Affinage

SEMA3A

Semaphorin-3A · UniProt Q14563

Length
771 aa
Mass
88.9 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEMA3A is a secreted semaphorin that functions as a chemorepulsive guidance cue for axons, a regulator of vascular patterning, and a modulator of bone homeostasis, acting through a 2:2:2 holoreceptor complex of Neuropilin-1 and PlexinA1/A4 that was resolved by cryo-EM at 3.7 Å (PMID:34039996). Receptor engagement activates a cascade involving FARP2-mediated Rac1 activation, Rnd1/R-Ras downregulation, PTEN-dependent GSK-3 activation, PlexinA1 Rap1 GAP activity, and CRMP1/doublecortin phosphorylation, collectively remodeling actin and microtubule cytoskeleton to collapse growth cones (PMID:16286926, PMID:16495486, PMID:30353093, PMID:25358863), while a mechanistically distinct integrin/FAK-dependent pathway mediates SEMA3A's dendrite growth-promoting effects (PMID:19454481). Beyond neural guidance — including patterning of sympathetic cardiac innervation, inner ear afferents, and cerebellar circuits (PMID:17417650, PMID:23991118, PMID:23602477) — SEMA3A maintains corneal avascularity by competing with VEGF165 for NRP1 binding (PMID:24809797, PMID:16684957), regulates bone mass through sensory nerve innervation and an osteocyte autocrine survival loop via NRP1-sGC-cGMP signaling (PMID:23644455, PMID:30661929), directly inhibits the Kv4.3 potassium channel by physical binding (PMID:24963029), and positions tumor-associated macrophages through PlexinA1/A4-dependent signaling (PMID:24332039).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Establishing the intracellular effectors of SEMA3A-induced growth cone collapse: Rac1 was identified as a required downstream mediator, with its effector-binding domain (aa 17–32) engaging PAK to drive collapse, distinguishing the mechanism from N-WASP-dependent pathways.

    Evidence Cell-permeable peptide competition and growth cone collapse assays in neuronal cultures

    PMID:10508610

    Open questions at the time
    • Rac1 activation versus inactivation kinetics not resolved
    • Identity of the GEF activating Rac1 unknown at this time
  2. 2000 High

    Defining the receptor complex: L1 CAM was identified as a component of the Sema3A receptor through direct association with NRP1, and NRP1-dependent inhibition of lung branching morphogenesis established that SEMA3A signaling extends beyond neural guidance.

    Evidence Co-immunoprecipitation, L1-deficient mouse axon repulsion assays, and fetal lung explant cultures with Nrp1-null controls

    PMID:10985345 PMID:11025205

    Open questions at the time
    • Signal-transducing co-receptor (Plexin) identity not yet established in these assays
    • Whether L1 modulates all SEMA3A responses or only specific contexts unclear
  3. 2002 High

    Demonstrating SEMA3A's in vivo role in sympathetic nervous system morphogenesis: NRP1- and Sema3A-null embryos showed displacement of sympathetic neuron precursors, establishing a non-redundant guidance function for SEMA3A in autonomic development.

    Evidence Sema3A and Nrp1 knockout mice with in vitro migration assays of receptor-null neurons

    PMID:11830568

    Open questions at the time
    • Plexin co-receptor identity for sympathetic guidance not determined
    • Downstream signaling in sympathetic neurons not addressed
  4. 2005 High

    Resolving the GEF-to-GAP signaling cascade: FARP2 was identified as the Rac GEF whose release from PlexinA1 upon Sema3A binding initiates a sequential pathway through Rnd1 recruitment, R-Ras inactivation, and PIPKIγ661 sequestration from talin.

    Evidence Pulldown, co-immunoprecipitation, GEF activity assays, mutagenesis, and collapse assay in neurons

    PMID:16286926

    Open questions at the time
    • Structural basis for FARP2 release from PlexinA1 unknown
    • Whether FARP2 pathway operates in non-neuronal SEMA3A signaling untested
  5. 2006 High

    Identifying PTEN as a critical phosphatase node and establishing SEMA3A's anti-angiogenic mechanism: PTEN was shown to accumulate at the growth cone membrane after SEMA3A exposure to suppress PI3K and activate GSK-3, while competitive NRP1 binding with higher affinity than VEGF165 was demonstrated to restrain angiogenesis.

