eye size or retinal patterning; rescue experiments with Sema6A-ΔC distinguish forward (PlexinA2-mediated) from reverse signaling roles.","method":"Sema6A morphant rescue experiments with full-length vs. ΔC (intracellular domain deleted) Sema6A in zebrafish, retinal histology, Müller glia analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific rescue dissecting forward vs reverse signaling; morpholino-based but domain deletion approach is mechanistically informative","pmids":["38963001"],"is_preprint":false},{"year":2024,"finding":"In developing hippocampal mossy fibers, Sema6A reverse signaling (via its intracellular domain) contributes to mossy fiber partitioning into suprapyramidal and infrapyramidal tracts; PlexinA2 (using GAP-independent signaling) and PlexinA4 (requiring GAP catalytic activity) mediate distinct and overlapping aspects of this guidance, with a genetic interaction identified between Plxna2 and Ncam1.","method":"Sema6A KO mouse, PlexinA2 and PlexinA4 KO and GAP-domain mutant mice, anti-PlxnA2 proximity biotinylation (BioID), genetic epistasis (double KO with Ncam1), axonal tracing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple KO/mutant lines with epistasis and proteomics; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"SEMA6A is a transmembrane class 6 semaphorin that signals bidirectionally: in trans (forward signaling), its extracellular sema domain engages PlexinA2 or PlexinA4 as receptors to regulate cerebellar granule cell migration (by controlling nucleus-centrosome coupling), retinal progenitor interkinetic migration, oligodendrocyte differentiation and myelination, adult CNS axon growth inhibition, GnRH neuron patterning via median eminence vascular permeability, osteoclastogenesis (via PLCγ/NFATc1), and pericyte recruitment (counteracting miR-27b); in cis, co-expression of Sema6A with PlexinA4 on the same cell attenuates responsiveness to exogenous Sema6A ligand; in reverse (intracellular) signaling, its cytoplasmic domain binds FADD to modulate apoptosis and, through EVL (Ena/VASP-like protein) binding at a zyxin-like C-terminal domain, links to actin dynamics; additionally, SEMA6A activates the RhoA/YAP axis in melanoma and interacts with SEC62 to stabilize β-catenin in renal carcinoma, while its transcription is regulated epigenetically by C11orf46/SETDB1 and transcriptionally by HIF-2α."},"narrative":{"teleology":[{"year":2000,"claim":"The discovery that SEMA6A binds EVL via a C-terminal zyxin-like domain established that transmembrane semaphorins can engage cytoskeletal regulators intracellularly, opening the concept of semaphorin reverse signaling.","evidence":"Yeast two-hybrid and co-immunoprecipitation in heterologous systems","pmids":["10993894"],"confidence":"Medium","gaps":["Binding detected by yeast two-hybrid and co-IP without reconstitution of downstream actin remodeling","Functional consequence of EVL binding on cell behavior not demonstrated","No in vivo validation"]},{"year":2005,"claim":"Knockout mouse studies demonstrated that SEMA6A is required for cerebellar granule cell migration, establishing the first in vivo developmental function for this semaphorin.","evidence":"Sema6A knockout mouse and chimera analysis of cerebellar granule cell migration","pmids":["16205717"],"confidence":"High","gaps":["Receptor identity unknown at this point","Cell-autonomous vs non-cell-autonomous mechanism not fully resolved for all cell populations"]},{"year":2008,"claim":"Identification of PlexinA2 as the functional receptor for SEMA6A in granule cells, with demonstration that their interaction controls nucleus-centrosome coupling, established the molecular mechanism underlying SEMA6A-dependent neuronal migration.","evidence":"PlexinA2 KO and ENU point mutant mice, binding assays, live imaging of nucleus-centrosome dynamics","pmids":["18327254"],"confidence":"High","gaps":["Downstream intracellular signaling cascade from PlexinA2 to centrosome positioning not identified","Whether other plexins contribute in this context not excluded"]},{"year":2010,"claim":"The finding that SEMA6A and PlexinA4 interact in cis on the same neuron to attenuate trans signaling revealed a novel regulatory mechanism whereby co-expression of ligand and receptor gates guidance responses.","evidence":"Heterologous cis/trans binding assays, growth cone collapse assays in Sema6A KO and PlexinA4 knockdown neurons","pmids":["20606624"],"confidence":"High","gaps":["Structural basis of cis vs trans binding selectivity not resolved","Whether cis inhibition operates in non-neuronal tissues unknown"]},{"year":2012,"claim":"Parallel studies showed SEMA6A functions in oligodendrocyte biology: it promotes oligodendrocyte differentiation and myelination, while oligodendrocyte-derived SEMA6A acts via PlexinA2 to inhibit adult CNS axon regeneration after injury.","evidence":"Sema6A and PlexinA2 KO mice; oligodendrocyte differentiation assays, DRG-OL co-culture myelination, pyramidotomy model with behavioral recovery","pmids":["22777942","22564823"],"confidence":"High","gaps":["Whether