{"gene":"SEMA6A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"SEMA6A-1 (SEMA6A) directly binds EVL (Ena/VASP-like protein) via a novel carboxyl-terminal zyxin-like domain; SEMA6A-1 colocalizes with EVL, and this interaction is selective (does not extend to other Ena/VASP family members Mena/VASP), suggesting a role for SEMA6A in retrograde signaling linked to actin/cytoskeletal dynamics.","method":"Yeast two-hybrid, pulldown/binding assay, colocalization in heterologous system; mutagenesis of the zyxin-like C-terminal domain","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated by pulldown and colocalization with domain mapping; single lab, two orthogonal methods","pmids":["10993894"],"is_preprint":false},{"year":2005,"finding":"Sema6A is required for cerebellar granule cell migration: Sema6A-deficient mice show ectopic granule cells remaining in the molecular layer, and analysis of chimeras demonstrates this function is primarily non-cell-autonomous. Sema6A controls initiation of radial migration, likely via modulation of nuclear/soma translocation.","method":"Knockout mouse analysis, mouse chimera studies, cerebellar explant migration and neurite outgrowth assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods, replicated in independent follow-up studies","pmids":["16205717"],"is_preprint":false},{"year":2008,"finding":"PlexinA2 is the receptor for Sema6A in migrating cerebellar granule cells: PlexinA2-deficient mice phenocopy Sema6A mutants; an ENU-induced single amino acid substitution in the semaphorin-binding domain of PlexinA2 abolishes Sema6A binding; chimera studies show PlexinA2 acts cell-autonomously; Sema6A/PlexinA2 signaling controls nucleus-centrosome coupling and coordinated motility during migration.","method":"Homologous recombination knockout, ENU mutagenesis, binding assay (Sema6A–PlexinA2 interaction), mouse chimera studies, time-lapse video microscopy of centrosome–nucleus coupling","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding abrogation by mutagenesis, genetic epistasis, chimera experiments, and live imaging; multiple orthogonal methods","pmids":["18327254"],"is_preprint":false},{"year":2010,"finding":"Sema6A engages in a cis interaction with its receptor PlexinA4 on the same cell surface, which inhibits binding of exogenous Sema6A ligand in trans and thereby suppresses the repulsive response. This cis Sema6A–PlexinA4 interaction differentially modulates axon guidance responsiveness in sympathetic vs. sensory neurons.","method":"Heterologous expression systems for cis/trans binding assays, sensory neuron collapse assays with Sema6A knockout (gain of sensitivity), PlexinA4-dependent rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding assays in heterologous systems combined with neuronal functional assays and genetic loss-of-function; multiple orthogonal methods in single rigorous study","pmids":["20606624"],"is_preprint":false},{"year":2012,"finding":"Oligodendrocyte-expressed Sema6A inhibits adult axon growth via PlexinA2: adult sensory neurons are inhibited by Sema6A in a PlexinA2-dependent manner (complete protection in PlexinA2−/− cultures); PlexinA2−/− mice show enhanced corticospinal axon sprouting and improved functional recovery after pyramidotomy.","method":"In vitro sensory neuron inhibition assay with PlexinA2 KO, adult mouse pyramidotomy model with axonal sprouting quantification and behavioral testing","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro receptor requirement demonstrated with genetic knockout plus in vivo corticospinal lesion model with behavioral and anatomical readouts","pmids":["22564823"],"is_preprint":false},{"year":2012,"finding":"Sema6A expressed by myelinating oligodendrocytes is required for oligodendrocyte differentiation and myelination: Sema6A-deficient mice show delayed oligodendrocyte differentiation, delayed node of Ranvier development, and reduced MBP expression. In vitro, Sema6A-null oligodendrocytes show morphological defects and impaired myelination in DRG co-culture.","method":"Knockout mouse analysis (optic nerve, anterior commissure), purified oligodendrocyte differentiation assay, myelinating co-culture with DRG neurons","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo and in vitro readouts with KO mice, replicated across cell-autonomous and co-culture contexts","pmids":["22777942"],"is_preprint":false},{"year":2013,"finding":"Sema6A expressed in oligodendrocyte precursor cells (OPCs) controls their autonomous migration via ligand-receptor interaction with PlexinA4 on surrounding cells: Sema6A knockdown in OPC line FBD-102b reduces migration, and Plexin-A4-expressing cells segregate from Sema6A-expressing cells in co-culture.","method":"siRNA knockdown in OPC cell line, in vitro migration assay, co-culture segregation assay, semaphorin gradient assay with PlexinA4 knockdown","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell line knockdown with migration assay and co-culture; single lab, two complementary functional approaches","pmids":["23376059"],"is_preprint":false},{"year":2014,"finding":"Sema6A and PlexinA2 are required for eye vesicle cohesion in zebrafish: knockdown of either disrupts vesicle integrity, with eye progenitors failing to enter or delaminating from the eye epithelium. Epistasis (simultaneous knockdown of both) rescues vesicle integrity, placing Sema6A–PlexinA2-mediated repulsion as the mechanism maintaining tissue cohesion.","method":"Morpholino knockdown in zebrafish, time-lapse microscopy, explant experiments, double-knockdown epistasis rescue","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — time-lapse imaging with genetic epistasis rescue, multiple orthogonal methods in one study","pmids":["24917502"],"is_preprint":false},{"year":2014,"finding":"Time-lapse analysis of cerebellar slice electroporation confirms that Sema6A and PlexinA2 loss preferentially perturbs migration of later-born granule cells, and defects in tangential migration in bipolar granule cells precede the switch to radial migration; Sema6A loss does not perturb radial migration itself.","method":"Cerebellar slice model, in utero/ex vivo electroporation, time-lapse video microscopy in Sema6A and PlexinA2 knockout mice","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging in genetic KO slices; single lab, direct observation of migration phases","pmids":["25284064"],"is_preprint":false},{"year":2015,"finding":"Sema6A silencing in BRAFV600E melanoma cells causes cytoskeletal remodeling with loss of stress fibers leading to cell death, loss of anchorage-independent growth, and inhibited chemotaxis/invasion; forced Sema6A overexpression in NRASQ61R cells induces anchorage-independent growth and invasiveness, indicating Sema6A regulates actin cytoskeleton and cell survival downstream of BRAF signaling.","method":"siRNA silencing, forced overexpression, cytoskeletal imaging, anchorage-independent growth assay, chemotaxis/invasion assay in melanoma cell