differentiation and axon inhibition roles are mechanistically coupled or independent","Downstream signaling in oligodendrocytes not characterized"]},{"year":2014,"claim":"Time-lapse imaging in KO cerebella and zebrafish eye vesicles refined the migratory defect to the tangential-to-radial mode-switching phase and extended the SEMA6A/PlexinA2 partnership to epithelial tissue integrity beyond the mammalian CNS.","evidence":"Cerebellar slice electroporation with live imaging in KO mice; morpholino knockdown with time-lapse in zebrafish eye progenitors","pmids":["25284064","24917502"],"confidence":"High","gaps":["Zebrafish data relies on morpholinos rather than genetic mutants","Whether mode-switching signal is contact-dependent or secreted not determined"]},{"year":2017,"claim":"The discovery that miR-27b represses SEMA6A to promote pericyte-endothelial adhesion expanded SEMA6A's role to vascular biology, identifying it as a repulsive cue that normally limits pericyte recruitment.","evidence":"miR-27b overexpression/inhibition with SEMA6A siRNA rescue in endothelial cells, in vivo antisense oligonucleotide treatment, femoral artery explant","pmids":["28453731"],"confidence":"Medium","gaps":["Which plexin receptor mediates repulsion in pericytes not identified","Relative contribution of SEMA6A vs SEMA6D in this context not fully resolved"]},{"year":2018,"claim":"Two studies established intracellular (reverse) signaling functions: the SEMA6A extracellular domain normally suppresses FADD-mediated apoptosis via its cytoplasmic tail, while SEMA6A also guides accessory optic system axons, broadening its circuit-level roles.","evidence":"Domain truncation, FADD co-IP, and tumor growth assays in lung cancer cells; Sema6A null mouse axonal tracing in midbrain","pmids":["30518871","30076594"],"confidence":"Medium","gaps":["FADD interaction demonstrated by co-IP without reciprocal pull-down or structural data","Whether apoptotic signaling operates in normal tissues or only cancer contexts unknown","Downstream effectors linking FADD binding to apoptosis modulation not mapped"]},{"year":2019,"claim":"SEMA6A was placed downstream of C11orf46/SETDB1 epigenetic regulation critical for corpus callosum connectivity, and separately shown to stimulate osteoclastogenesis via PLCγ/NFATc1, revealing both transcriptional control mechanisms and a bone biology function.","evidence":"dCas9-SunTag epigenetic editing with in vivo callosal rescue; Fc-Sema6A/PlexinA2 co-IP with PLCγ inhibitor in osteoclast cultures","pmids":["31511512","30826495"],"confidence":"High","gaps":["Whether SETDB1-mediated repression of SEMA6A operates in non-neuronal tissues not tested","Full signaling cascade from PlexinA2 to PLCγ activation in osteoclasts not mapped"]},{"year":2022,"claim":"In melanoma, SEMA6A was shown to activate a RhoA/YAP axis that mediates fibroblast-dependent resistance to BRAF/MEK inhibition, linking SEMA6A to mechanotransduction and tumor-stroma crosstalk.","evidence":"Inducible SEMA6A knockdown, RhoA and YAP activity assays, fibroblast co-culture under dabrafenib/trametinib treatment","pmids":["35440004"],"confidence":"Medium","gaps":["Which plexin receptor activates RhoA in this context not identified","Whether RhoA/YAP axis operates downstream of SEMA6A in normal physiology unknown"]},{"year":2023,"claim":"Two studies expanded SEMA6A's physiological scope: in the median eminence, oligodendrocyte-expressed SEMA6A/PlexinA2 controls fenestrated capillary permeability to regulate GnRH neuron innervation and puberty, while in renal carcinoma, HIF-2α transcriptionally activates SEMA6A which then interacts with SEC62 to stabilize β-catenin.","evidence":"Sema6A KO mouse with vascular permeability assays and human variant identification; ChIP for HIF-2α at SEMA6A promoter, co-IP of SEMA6A–SEC62, in vivo tumor models","pmids":["38062045","36739418"],"confidence":"High","gaps":["Mechanism by which SEMA6A/PlexinA2 alters endothelial fenestration not defined","Structural basis of SEMA6A–SEC62 interaction not resolved","Whether SEC62 interaction is cancer-specific or generalizable unknown"]},{"year":2024,"claim":"Domain-deletion rescue experiments in zebrafish formally dissected forward from reverse signaling: the intracellular domain of SEMA6A is specifically required for Müller glia end-feet integrity and retinal cell survival but dispensable for eye patterning, establishing non-overlapping outputs of SEMA6A's bidirectional signaling.","evidence":"Full-length vs ΔC Sema6A rescue in zebrafish sema6a morphants with retinal histology and Müller glia analysis","pmids":["38963001"],"confidence":"Medium","gaps":["Morpholino-based approach; genetic mutant confirmation needed","Intracellular effectors mediating Müller glia protection not identified"]},{"year":null,"claim":"Major unresolved questions include the structural basis of cis vs trans PlexinA binding selectivity, the identity of downstream effectors linking reverse signaling to cytoskeletal and survival outcomes, and whether SEMA6A's diverse tissue-specific functions employ a common or divergent intracellular signaling logic.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of SEMA6A in cis vs trans plexin complexes","Reverse signaling effectors beyond EVL and FADD not mapped","No unifying model connecting PlexinA2-dependent and PlexinA4-dependent pathways across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,3,5,14,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,12,19]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,4,8,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,14,16,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,16,18]}],"complexes":[],"partners":["PLXNA2","PLXNA4","EVL","FADD","SEC62"],"other_free_text":[]},"mechanistic_narrative":"SEMA6A is a transmembrane class 6 semaphorin that functions as a bidirectional signaling molecule, engaging PlexinA2 and PlexinA4 as receptors in trans (forward signaling) to regulate neuronal migration, axon guidance, oligodendrocyte differentiation and myelination, osteoclastogenesis, and neuroendocrine vascular permeability, while its intracellular domain mediates reverse signaling through interactions with EVL and FADD to control actin dynamics, apoptosis, and retinal integrity [PMID:16205717, PMID:18327254, PMID:22777942, PMID:38062045, PMID:10993894, PMID:30518871, PMID:38963001]. Forward signaling through PlexinA2 controls nucleus-centrosome coupling during cerebellar granule cell migration and regulates fenestrated capillary permeability in the median eminence to govern GnRH neuron innervation and puberty onset [PMID:18327254, PMID:38062045]. Co-expression of SEMA6A with PlexinA4 on the same cell acts as a cis-inhibitory mechanism that attenuates responsiveness to exogenous SEMA6A in trans [PMID:20606624]. SEMA6A transcription is regulated epigenetically by the C11orf46/SETDB1 repressor complex and by HIF-2α under hypoxia, and in cancer contexts SEMA6A activates a RhoA/YAP signaling axis in melanoma and stabilizes β-catenin through interaction with SEC62 in renal cell carcinoma [PMID:31511512, PMID:36739418, PMID:35440004]."},"prefetch_data":{"uniprot":{"accession":"Q9H2E6","full_name":"Semaphorin-6A","aliases":["Semaphorin VIA","Sema VIA","Semaphorin-6A-1","SEMA6A-1"],"length_aa":1030,"mass_kda":114.4,"function":"Cell surface receptor for PLXNA2 that plays an important role in cell-cell signaling. Required for normal granule cell migration in the developing cerebellum. Promotes reorganization of the actin cytoskeleton and plays an important role in axon guidance in the developing central nervous system. Can act as repulsive axon guidance cue. Has repulsive action towards migrating granular neurons. May play a role in channeling sympathetic axons into the sympathetic chains and controlling the temporal sequence of sympathetic target innervation (Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H2E6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA6A","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA6A","total_profiled":1310},"omim":[{"mim_id":"618867","title":"RAS HOMOLOG GENE FAMILY, MEMBER F, FILOPODIA-ASSOCIATED; RHOF","url":"https://www.omim.org/entry/618867"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"608873","title":"SEMAPHORIN 6B; SEMA6B","url":"https://www.omim.org/entry/608873"},{"mim_id":"605885","title":"SEMAPHORIN 6A; SEMA6A","url":"https://www.omim.org/entry/605885"},{"mim_id":"604280","title":"PLEXIN A4; PLXNA4","url":"https://www.omim.org/entry/604280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal 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gland","date":"2025-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.22.666120","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42778,"output_tokens":5465,"usd":0.105154},"stage2":{"model":"claude-opus-4-6","input_tokens":9024,"output_tokens":3360,"usd":0.19368},"total_usd":0.298834,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SEMA6A-1 (human and murine) directly binds EVL (Ena/VASP-like protein) via a novel carboxyl-terminal zyxin-like domain, physically linking the semaphorin and Ena/VASP protein families and suggesting a role for transmembrane semaphorins in retrograde signaling.\",\n      \"method\": \"Yeast two-hybrid, co-localization, binding assays (pulldown/co-IP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-localization and binding data; novel finding but limited orthogonal validation\",\n      \"pmids\": [\"10993894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sema6A controls cerebellar granule cell migration; in Sema6A-deficient mice, postmitotic granule cells fail to initiate radial migration and remain ectopic in the molecular layer, with chimera analysis indicating this function is primarily non-cell-autonomous.