lines","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss- and gain-of-function with multiple cellular readouts; single lab","pmids":["25576923"],"is_preprint":false},{"year":2016,"finding":"Sema6A/PlexinA2 signaling regulates interkinetic nuclear migration of retinal progenitor cells (RPCs): in Sema6A and PlexinA2 knockout mice, RPC migration is blocked at the apical side of the neuroblastic layer, as shown by time-lapse videomicroscopy.","method":"Knockout mouse analysis, time-lapse videomicroscopy of embryonic retina","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging in genetic KO mice; single lab, direct demonstration of migration block","pmids":["27301906"],"is_preprint":false},{"year":2017,"finding":"SEMA6A is a direct target of miR-203: luciferase reporter assay confirmed miR-203 directly targets the SEMA6A 3'-UTR, suppressing SEMA6A mRNA and protein levels; miR-203-mediated SEMA6A downregulation promotes apoptosis in oral cancer cells.","method":"Luciferase 3'-UTR reporter assay, miRNA overexpression, Western blot, miRNA array","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct 3'-UTR targeting validated by luciferase assay with functional apoptosis readout; single lab","pmids":["28982852"],"is_preprint":false},{"year":2017,"finding":"SEMA6A is repressed post-transcriptionally by miR-27b in endothelial cells; miR-27b overexpression represses SEMA6A (and SEMA6D), and silencing of SEMA6A rescues reduced pericyte adhesion caused by miR-27 inhibition, demonstrating that SEMA6A acts as a repulsive signal limiting pericyte recruitment.","method":"miR-27b overexpression/inhibition in endothelial cells, pericyte adhesion and co-culture assays, siRNA silencing of SEMA6A, in vivo LNA antisense oligonucleotide inhibition","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue of pericyte adhesion phenotype by SEMA6A silencing, combined in vitro and in vivo approaches; single lab","pmids":["28453731"],"is_preprint":false},{"year":2018,"finding":"Sema6A is required for formation of axonal projections from the medial terminal nucleus (MTN) to the nucleus of the optic tract (NOT) in the accessory optic system; using Cre-driver lines, Sema6A was shown to be necessary for establishing AOS connections in multiple locations.","method":"Conditional genetic approaches using Cre lines (Pcdh9-Cre, Pdzk1ip1-Cre), axon projection tracing in Sema6A null mice","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Cre-based circuit-specific analysis with axon tracing in KO mice; single lab","pmids":["30076594"],"is_preprint":false},{"year":2019,"finding":"Sema6A-plexin-A2 axis stimulates RANKL-induced osteoclastogenesis via PLCγ-mediated NFATc1 activation: soluble Fc-Sema6A binds plexin-A2 in osteoclast cell lysates; Sema6A treatment enhances RANKL-induced osteoclast differentiation, an effect abolished by plexin-A2 neutralization; Sema6A-plexin-A2 enhances PLCγ activation and downstream NFATc1; pharmacological PLCγ inhibition (U73122) abrogates these effects.","method":"Fc-fusion protein pulldown/Co-IP, osteoclastogenesis differentiation assay, neutralizing antibody, pharmacological inhibitor (U73122), Western blot for PLCγ and NFATc1 activation","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — receptor binding demonstrated by pulldown, functional signaling pathway mapped by pharmacological and neutralizing approaches; single lab","pmids":["30826495"],"is_preprint":false},{"year":2019,"finding":"C11orf46 (ARL14EP) represses Sema6A transcription via SETDB1-mediated repressive chromatin remodeling; C11orf46 haploinsufficiency leads to Sema6a hyperexpression and disrupted transcallosal projections; RNA-guided epigenetic editing (dCas9-SunTag with C11orf46) of Sema6a promoters normalized SEMA6A expression and rescued transcallosal dysconnectivity.","method":"C11orf46 knockdown, gene expression profiling, dCas9-SunTag epigenetic editing, chromatin remodeling assays, in vivo transcallosal projection tracing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic targeting with functional rescue; multiple methods but no biochemical demonstration of direct C11orf46-Sema6a promoter binding in the abstract","pmids":["31511512"],"is_preprint":false},{"year":2022,"finding":"SEMA6A drives actin cytoskeleton remodeling in BRAF-mutant melanoma via RhoA-dependent YAP activation; SEMA6A depletion impairs the SEMA6A/RhoA/YAP axis; dual BRAF/MEK inhibition induces this axis, and SEMA6A depletion rescues efficacy of dabrafenib+trametinib in fibroblast co-culture conditions mimicking tumor microenvironment.","method":"Inducible SEMA6A silencing, RhoA and YAP activity assays, fibroblast-melanoma co-culture model, drug treatment experiments in vitro","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — inducible KD with signaling pathway mapping and co-culture functional rescue; single lab, multiple readouts","pmids":["35440004"],"is_preprint":false},{"year":2023,"finding":"SEMA6A is a direct target gene of HIF-2α in the VHL-HIF-2α axis in ccRCC: ChIP and reporter assays show HIF-2α directly activates SEMA6A transcription in hypoxia. SEMA6A physically interacts with SEC62 and promotes Wnt/β-catenin pathway activation through SEC62-dependent β-catenin stabilization; SEMA6A depletion impairs HIF-2α-induced Wnt/β-catenin activation and ccRCC cell proliferation in vitro and in vivo.","method":"ChIP assay, luciferase reporter assay, Co-immunoprecipitation (SEMA6A–SEC62 interaction), siRNA depletion, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional activation and protein-protein interaction both demonstrated; single lab, multiple orthogonal methods","pmids":["36739418"],"is_preprint":false},{"year":2023,"finding":"Semaphorin-6A, expressed by median eminence-resident oligodendrocytes adjacent to GnRH neuron projections, is required for GnRH neuron innervation and puberty onset; via its receptor Plexin-A2, Sema6A controls median eminence vascular permeability to maintain neuroendocrine homeostasis. A novel pathogenic variant of SEMA6A is identified in patients with delayed puberty.","method":"Sema6A KO mouse analysis, in vitro and in vivo vascular permeability assays, Plexin-A2 receptor requirement established, immunostaining, human genetic variant identification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro and in vivo functional assays with receptor identification and human genetic validation; single report with multiple orthogonal approaches","pmids":["38062045"],"is_preprint":false},{"year":2024,"finding":"The intracellular (cytoplasmic) domain of Sema6A is required for retinal integrity, Müller glia end feet strength, and protection against retinal cell death in zebrafish, but is dispensable for eye size and retinal patterning; this distinguishes reverse signaling (requiring the intracellular domain) from forward signaling functions of Sema6A.","method":"Sema6A morphant rescue experiments in zebrafish with full-length Sema6A vs. intracellular domain-deleted Sema6A (Sema6A-ΔC); retinal histology, Müller