\",\n      \"method\": \"Knockout mouse analysis, chimera studies, cerebellar explant migration assay, neurite outgrowth assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotype replicated with chimera and explant assays, published in high-impact journal\",\n      \"pmids\": [\"16205717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Plexin-A2 is the functional receptor for Sema6A in migrating cerebellar granule cells; Sema6A binds Plexin-A2, and loss of either Sema6A or Plexin-A2 disrupts nucleus-centrosome coupling and coordinated motility during migration, demonstrating semaphorin-plexin signaling controls cell migration by modulating centrosome positioning.\",\n      \"method\": \"Plexin-A2 knockout mouse (homologous recombination), ENU mutagenesis point mutant (abolishes Sema6A binding), chimera analysis, time-lapse video microscopy, binding assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic and biochemical evidence (binding abolished by single AA substitution), live imaging, chimera; replicates and extends prior Sema6A KO findings\",\n      \"pmids\": [\"18327254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema6A engages in a cis interaction with its receptor Plexin-A4 in sensory neurons, which inhibits binding of exogenous Sema6A ligand in trans and suppresses responsiveness to Sema6A, revealing that co-expression of a transmembrane semaphorin with its receptor acts as a guidance response modulator.\",\n      \"method\": \"Heterologous expression (cis vs trans binding assay), sensory/sympathetic neuron collapse assay, Sema6A knockout neurons, Plexin-A4 knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (neuron collapse assay, binding inhibition, KO neurons, knockdown), mechanistically resolves cis vs trans signaling\",\n      \"pmids\": [\"20606624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema6A is highly expressed by myelinating oligodendrocytes; Sema6A-deficient mice show delayed oligodendrocyte differentiation, delayed node of Ranvier development, and impaired myelination in co-culture, establishing a role for Sema6A in oligodendrocyte differentiation.\",\n      \"method\": \"Sema6A knockout mouse, optic nerve and anterior commissure analysis, in vitro oligodendrocyte differentiation assay, dorsal root ganglion neuron/oligodendrocyte co-culture myelination assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotypes corroborated by in vitro differentiation and myelination co-culture assays\",\n      \"pmids\": [\"22777942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PlexinA2 mediates the inhibitory effect of oligodendrocyte-derived Sema6A on adult sensory axon growth; PlexinA2 null mice show greater corticospinal axon sprouting and functional recovery after pyramidotomy, establishing a PlexinA2-Sema6A axis that limits adult CNS axon growth after injury.\",\n      \"method\": \"PlexinA2 knockout mouse, adult dorsal root ganglion neurite inhibition assay, unilateral pyramidotomy model, immunohistochemistry (synaptophysin), behavioral assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined in vitro and in vivo phenotypes, functional behavioral readout; builds on established Sema6A/PlexinA2 ligand-receptor relationship\",\n      \"pmids\": [\"22564823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sema6A expressed in oligodendrocyte precursor cells (OPCs) promotes their autonomous migration through cis and trans ligand-receptor interactions with Plexin-A4; Sema6A knockdown in OPC-like FBD-102b cells represses migration, and co-culture segregation experiments confirm Sema6A/Plexin-A4 repulsive interaction.\",\n      \"method\": \"Sema6A siRNA knockdown in FBD-102b cells, in vitro migration assay, co-culture segregation assay, gradient exposure assay, Plexin-A4 knockdown\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple in vitro assays but cell line model; consistent with prior in vivo findings\",\n      \"pmids\": [\"23376059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sema6a and Plexin-A2 cooperate in a cell-autonomous, tissue-autonomous manner to keep zebrafish eye vesicle progenitor cells integrated within the epithelium; knockdown of either disrupts eye vesicle integrity with progenitors failing to enter or delaminating from the vesicle, as shown by time-lapse microscopy.\",\n      \"method\": \"Morpholino knockdown in zebrafish, time-lapse microscopy of eye progenitors, explant rescue experiments, double knockdown epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with epistasis (double KD rescue), but morpholino-based; zebrafish ortholog consistent with mammalian Sema6A/PlexinA2\",\n      \"pmids\": [\"24917502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Time-lapse analysis of Sema6A and PlexinA2 knockout cerebella reveals that lack of Sema6A preferentially perturbs later-born granule cells and that defects in tangential migration (bipolar cell stage) precede the failure to initiate radial migration, confirming that Sema6A/PlexinA2 regulate mode-switching in granule cell migration.