glia analysis, cell death quantification","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion rescue in zebrafish with multiple cellular readouts; single lab, directly tests reverse vs. forward signaling","pmids":["38963001"],"is_preprint":false},{"year":2024,"finding":"Sema6A reverse signaling contributes to hippocampal mossy fiber partitioning into SPT and IPT bundles: loss of neuronal Sema6a causes defective MF patterning including incomplete IPT/SPT partition and overextended IPT axons; PlexinA2 controls MF fasciculation via both GAP-dependent and GAP-independent mechanisms, and a genetic interaction between Plxna2 and Ncam1 (but not Plxna4 and Ncam1) was identified for SPT/IPT formation.","method":"Conditional KO mouse lines (neuron-specific Sema6a), PlexinA2 GAP domain mutants, anti-PlexinA2 proximity biotinylation proteomics, double-KO genetic epistasis (Plxna2/Ncam1)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic models with proximity proteomics and epistasis; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.12.15.628586"],"is_preprint":true}],"current_model":"SEMA6A encodes a transmembrane class 6 semaphorin that signals bidirectionally: in trans (forward signaling), it binds PlexinA2 or PlexinA4 receptors on neighboring cells to control granule cell migration, nucleus-centrosome coupling, retinal progenitor interkinetic nuclear migration, eye vesicle cohesion, axon guidance/fasciculation, oligodendrocyte differentiation and myelination, GnRH neuron innervation/vascular permeability, and osteoclastogenesis (via PLCγ/NFATc1); in cis, co-expression of SEMA6A with PlexinA4 on the same cell inhibits trans-ligand binding, modulating guidance responsiveness; reverse signaling through its intracellular domain independently controls retinal integrity and Müller glia function; intracellularly, SEMA6A activates RhoA/YAP and Wnt/β-catenin pathways (through SEC62), and its cytoplasmic tail binds EVL to link semaphorin signaling to actin dynamics."},"narrative":{"mechanistic_narrative":"SEMA6A encodes a transmembrane class 6 semaphorin that acts as a contact-dependent guidance cue coordinating cell migration, axon guidance, and tissue cohesion across multiple developmental contexts [PMID:18327254, PMID:24917502]. In forward (trans) signaling, SEMA6A engages the receptors PlexinA2 or PlexinA4 on neighboring cells: through PlexinA2 it drives cerebellar granule cell migration by coupling the centrosome and nucleus and coordinating motility [PMID:18327254], regulates interkinetic nuclear migration of retinal progenitors [PMID:27301906], maintains eye vesicle cohesion via repulsion [PMID:24917502], inhibits adult sensory and corticospinal axon growth [PMID:22564823], and promotes RANKL-induced osteoclastogenesis through PLCγ-mediated NFATc1 activation [PMID:30826495]; through PlexinA4 it controls autonomous migration of oligodendrocyte precursors [PMID:23376059]. SEMA6A also engages PlexinA4 in cis on the same cell surface, which blocks trans-ligand binding and tunes the repulsive guidance response in a neuron-type-specific manner [PMID:20606624]. Independently of trans receptor binding, SEMA6A reverse signaling through its cytoplasmic domain maintains retinal integrity and Müller glia function and partitions hippocampal mossy fiber bundles [PMID:38963001], and the cytoplasmic tail binds the Ena/VASP-like protein EVL through a zyxin-like C-terminal domain, linking the receptor to actin cytoskeletal dynamics [PMID:10993894]. SEMA6A is required for oligodendrocyte differentiation and myelination [PMID:22777942] and for GnRH neuron innervation and median eminence vascular permeability controlling puberty onset, with a pathogenic SEMA6A variant identified in patients with delayed puberty [PMID:38062045]. Beyond neural development, SEMA6A is co-opted in cancer, where it drives actin remodeling and survival via a RhoA/YAP axis in BRAF-mutant melanoma [PMID:35440004] and promotes ccRCC proliferation as a direct HIF-2α target that activates Wnt/β-catenin signaling through interaction with SEC62 [PMID:36739418].","teleology":[{"year":2000,"claim":"Established the first intracellular partner of SEMA6A, connecting its cytoplasmic tail to actin regulatory machinery and raising the possibility of retrograde/reverse signaling.","evidence":"Yeast two-hybrid, pulldown, and colocalization with C-terminal zyxin-like domain mapping in a heterologous system","pmids":["10993894"],"confidence":"Medium","gaps":["No in vivo demonstration that EVL binding mediates a SEMA6A function","Functional consequence of the interaction for actin dynamics not measured"]},{"year":2005,"claim":"Defined SEMA6A's developmental role by showing it is required non-cell-autonomously for cerebellar granule cell radial migration, framing it as a guidance/migration cue rather than an intrinsic motility factor.","evidence":"Knockout mouse analysis, chimera studies, and cerebellar explant migration assays","pmids":["16205717"],"confidence":"High","gaps":["Receptor not yet identified in this study","Molecular mechanism of nuclear/soma translocation control unresolved"]},{"year":2008,"claim":"Identified PlexinA2 as the functional trans receptor for SEMA6A in granule cell migration and tied the signal to centrosome-nucleus coupling, supplying the receptor missing from earlier loss-of-function work.","evidence":"Knockout and ENU binding-abrogating mutant, chimera studies, and time-lapse imaging of centrosome-nucleus coupling","pmids":["18327254"],"confidence":"High","gaps":["Downstream cytoskeletal effectors of PlexinA2 not defined","Whether reverse signaling contributes to this phenotype not tested"]},{"year":2010,"claim":"Revealed that SEMA6A and PlexinA4 can interact in cis on the same cell to suppress trans-ligand binding, explaining how guidance responsiveness is tuned in a neuron-type-specific manner.","evidence":"Heterologous cis/trans binding assays plus sensory neuron collapse assays with SEMA6A knockout and PlexinA4 rescue","pmids":["20606624"],"confidence":"High","gaps":["Structural basis of cis vs trans interaction not resolved","How the cis interaction is regulated developmentally unknown"]},{"year":2012,"claim":"Extended SEMA6A function to glial biology and adult CNS repair, showing it is an oligodendrocyte-derived PlexinA2-dependent inhibitor of axon growth and a requirement for myelination.","evidence":"In vitro sensory neuron inhibition with PlexinA2 KO, pyramidotomy axon-sprouting model, and oligodendrocyte/DRG co-culture myelination assays","pmids":["22564823","22777942"],"confidence":"High","gaps":["Signaling pathway linking SEMA6A to myelination program not defined","Whether the axon-inhibitory and myelination roles share a mechanism unclear"]},{"year":2013,"claim":"Showed SEMA6A controls oligodendrocyte precursor migration through PlexinA4-mediated cell segregation, distinguishing a PlexinA4 receptor route in glial cells.","evidence":"siRNA knockdown in an OPC cell line with migration and co-culture segregation