\",\n      \"method\": \"Cerebellar slice electroporation, time-lapse video microscopy in Sema6A and PlexinA2 KO mice\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell imaging in KO mice, mechanistically pinpoints the tangential phase as the primary defect\",\n      \"pmids\": [\"25284064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sema6A silencing in BRAFV600E melanoma cells causes cytoskeletal remodeling, loss of stress fibers, cell death, and loss of anchorage-independent growth; forced Sema6A overexpression promotes invasiveness, establishing Sema6A as a regulator of actin cytoskeleton and cell viability in melanoma complexed with plexins.\",\n      \"method\": \"Sema6A siRNA knockdown, overexpression in NRASQ61R clones, cytoskeletal imaging, anchorage-independent growth assay, chemotaxis/invasion assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple functional readouts; mechanism (plexin complex, actin) inferred but not fully reconstituted\",\n      \"pmids\": [\"25576923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sema6A/PlexinA2 signaling participates in interkinetic nuclear migration of retinal progenitor cells (RPCs) around birth; loss of either Sema6A or PlexinA2 blocks RPC migration at the apical side of the neuroblastic layer.\",\n      \"method\": \"Sema6A and PlexinA2 knockout mouse retina analysis, time-lapse videomicroscopy\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with live imaging, but single lab\",\n      \"pmids\": [\"27301906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Shear stress-induced miR-27b promotes pericyte recruitment to endothelial cells partly by repressing SEMA6A and SEMA6D; silencing of SEMA6A rescues reduced pericyte adhesion caused by miR-27 inhibition, identifying SEMA6A as a repulsive cue that normally inhibits pericyte-endothelial interaction.\",\n      \"method\": \"miR-27b overexpression/inhibition in endothelial cells, SEMA6A/SEMA6D siRNA knockdown, pericyte adhesion assay, in vivo locked nucleic acid antisense oligonucleotide treatment, ex vivo femoral artery explant\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rescue experiment (SEMA6A KD rescues miR-27 inhibition phenotype), in vivo validation, multiple methods\",\n      \"pmids\": [\"28453731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The extracellular SEMA domain of SEMA6A attenuates intracellular apoptotic signaling: truncation of the SEMA domain or the entire extracellular region causes increased apoptosis, and re-introduction of the SEMA domain rescues this. FADD binds the cytosolic region of truncated SEMA6A and mediates apoptosis induction, revealing a novel mechanism of SEMA6A intracellular signaling.\",\n      \"method\": \"Domain truncation transfection into lung cancer cells, co-immunoprecipitation (FADD–cytosolic SEMA6A), co-culture assay, gene silencing, in vivo tumor growth assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis plus Co-IP identifying FADD as binding partner; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30518871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sema6A is required for the formation of axonal projections from the medial terminal nucleus (MTN) to the nucleus of the optic tract (NOT) in the accessory optic system, demonstrating a role for Sema6A in establishing midbrain circuits mediating motion perception.\",\n      \"method\": \"Genetic characterization using Cre-driver lines, Sema6A null mouse analysis, axonal tracing\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined axonal projection phenotype in a specific circuit; single lab\",\n      \"pmids\": [\"30076594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sema6A-plexin-A2 signaling stimulates RANKL-induced osteoclastogenesis through PLCγ-mediated NFATc1 activation; soluble Fc-Sema6A binds plexin-A2 from osteoclast lysates, and pharmacological inhibition of PLCγ abrogates Sema6A-stimulated NFATc1 activation.\",\n      \"method\": \"Co-immunoprecipitation (Fc-Sema6A + plexin-A2), plexin-A2 neutralization, PLCγ inhibitor (U73122), NFATc1 activation assay, osteoclastogenesis assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding confirmed by Co-IP, pathway dissected by inhibitor and neutralization; single lab\",\n      \"pmids\": [\"30826495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Multiple genes including Sema6a are hyperexpressed when C11orf46 is knocked down in neurons; in vivo epigenetic editing of the Sema6a promoter using dCas9-SunTag with C11orf46 (recruiting SETDB1 repressor complex) normalizes SEMA6A expression and rescues transcallosal dysconnectivity, placing Sema6a downstream of C11orf46/SETDB1-mediated chromatin regulation in corpus callosum axon guidance.\",\n      \"method\": \"C11orf46 shRNA knockdown, RNA-guided epigenetic editing (dCas9-SunTag-C11orf46/SETDB1), in vivo transcallosal axon tracing, rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by targeted chromatin editing in vivo with rescue; multiple orthogonal methods\",\n      \"pmids\": [\"31511512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In BRAF-mutant melanoma, SEMA6A coordinates actin cytoskeleton remodeling via RhoA-dependent YAP activation (SEMA6A/RhoA/YAP axis); SEMA6A depletion abrogates fibroblast-mediated protection from dual BRAF/MEK inhibition, identifying SEMA6A as a mediator of tumor-stroma interactions conferring targeted therapy resistance.