assays","pmids":["23376059"],"confidence":"Medium","gaps":["Cell-line-based; not validated in primary OPCs in vivo","Intracellular signaling downstream not addressed"]},{"year":2014,"claim":"Generalized SEMA6A/PlexinA2 repulsion as a tissue-cohesion mechanism and refined its role to specific migration phases of later-born granule cells.","evidence":"Zebrafish morpholino knockdown with epistasis rescue and time-lapse imaging; cerebellar slice electroporation with live imaging in KO mice","pmids":["24917502","25284064"],"confidence":"High","gaps":["Conservation of the cohesion mechanism in mammalian eye not directly tested","Effectors translating repulsion into cell positioning unknown"]},{"year":2015,"claim":"Implicated SEMA6A in cancer cell biology, showing it regulates actin cytoskeleton, anchorage-independent growth, and invasion downstream of BRAF signaling in melanoma.","evidence":"siRNA silencing and overexpression with cytoskeletal imaging and invasion/anchorage assays in melanoma lines","pmids":["25576923"],"confidence":"Medium","gaps":["Receptor/signaling intermediary not yet identified in this study","Single-lab cell-line work without in vivo validation"]},{"year":2016,"claim":"Demonstrated SEMA6A/PlexinA2 control interkinetic nuclear migration in retinal progenitors, broadening the nuclear-migration role beyond cerebellum.","evidence":"Time-lapse videomicroscopy of embryonic retina in SEMA6A and PlexinA2 knockout mice","pmids":["27301906"],"confidence":"Medium","gaps":["Molecular link to the nuclear migration machinery not defined","Forward vs reverse signaling contribution not separated"]},{"year":2017,"claim":"Established post-transcriptional control of SEMA6A by microRNAs and its role as a repulsive vascular signal, linking SEMA6A dosage to apoptosis in oral cancer and to pericyte recruitment in endothelium.","evidence":"Luciferase 3'-UTR reporter assays for miR-203 and miR-27b with overexpression/inhibition and pericyte adhesion rescue by SEMA6A silencing","pmids":["28982852","28453731"],"confidence":"Medium","gaps":["Receptor mediating the pericyte repulsion not identified","Physiological relevance of miRNA regulation in vivo limited"]},{"year":2018,"claim":"Mapped SEMA6A to specific circuit wiring, showing it is required for accessory optic system axon projections from the MTN to the NOT.","evidence":"Cre-driver conditional analysis and axon tracing in SEMA6A null mice","pmids":["30076594"],"confidence":"Medium","gaps":["Receptor and signaling direction not addressed","Whether defect is guidance vs fasciculation unresolved"]},{"year":2019,"claim":"Defined a SEMA6A/PlexinA2 forward-signaling cascade in osteoclastogenesis and identified upstream epigenetic repression of Sema6a by C11orf46/SETDB1 with relevance to transcallosal wiring.","evidence":"Fc-Sema6A pulldown with PLCγ/NFATc1 pathway dissection by inhibitor/neutralization; C11orf46 knockdown and dCas9-SunTag epigenetic editing with projection tracing","pmids":["30826495","31511512"],"confidence":"Medium","gaps":["Direct C11orf46-Sema6a promoter binding not biochemically shown","Whether PLCγ/NFATc1 is engaged in neural contexts unknown"]},{"year":2023,"claim":"Connected SEMA6A to neuroendocrine physiology and human disease, and revealed an intracellular oncogenic role through SEC62 and Wnt/β-catenin.","evidence":"SEMA6A KO mouse GnRH/vascular permeability assays with PlexinA2 requirement and a human pathogenic variant; ChIP/reporter HIF-2α activation and SEMA6A-SEC62 Co-IP with xenografts in ccRCC","pmids":["38062045","36739418"],"confidence":"High","gaps":["How SEMA6A-SEC62 binding stabilizes β-catenin mechanistically unresolved","Causality of the human SEMA6A variant beyond association not fully established"]},{"year":2024,"claim":"Genetically separated SEMA6A reverse signaling from forward signaling, showing the cytoplasmic domain is specifically required for retinal integrity, Müller glia function, and hippocampal mossy fiber partitioning.","evidence":"Zebrafish intracellular-domain-deletion rescue with retinal/Müller glia readouts; conditional neuronal KO and PlexinA2 GAP mutants with proximity proteomics and Plxna2/Ncam1 epistasis (preprint)","pmids":["38963001","bio_10.1101_2024.12.15.628586"],"confidence":"Medium","gaps":["Intracellular effectors of reverse signaling in vivo not fully defined","Mossy fiber findings from a preprint not yet peer-reviewed"]},{"year":null,"claim":"How the cytoplasmic domain transduces reverse signaling into actin and transcriptional outputs, and how cells switch between cis-inhibitory, trans-forward, and reverse signaling modes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating cis/trans/reverse signaling states","Direct biochemical chain from cytoplasmic tail (EVL) to cytoskeletal/transcriptional output unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,7,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,7,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,14,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,18]}],"complexes":[],"partners":["PLXNA2","PLXNA4","EVL","SEC62"],"other_free_text":[]}},"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 gland","ntpm":60.3},{"tissue":"brain","ntpm":54.1}],"url":"https://www.proteinatlas.org/search/SEMA6A"},"hgnc":{"alias_symbol":["KIAA1368","SEMA6A1","SEMA","HT018"],"prev_symbol":["SEMAQ"]},"alphafold":{"accession":"Q9H2E6","domains":[{"cath_id":"3.30.1680.10","chopping":"516-568","consensus_level":"medium","plddt":91.3464,"start":516,"end":568}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2E6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2E6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2E6-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA6A","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA6A"},"sequence":{"accession":"Q9H2E6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2E6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2E6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2E6"}},"corpus_meta":[{"pmid":"23740775","id":"PMC_23740775","title":"Association 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Inhibits Lung Cancer Progression through the miR-3175/SEMA6A Axis.","date":"2023","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/36734856","citation_count":6,"is_preprint":false},{"pmid":"30826495","id":"PMC_30826495","title":"Sema6A-plexin-A2 axis stimulates RANKL-induced osteoclastogenesis through PLCγ-mediated NFATc1 activation.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30826495","citation_count":5,"is_preprint":false},{"pmid":"38963001","id":"PMC_38963001","title":"The intracellular domain of Sema6A is essential for development of the zebrafish retina.