\",\n      \"method\": \"Inducible SEMA6A silencing, fibroblast co-culture model, RhoA and YAP activity assays, pharmacological BRAF/MEK inhibition (dabrafenib+trametinib)\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with inducible KD and co-culture model; single lab but multiple readouts\",\n      \"pmids\": [\"35440004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Semaphorin-6A expressed by median eminence-resident oligodendrocytes controls GnRH neuron innervation and puberty onset via its receptor Plexin-A2 by regulating vascular permeability of fenestrated capillaries in the median eminence; in vitro and in vivo experiments establish a role in neuroendocrine homeostasis.\",\n      \"method\": \"Sema6A knockout mouse, in vivo GnRH neuron tracing, vascular permeability assays (in vitro and in vivo), Plexin-A2 receptor identification, human patient variant identification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with mechanistic in vitro and in vivo assays, receptor identified (PlexinA2), human genetics supporting pathogenicity; multiple methods\",\n      \"pmids\": [\"38062045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEMA6A is a direct transcriptional target of HIF-2α in hypoxic ccRCC cells (VHL-HIF-2α axis); SEMA6A physically interacts with SEC62 to promote β-catenin stabilization and Wnt/β-catenin pathway activation, driving ccRCC progression.\",\n      \"method\": \"Chromatin immunoprecipitation (HIF-2α binding to SEMA6A promoter), luciferase reporter assay, co-immunoprecipitation (SEMA6A–SEC62), SEC62 knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + Co-IP + functional rescue; single lab\",\n      \"pmids\": [\"36739418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intracellular domain of Sema6A (reverse signaling) is required for retinal integrity, Müller glia end-feet strength, and protection against retinal cell death in zebrafish, but not for eye size or retinal patterning; rescue experiments with Sema6A-ΔC distinguish forward (PlexinA2-mediated) from reverse signaling roles.\",\n      \"method\": \"Sema6A morphant rescue experiments with full-length vs. ΔC (intracellular domain deleted) Sema6A in zebrafish, retinal histology, Müller glia analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific rescue dissecting forward vs reverse signaling; morpholino-based but domain deletion approach is mechanistically informative\",\n      \"pmids\": [\"38963001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In developing hippocampal mossy fibers, Sema6A reverse signaling (via its intracellular domain) contributes to mossy fiber partitioning into suprapyramidal and infrapyramidal tracts; PlexinA2 (using GAP-independent signaling) and PlexinA4 (requiring GAP catalytic activity) mediate distinct and overlapping aspects of this guidance, with a genetic interaction identified between Plxna2 and Ncam1.\",\n      \"method\": \"Sema6A KO mouse, PlexinA2 and PlexinA4 KO and GAP-domain mutant mice, anti-PlxnA2 proximity biotinylation (BioID), genetic epistasis (double KO with Ncam1), axonal tracing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO/mutant lines with epistasis and proteomics; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEMA6A is a transmembrane class 6 semaphorin that signals bidirectionally: in trans (forward signaling), its extracellular sema domain engages PlexinA2 or PlexinA4 as receptors to regulate cerebellar granule cell migration (by controlling nucleus-centrosome coupling), retinal progenitor interkinetic migration, oligodendrocyte differentiation and myelination, adult CNS axon growth inhibition, GnRH neuron patterning via median eminence vascular permeability, osteoclastogenesis (via PLCγ/NFATc1), and pericyte recruitment (counteracting miR-27b); in cis, co-expression of Sema6A with PlexinA4 on the same cell attenuates responsiveness to exogenous Sema6A ligand; in reverse (intracellular) signaling, its cytoplasmic domain binds FADD to modulate apoptosis and, through EVL (Ena/VASP-like protein) binding at a zyxin-like C-terminal domain, links to actin dynamics; additionally, SEMA6A activates the RhoA/YAP axis in melanoma and interacts with SEC62 to stabilize β-catenin in renal carcinoma, while its transcription is regulated epigenetically by C11orf46/SETDB1 and transcriptionally by HIF-2α.