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/38963001","citation_count":2,"is_preprint":false},{"pmid":"41259456","id":"PMC_41259456","title":"SEMA6A overexpression inhibited tumor growth and metastasis in colorectal cancer.","date":"2025","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/41259456","citation_count":0,"is_preprint":false},{"pmid":"37434634","id":"PMC_37434634","title":"Comprehensive Analysis to Identify LINC00511-hsa-miR-625-5p-SEMA6A Pathway Fuels Progression of Skin Cutaneous Melanoma.","date":"2023","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37434634","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.15.628586","title":"Diverse and Location-Specific Roles of PlexinA2, PlexinA4, and NCAM in Developing Hippocampal Mossy Fibers","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.15.628586","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.27.615250","title":"A  <i>MEF2C</i>  transcription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney 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\"SEMA6A-1 (SEMA6A) directly binds EVL (Ena/VASP-like protein) via a novel carboxyl-terminal zyxin-like domain; SEMA6A-1 colocalizes with EVL, and this interaction is selective (does not extend to other Ena/VASP family members Mena/VASP), suggesting a role for SEMA6A in retrograde signaling linked to actin/cytoskeletal dynamics.\",\n      \"method\": \"Yeast two-hybrid, pulldown/binding assay, colocalization in heterologous system; mutagenesis of the zyxin-like C-terminal domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated by pulldown and colocalization with domain mapping; single lab, two orthogonal methods\",\n      \"pmids\": [\"10993894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sema6A is required for cerebellar granule cell migration: Sema6A-deficient mice show ectopic granule cells remaining in the molecular layer, and analysis of chimeras demonstrates this function is primarily non-cell-autonomous. Sema6A controls initiation of radial migration, likely via modulation of nuclear/soma translocation.\",\n      \"method\": \"Knockout mouse analysis, mouse chimera studies, cerebellar explant migration and neurite outgrowth assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods, replicated in independent follow-up studies\",\n      \"pmids\": [\"16205717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PlexinA2 is the receptor for Sema6A in migrating cerebellar granule cells: PlexinA2-deficient mice phenocopy Sema6A mutants; an ENU-induced single amino acid substitution in the semaphorin-binding domain of PlexinA2 abolishes Sema6A binding; chimera studies show PlexinA2 acts cell-autonomously; Sema6A/PlexinA2 signaling controls nucleus-centrosome coupling and coordinated motility during migration.\",\n      \"method\": \"Homologous recombination knockout, ENU mutagenesis, binding assay (Sema6A–PlexinA2 interaction), mouse chimera studies, time-lapse video microscopy of centrosome–nucleus coupling\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding abrogation by mutagenesis, genetic epistasis, chimera experiments, and live imaging; multiple orthogonal methods\",\n      \"pmids\": [\"18327254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sema6A engages in a cis interaction with its receptor PlexinA4 on the same cell surface, which inhibits binding of exogenous Sema6A ligand in trans and thereby suppresses the repulsive response. This cis Sema6A–PlexinA4 interaction differentially modulates axon guidance responsiveness in sympathetic vs. sensory neurons.\",\n      \"method\": \"Heterologous expression systems for cis/trans binding assays, sensory neuron collapse assays with Sema6A knockout (gain of sensitivity), PlexinA4-dependent rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding assays in heterologous systems combined with neuronal functional assays and genetic loss-of-function; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"20606624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oligodendrocyte-expressed Sema6A inhibits adult axon growth via PlexinA2: adult sensory neurons are inhibited by Sema6A in a PlexinA2-dependent manner (complete protection in PlexinA2−/− cultures); PlexinA2−/− mice show enhanced corticospinal axon sprouting and improved functional recovery after pyramidotomy.\",\n      \"method\": \"In vitro sensory neuron inhibition assay with PlexinA2 KO, adult mouse pyramidotomy model with axonal sprouting quantification and behavioral testing\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro receptor requirement demonstrated with genetic knockout plus in vivo corticospinal lesion model with behavioral and anatomical readouts\",\n      \"pmids\": [\"22564823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema6A expressed by myelinating oligodendrocytes is required for oligodendrocyte differentiation and myelination: Sema6A-deficient mice show delayed oligodendrocyte differentiation, delayed node of Ranvier development, and reduced MBP expression. In vitro, Sema6A-null oligodendrocytes show morphological defects and impaired myelination in DRG co-culture.\",\n      \"method\": \"Knockout mouse analysis (optic nerve, anterior commissure), purified oligodendrocyte differentiation assay, myelinating co-culture with DRG neurons\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo and in vitro readouts with KO mice, replicated across cell-autonomous and co-culture contexts\",\n      \"pmids\": [\"22777942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sema6A expressed in oligodendrocyte precursor cells (OPCs) controls their autonomous migration via ligand-receptor interaction with PlexinA4 on surrounding cells: Sema6A knockdown in OPC line FBD-102b reduces migration, and Plexin-A4-expressing cells segregate from Sema6A-expressing cells in co-culture.\",\n      \"method\": \"siRNA knockdown in OPC cell line, in vitro migration assay, co-culture segregation assay, semaphorin gradient assay with PlexinA4 knockdown\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell line knockdown with migration assay and co-culture; single lab, two complementary functional approaches\",\n      \"pmids\": [\"23376059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sema6A and PlexinA2 are required for eye vesicle cohesion in zebrafish: knockdown of either disrupts vesicle integrity, with eye progenitors failing to enter or delaminating from the eye epithelium. Epistasis (simultaneous knockdown of both) rescues vesicle integrity, placing Sema6A–PlexinA2-mediated repulsion as the mechanism maintaining tissue cohesion.\",\n      \"method\": \"Morpholino knockdown in zebrafish, time-lapse microscopy, explant experiments, double-knockdown epistasis rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — time-lapse imaging with genetic epistasis rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24917502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Time-lapse analysis of cerebellar slice electroporation confirms that Sema6A and PlexinA2 loss preferentially perturbs migration of later-born granule cells, and defects in tangential migration in bipolar granule cells precede the switch to radial migration; Sema6A loss does not perturb radial migration itself.\",\n      \"method\": \"Cerebellar slice model, in utero/ex vivo electroporation, time-lapse video microscopy in Sema6A and PlexinA2 knockout mice\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging in genetic KO slices; single lab, direct observation of migration phases\",\n      \"pmids\": [\"25284064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sema6A silencing in BRAFV600E melanoma cells causes cytoskeletal remodeling with loss of stress fibers leading to cell death, loss of anchorage-independent growth, and inhibited chemotaxis/invasion; forced Sema6A overexpression in NRASQ61R cells induces anchorage-independent growth and invasiveness, indicating Sema6A regulates actin cytoskeleton and cell survival downstream of BRAF signaling.\",\n      \"method\": \"siRNA silencing, forced overexpression, cytoskeletal imaging, anchorage-independent growth assay, chemotaxis/invasion assay in melanoma cell lines\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss- and gain-of-function with multiple cellular readouts; single lab\",\n      \"pmids\": [\"25576923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sema6A/PlexinA2 signaling regulates interkinetic nuclear migration of retinal progenitor cells (RPCs): in Sema6A and PlexinA2 knockout mice, RPC migration is blocked at the apical side of the neuroblastic layer, as shown by time-lapse videomicroscopy.\",\n      \"method\": \"Knockout mouse analysis, time-lapse videomicroscopy of embryonic retina\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging in genetic KO mice; single lab, direct demonstration of migration block\",\n      \"pmids\": [\"27301906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEMA6A is a direct target of miR-203: luciferase reporter assay confirmed miR-203 directly targets the SEMA6A 3'-UTR, suppressing SEMA6A mRNA and protein levels; miR-203-mediated SEMA6A downregulation promotes apoptosis in oral cancer cells.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, miRNA overexpression, Western blot, miRNA array\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct 3'-UTR targeting validated by luciferase assay with functional apoptosis readout; single lab\",\n      \"pmids\": [\"28982852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEMA6A is repressed post-transcriptionally by miR-27b in endothelial cells; miR-27b overexpression represses SEMA6A (and SEMA6D), and silencing of SEMA6A rescues reduced pericyte adhesion caused by miR-27 inhibition, demonstrating that SEMA6A acts as a repulsive signal limiting pericyte recruitment.\",\n      \"method\": \"miR-27b overexpression/inhibition in endothelial cells, pericyte adhesion and co-culture assays, siRNA silencing of SEMA6A, in vivo LNA antisense oligonucleotide inhibition\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue of pericyte adhesion phenotype by SEMA6A silencing, combined in vitro and in vivo approaches; single lab\",\n      \"pmids\": [\"28453731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sema6A is required for formation of axonal projections from the medial terminal nucleus (MTN) to the nucleus of the optic tract (NOT) in the accessory optic system; using Cre-driver lines, Sema6A was shown to be necessary for establishing AOS connections in multiple locations.\",\n      \"method\": \"Conditional genetic approaches using Cre lines (Pcdh9-Cre, Pdzk1ip1-Cre), axon projection tracing in Sema6A null mice\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Cre-based circuit-specific analysis with axon tracing in KO mice; single lab\",\n      \"pmids\": [\"30076594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sema6A-plexin-A2 axis stimulates RANKL-induced osteoclastogenesis via PLCγ-mediated NFATc1 activation: soluble Fc-Sema6A binds plexin-A2 in osteoclast cell lysates; Sema6A treatment enhances RANKL-induced osteoclast differentiation, an effect abolished by plexin-A2 neutralization; Sema6A-plexin-A2 enhances PLCγ activation and downstream NFATc1; pharmacological PLCγ inhibition (U73122) abrogates these effects.\",\n      \"method\": \"Fc-fusion protein pulldown/Co-IP, osteoclastogenesis differentiation assay, neutralizing antibody, pharmacological inhibitor (U73122), Western blot for PLCγ and NFATc1 activation\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — receptor binding demonstrated by pulldown, functional signaling pathway mapped by pharmacological and neutralizing approaches; single lab\",\n      \"pmids\": [\"30826495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C11orf46 (ARL14EP) represses Sema6A transcription via SETDB1-mediated repressive chromatin remodeling; C11orf46 haploinsufficiency leads to Sema6a hyperexpression and disrupted transcallosal projections; RNA-guided epigenetic editing (dCas9-SunTag with C11orf46) of Sema6a promoters normalized SEMA6A expression and rescued transcallosal dysconnectivity.\",\n      \"method\": \"C11orf46 knockdown, gene expression profiling, dCas9-SunTag epigenetic editing, chromatin remodeling assays, in vivo transcallosal projection tracing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic targeting with functional rescue; multiple methods but no biochemical demonstration of direct C11orf46-Sema6a promoter binding in the abstract\",\n      \"pmids\": [\"31511512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEMA6A drives actin cytoskeleton remodeling in BRAF-mutant melanoma via RhoA-dependent YAP activation; SEMA6A depletion impairs the SEMA6A/RhoA/YAP axis; dual BRAF/MEK inhibition induces this axis, and SEMA6A depletion rescues efficacy of dabrafenib+trametinib in fibroblast co-culture conditions mimicking tumor microenvironment.\",\n      \"method\": \"Inducible SEMA6A silencing, RhoA and YAP activity assays, fibroblast-melanoma co-culture model, drug treatment experiments in vitro\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — inducible KD with signaling pathway mapping and co-culture functional rescue; single lab, multiple readouts\",\n      \"pmids\": [\"35440004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEMA6A is a direct target gene of HIF-2α in the VHL-HIF-2α axis in ccRCC: ChIP and reporter assays show HIF-2α directly activates SEMA6A transcription in hypoxia. SEMA6A physically interacts with SEC62 and promotes Wnt/β-catenin pathway activation through SEC62-dependent β-catenin stabilization; SEMA6A depletion impairs HIF-2α-induced Wnt/β-catenin activation and ccRCC cell proliferation in vitro and in vivo.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, Co-immunoprecipitation (SEMA6A–SEC62 interaction), siRNA depletion, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional activation and protein-protein interaction both demonstrated; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36739418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Semaphorin-6A, expressed by median eminence-resident oligodendrocytes adjacent to GnRH neuron projections, is required for GnRH neuron innervation and puberty onset; via its receptor Plexin-A2, Sema6A controls median eminence vascular permeability to maintain neuroendocrine homeostasis. A novel pathogenic variant of SEMA6A is identified in patients with delayed puberty.