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEMA6A is a transmembrane class 6 semaphorin that functions as a bidirectional signaling molecule, engaging PlexinA2 and PlexinA4 as receptors in trans (forward signaling) to regulate neuronal migration, axon guidance, oligodendrocyte differentiation and myelination, osteoclastogenesis, and neuroendocrine vascular permeability, while its intracellular domain mediates reverse signaling through interactions with EVL and FADD to control actin dynamics, apoptosis, and retinal integrity [PMID:16205717, PMID:18327254, PMID:22777942, PMID:38062045, PMID:10993894, PMID:30518871, PMID:38963001]. Forward signaling through PlexinA2 controls nucleus-centrosome coupling during cerebellar granule cell migration and regulates fenestrated capillary permeability in the median eminence to govern GnRH neuron innervation and puberty onset [PMID:18327254, PMID:38062045]. Co-expression of SEMA6A with PlexinA4 on the same cell acts as a cis-inhibitory mechanism that attenuates responsiveness to exogenous SEMA6A in trans [PMID:20606624]. SEMA6A transcription is regulated epigenetically by the C11orf46/SETDB1 repressor complex and by HIF-2α under hypoxia, and in cancer contexts SEMA6A activates a RhoA/YAP signaling axis in melanoma and stabilizes β-catenin through interaction with SEC62 in renal cell carcinoma [PMID:31511512, PMID:36739418, PMID:35440004].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The discovery that SEMA6A binds EVL via a C-terminal zyxin-like domain established that transmembrane semaphorins can engage cytoskeletal regulators intracellularly, opening the concept of semaphorin reverse signaling.\",\n      \"evidence\": \"Yeast two-hybrid and co-immunoprecipitation in heterologous systems\",\n      \"pmids\": [\"10993894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding detected by yeast two-hybrid and co-IP without reconstitution of downstream actin remodeling\", \"Functional consequence of EVL binding on cell behavior not demonstrated\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Knockout mouse studies demonstrated that SEMA6A is required for cerebellar granule cell migration, establishing the first in vivo developmental function for this semaphorin.\",\n      \"evidence\": \"Sema6A knockout mouse and chimera analysis of cerebellar granule cell migration\",\n      \"pmids\": [\"16205717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unknown at this point\", \"Cell-autonomous vs non-cell-autonomous mechanism not fully resolved for all cell populations\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of PlexinA2 as the functional receptor for SEMA6A in granule cells, with demonstration that their interaction controls nucleus-centrosome coupling, established the molecular mechanism underlying SEMA6A-dependent neuronal migration.\",\n      \"evidence\": \"PlexinA2 KO and ENU point mutant mice, binding assays, live imaging of nucleus-centrosome dynamics\",\n      \"pmids\": [\"18327254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intracellular signaling cascade from PlexinA2 to centrosome positioning not identified\", \"Whether other plexins contribute in this context not excluded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The finding that SEMA6A and PlexinA4 interact in cis on the same neuron to attenuate trans signaling revealed a novel regulatory mechanism whereby co-expression of ligand and receptor gates guidance responses.\",\n      \"evidence\": \"Heterologous cis/trans binding assays, growth cone collapse assays in Sema6A KO and PlexinA4 knockdown neurons\",\n      \"pmids\": [\"20606624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cis vs trans binding selectivity not resolved\", \"Whether cis inhibition operates in non-neuronal tissues unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Parallel studies showed SEMA6A functions in oligodendrocyte biology: it promotes oligodendrocyte differentiation and myelination, while oligodendrocyte-derived SEMA6A acts via PlexinA2 to inhibit adult CNS axon regeneration after injury.\",\n      \"evidence\": \"Sema6A and PlexinA2 KO mice; oligodendrocyte differentiation assays, DRG-OL co-culture myelination, pyramidotomy model with behavioral recovery\",\n      \"pmids\": [\"22777942\", \"22564823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether differentiation and axon inhibition roles are mechanistically coupled or independent\", \"Downstream signaling in oligodendrocytes not characterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Time-lapse imaging in KO cerebella and zebrafish eye vesicles refined the migratory defect to the tangential-to-radial mode-switching phase and extended the SEMA6A/PlexinA2 partnership to epithelial tissue integrity beyond the mammalian CNS.\",\n      \"evidence\": \"Cerebellar slice electroporation with live imaging in KO mice; morpholino knockdown with time-lapse in zebrafish eye progenitors\",\n      \"pmids\": [\"25284064\", \"24917502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Zebrafish data relies on morpholinos rather than genetic mutants\", \"Whether mode-switching signal is contact-dependent or secreted not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The discovery that miR-27b represses SEMA6A to promote pericyte-endothelial adhesion expanded SEMA6A's role to vascular biology, identifying it as a repulsive cue that normally limits pericyte recruitment.