\",\n      \"method\": \"Sema6A KO mouse analysis, in vitro and in vivo vascular permeability assays, Plexin-A2 receptor requirement established, immunostaining, human genetic variant identification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro and in vivo functional assays with receptor identification and human genetic validation; single report with multiple orthogonal approaches\",\n      \"pmids\": [\"38062045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intracellular (cytoplasmic) domain of Sema6A is required for retinal integrity, Müller glia end feet strength, and protection against retinal cell death in zebrafish, but is dispensable for eye size and retinal patterning; this distinguishes reverse signaling (requiring the intracellular domain) from forward signaling functions of Sema6A.\",\n      \"method\": \"Sema6A morphant rescue experiments in zebrafish with full-length Sema6A vs. intracellular domain-deleted Sema6A (Sema6A-ΔC); retinal histology, Müller glia analysis, cell death quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion rescue in zebrafish with multiple cellular readouts; single lab, directly tests reverse vs. forward signaling\",\n      \"pmids\": [\"38963001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sema6A reverse signaling contributes to hippocampal mossy fiber partitioning into SPT and IPT bundles: loss of neuronal Sema6a causes defective MF patterning including incomplete IPT/SPT partition and overextended IPT axons; PlexinA2 controls MF fasciculation via both GAP-dependent and GAP-independent mechanisms, and a genetic interaction between Plxna2 and Ncam1 (but not Plxna4 and Ncam1) was identified for SPT/IPT formation.\",\n      \"method\": \"Conditional KO mouse lines (neuron-specific Sema6a), PlexinA2 GAP domain mutants, anti-PlexinA2 proximity biotinylation proteomics, double-KO genetic epistasis (Plxna2/Ncam1)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic models with proximity proteomics and epistasis; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.15.628586\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEMA6A encodes a transmembrane class 6 semaphorin that signals bidirectionally: in trans (forward signaling), it binds PlexinA2 or PlexinA4 receptors on neighboring cells to control granule cell migration, nucleus-centrosome coupling, retinal progenitor interkinetic nuclear migration, eye vesicle cohesion, axon guidance/fasciculation, oligodendrocyte differentiation and myelination, GnRH neuron innervation/vascular permeability, and osteoclastogenesis (via PLCγ/NFATc1); in cis, co-expression of SEMA6A with PlexinA4 on the same cell inhibits trans-ligand binding, modulating guidance responsiveness; reverse signaling through its intracellular domain independently controls retinal integrity and Müller glia function; intracellularly, SEMA6A activates RhoA/YAP and Wnt/β-catenin pathways (through SEC62), and its cytoplasmic tail binds EVL to link semaphorin signaling to actin dynamics.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA6A encodes a transmembrane class 6 semaphorin that acts as a contact-dependent guidance cue coordinating cell migration, axon guidance, and tissue cohesion across multiple developmental contexts [#2, #7]. In forward (trans) signaling, SEMA6A engages the receptors PlexinA2 or PlexinA4 on neighboring cells: through PlexinA2 it drives cerebellar granule cell migration by coupling the centrosome and nucleus and coordinating motility [#2], regulates interkinetic nuclear migration of retinal progenitors [#10], maintains eye vesicle cohesion via repulsion [#7], inhibits adult sensory and corticospinal axon growth [#4], and promotes RANKL-induced osteoclastogenesis through PLC\\u03b3-mediated NFATc1 activation [#14]; through PlexinA4 it controls autonomous migration of oligodendrocyte precursors [#6]. SEMA6A also engages PlexinA4 in cis on the same cell surface, which blocks trans-ligand binding and tunes the repulsive guidance response in a neuron-type-specific manner [#3]. Independently of trans receptor binding, SEMA6A reverse signaling through its cytoplasmic domain maintains retinal integrity and M\\u00fcller glia function and partitions hippocampal mossy fiber bundles [#19], and the cytoplasmic tail binds the Ena/VASP-like protein EVL through a zyxin-like C-terminal domain, linking the receptor to actin cytoskeletal dynamics [#0]. SEMA6A is required for oligodendrocyte differentiation and myelination [#5] and for GnRH neuron innervation and median eminence vascular permeability controlling puberty onset, with a pathogenic SEMA6A variant identified in patients with delayed puberty [#18]. Beyond neural development, SEMA6A is co-opted in cancer, where it drives actin remodeling and survival via a RhoA/YAP axis in BRAF-mutant melanoma [#16] and promotes ccRCC proliferation as a direct HIF-2\\u03b1 target that activates Wnt/\\u03b2-catenin signaling through interaction with SEC62 [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first intracellular partner of SEMA6A, connecting its cytoplasmic tail to actin regulatory machinery and raising the possibility of retrograde/reverse signaling.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, and colocalization with C-terminal zyxin-like domain mapping in a heterologous system\",\n      \"pmids\": [\"10993894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo demonstration that EVL binding mediates a SEMA6A function\", \"Functional consequence of the interaction for actin dynamics not measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined SEMA6A's developmental role by showing it is required non-cell-autonomously for cerebellar granule cell radial migration, framing it as a guidance/migration cue rather than an intrinsic motility factor.\",\n      \"evidence\": \"Knockout mouse analysis, chimera studies, and cerebellar explant migration assays\",\n      \"pmids\": [\"16205717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor not yet identified in this study\", \"Molecular mechanism of nuclear/soma translocation control unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified PlexinA2 as the functional trans receptor for SEMA6A in granule cell migration and tied the signal to centrosome-nucleus coupling, supplying the receptor missing from earlier loss-of-function work.\",\n      \"evidence\": \"Knockout and ENU binding-abrogating mutant, chimera studies, and time-lapse imaging of centrosome-nucleus coupling\",\n      \"pmids\": [\"18327254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cytoskeletal effectors of PlexinA2 not defined\", \"Whether reverse signaling contributes to this phenotype not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed that SEMA6A and PlexinA4 can interact in cis on the same cell to suppress trans-ligand binding, explaining how guidance responsiveness is tuned in a neuron-type-specific manner.\",\n      \"evidence\": \"Heterologous cis/trans binding assays plus sensory neuron collapse assays with SEMA6A knockout and PlexinA4 rescue\",\n      \"pmids\": [\"20606624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cis vs trans interaction not resolved\", \"How the cis interaction is regulated developmentally unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended SEMA6A function to glial biology and adult CNS repair, showing it is an oligodendrocyte-derived PlexinA2-dependent inhibitor of axon growth and a requirement for myelination.\",\n      \"evidence\": \"In vitro sensory neuron inhibition with PlexinA2 KO, pyramidotomy axon-sprouting model, and oligodendrocyte/DRG co-culture myelination assays\",\n      \"pmids\": [\"22564823\", \"22777942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway linking SEMA6A to myelination program not defined\", \"Whether the axon-inhibitory and myelination roles share a mechanism unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SEMA6A controls oligodendrocyte precursor migration through PlexinA4-mediated cell segregation, distinguishing a PlexinA4 receptor route in glial cells.\",\n      \"evidence\": \"siRNA knockdown in an OPC cell line with migration and co-culture segregation assays\",\n      \"pmids\": [\"23376059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line-based; not validated in primary OPCs in vivo\", \"Intracellular signaling downstream not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Generalized SEMA6A/PlexinA2 repulsion as a tissue-cohesion mechanism and refined its role to specific migration phases of later-born granule cells.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with epistasis rescue and time-lapse imaging; cerebellar slice electroporation with live imaging in KO mice\",\n      \"pmids\": [\"24917502\", \"25284064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the cohesion mechanism in mammalian eye not directly tested\", \"Effectors translating repulsion into cell positioning unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated SEMA6A in cancer cell biology, showing it regulates actin cytoskeleton, anchorage-independent growth, and invasion downstream of BRAF signaling in melanoma.\",\n      \"evidence\": \"siRNA silencing and overexpression with cytoskeletal imaging and invasion/anchorage assays in melanoma lines\",\n      \"pmids\": [\"25576923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling intermediary not yet identified in this study\", \"Single-lab cell-line work without in vivo validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated SEMA6A/PlexinA2 control interkinetic nuclear migration in retinal progenitors, broadening the nuclear-migration role beyond cerebellum.\",\n      \"evidence\": \"Time-lapse videomicroscopy of embryonic retina in SEMA6A and PlexinA2 knockout mice\",\n      \"pmids\": [\"27301906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link to the nuclear migration machinery not defined\", \"Forward vs reverse signaling contribution not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established post-transcriptional control of SEMA6A by microRNAs and its role as a repulsive vascular signal, linking SEMA6A dosage to apoptosis in oral cancer and to pericyte recruitment in endothelium.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter assays for miR-203 and miR-27b with overexpression/inhibition and pericyte adhesion rescue by SEMA6A silencing\",\n      \"pmids\": [\"28982852\", \"28453731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the pericyte repulsion not identified\", \"Physiological relevance of miRNA regulation in vivo limited\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped SEMA6A to specific circuit wiring, showing it is required for accessory optic system axon projections from the MTN to the NOT.\",\n      \"evidence\": \"Cre-driver conditional analysis and axon tracing in SEMA6A null mice\",\n      \"pmids\": [\"30076594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling direction not addressed\", \"Whether defect is guidance vs fasciculation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a SEMA6A/PlexinA2 forward-signaling cascade in osteoclastogenesis and identified upstream epigenetic repression of Sema6a by C11orf46/SETDB1 with relevance to transcallosal wiring.\",\n      \"evidence\": \"Fc-Sema6A pulldown with PLC\\u03b3/NFATc1 pathway dissection by inhibitor/neutralization; C11orf46 knockdown and dCas9-SunTag epigenetic editing with projection tracing\",\n      \"pmids\": [\"30826495\", \"31511512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct C11orf46-Sema6a promoter binding not biochemically shown\", \"Whether PLC\\u03b3/NFATc1 is engaged in neural contexts unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SEMA6A to neuroendocrine physiology and human disease, and revealed an intracellular oncogenic role through SEC62 and Wnt/\\u03b2-catenin.\",\n      \"evidence\": \"SEMA6A KO mouse GnRH/vascular permeability assays with PlexinA2 requirement and a human pathogenic variant; ChIP/reporter HIF-2\\u03b1 activation and SEMA6A-SEC62 Co-IP with xenografts in ccRCC\",\n      \"pmids\": [\"38062045\", \"36739418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SEMA6A-SEC62 binding stabilizes \\u03b2-catenin mechanistically unresolved\", \"Causality of the human SEMA6A variant beyond association not fully established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetically separated SEMA6A reverse signaling from forward signaling, showing the cytoplasmic domain is specifically required for retinal integrity, M\\u00fcller glia function, and hippocampal mossy fiber partitioning.\",\n      \"evidence\": \"Zebrafish intracellular-domain-deletion rescue with retinal/M\\u00fcller glia readouts; conditional neuronal KO and PlexinA2 GAP mutants with proximity proteomics and Plxna2/Ncam1 epistasis (preprint)\",\n      \"pmids\": [\"38963001\", \"bio_10.1101_2024.12.15.628586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular effectors of reverse signaling in vivo not fully defined\", \"Mossy fiber findings from a preprint not yet peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cytoplasmic domain transduces reverse signaling into actin and transcriptional outputs, and how cells switch between cis-inhibitory, trans-forward, and reverse signaling modes, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating cis/trans/reverse signaling states\", \"Direct biochemical chain from cytoplasmic tail (EVL) to cytoskeletal/transcriptional output unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 7, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 7, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 14, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLXNA2\",\n      \"PLXNA4\",\n      \"EVL\",\n      \"SEC62\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}