\",\n      \"evidence\": \"miR-27b overexpression/inhibition with SEMA6A siRNA rescue in endothelial cells, in vivo antisense oligonucleotide treatment, femoral artery explant\",\n      \"pmids\": [\"28453731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which plexin receptor mediates repulsion in pericytes not identified\", \"Relative contribution of SEMA6A vs SEMA6D in this context not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two studies established intracellular (reverse) signaling functions: the SEMA6A extracellular domain normally suppresses FADD-mediated apoptosis via its cytoplasmic tail, while SEMA6A also guides accessory optic system axons, broadening its circuit-level roles.\",\n      \"evidence\": \"Domain truncation, FADD co-IP, and tumor growth assays in lung cancer cells; Sema6A null mouse axonal tracing in midbrain\",\n      \"pmids\": [\"30518871\", \"30076594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FADD interaction demonstrated by co-IP without reciprocal pull-down or structural data\", \"Whether apoptotic signaling operates in normal tissues or only cancer contexts unknown\", \"Downstream effectors linking FADD binding to apoptosis modulation not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SEMA6A was placed downstream of C11orf46/SETDB1 epigenetic regulation critical for corpus callosum connectivity, and separately shown to stimulate osteoclastogenesis via PLCγ/NFATc1, revealing both transcriptional control mechanisms and a bone biology function.\",\n      \"evidence\": \"dCas9-SunTag epigenetic editing with in vivo callosal rescue; Fc-Sema6A/PlexinA2 co-IP with PLCγ inhibitor in osteoclast cultures\",\n      \"pmids\": [\"31511512\", \"30826495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SETDB1-mediated repression of SEMA6A operates in non-neuronal tissues not tested\", \"Full signaling cascade from PlexinA2 to PLCγ activation in osteoclasts not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In melanoma, SEMA6A was shown to activate a RhoA/YAP axis that mediates fibroblast-dependent resistance to BRAF/MEK inhibition, linking SEMA6A to mechanotransduction and tumor-stroma crosstalk.\",\n      \"evidence\": \"Inducible SEMA6A knockdown, RhoA and YAP activity assays, fibroblast co-culture under dabrafenib/trametinib treatment\",\n      \"pmids\": [\"35440004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which plexin receptor activates RhoA in this context not identified\", \"Whether RhoA/YAP axis operates downstream of SEMA6A in normal physiology unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies expanded SEMA6A's physiological scope: in the median eminence, oligodendrocyte-expressed SEMA6A/PlexinA2 controls fenestrated capillary permeability to regulate GnRH neuron innervation and puberty, while in renal carcinoma, HIF-2α transcriptionally activates SEMA6A which then interacts with SEC62 to stabilize β-catenin.\",\n      \"evidence\": \"Sema6A KO mouse with vascular permeability assays and human variant identification; ChIP for HIF-2α at SEMA6A promoter, co-IP of SEMA6A–SEC62, in vivo tumor models\",\n      \"pmids\": [\"38062045\", \"36739418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SEMA6A/PlexinA2 alters endothelial fenestration not defined\", \"Structural basis of SEMA6A–SEC62 interaction not resolved\", \"Whether SEC62 interaction is cancer-specific or generalizable unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Domain-deletion rescue experiments in zebrafish formally dissected forward from reverse signaling: the intracellular domain of SEMA6A is specifically required for Müller glia end-feet integrity and retinal cell survival but dispensable for eye patterning, establishing non-overlapping outputs of SEMA6A's bidirectional signaling.\",\n      \"evidence\": \"Full-length vs ΔC Sema6A rescue in zebrafish sema6a morphants with retinal histology and Müller glia analysis\",\n      \"pmids\": [\"38963001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based approach; genetic mutant confirmation needed\", \"Intracellular effectors mediating Müller glia protection not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of cis vs trans PlexinA binding selectivity, the identity of downstream effectors linking reverse signaling to cytoskeletal and survival outcomes, and whether SEMA6A's diverse tissue-specific functions employ a common or divergent intracellular signaling logic.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of SEMA6A in cis vs trans plexin complexes\", \"Reverse signaling effectors beyond EVL and FADD not mapped\", \"No unifying model connecting PlexinA2-dependent and PlexinA4-dependent pathways across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 3, 5, 14, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 12, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 4, 8, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 14, 16, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 16, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLXNA2\",\n      \"PLXNA4\",\n      \"EVL\",\n      \"FADD\",\n      \"SEC62\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}