    Evidence Live-cell imaging, phospho-PTEN/GSK-3 immunoblots, pharmacological inhibition in neurons; co-IP with anti-NRP1 antibody and endothelial functional assays

    PMID:16495486 PMID:16684957

    Open questions at the time
    • How PTEN is recruited to the membrane downstream of PlexinA not resolved
    • Quantitative NRP1-binding competition kinetics between SEMA3A and VEGF165 in vivo unknown
  6. 2007 High

    Extending SEMA3A function to cardiac innervation patterning and identifying ERM/CHL1 as additional cytoplasmic effectors: SEMA3A expressed in Purkinje fibers was shown to establish the epicardial-to-endocardial sympathetic gradient, while CHL1-mediated ERM recruitment and ERM-dependent NRP1/L1 internalization were linked to growth cone collapse.

    Evidence Sema3A knockout and cardiac-specific overexpression with electrophysiology; CHL1 mutagenesis and phospho-ERM imaging in cortical neurons

    PMID:17417650 PMID:17995939 PMID:18651636

    Open questions at the time
    • How cardiac arrhythmias arise mechanistically from innervation imbalance not fully delineated
    • ERM phosphoregulation upstream of SEMA3A signaling unresolved
  7. 2009 High

    Demonstrating that SEMA3A triggers opposite responses in axons versus dendrites through distinct pathways: integrin/FAK-dependent signaling drives dendrite growth while an integrin-independent mechanism mediates axonal collapse.

    Evidence Conditional β1-integrin and FAK knockout hippocampal neurons with differential phosphorylation readouts

    PMID:19454481 PMID:20159040

    Open questions at the time
    • How NRP1/PlexinA differentially engages integrin-dependent versus -independent cascades is mechanistically unclear
    • Site-specific FAK phosphorylation–phenotype mapping incomplete
  8. 2010 High

    Mapping a critical receptor-activating residue: forward genetic identification of the K108N mutation showed that NRP1 binding is necessary but insufficient for signaling, establishing that a distinct Sema3A surface mediates holoreceptor activation.

    Evidence Forward genetic screen in mice with in vitro binding and collapse assays

    PMID:20410128

    Open questions at the time
    • Structural mechanism by which K108 engages PlexinA not resolved until cryo-EM
    • Whether K108 contacts NRP1 or PlexinA directly was unknown
  9. 2013 High

    Broadening SEMA3A's physiological roles to bone, tumor immunity, cerebellar wiring, and inner ear: neuron-derived Sema3A regulates bone mass via sensory innervation patterning; hypoxia-induced Sema3A positions tumor-associated macrophages via PlexinA1/A4-VEGFR1; sGC/FYN pathway mediates cerebellar basket axon branching; and Sema3A patterns inner ear afferents through NRP1/PlexinA1/A3.

    Evidence Cell-type-specific conditional knockouts (neuron, macrophage Nrp1), PlexinA1/A3 double KO, fyn-null mice, tumor models, histomorphometry

    PMID:23602477 PMID:23644455 PMID:23991118 PMID:24332039

    Open questions at the time
    • Osteocyte autocrine versus paracrine loop not yet distinguished
    • Whether sGC pathway is specific to cerebellar versus all branching contexts unclear
    • Inner ear Plexin specificity (A1/A3 vs A4) not reconciled with cortical PlexinA1/A4 requirement
  10. 2014 High

    Defining downstream cytoskeletal effector mechanisms and receptor regulation: phospho-CRMP1 weakens Filamin-A–mediated F-actin gelation to enable repulsion; ADAM10/17 cleavage of NRP1 terminates SEMA3A sensitivity during development; and GAG binding through the C-terminal basic region was biophysically characterized.

    Evidence AFM-based actin gelation, mutagenesis, ADAM10/17 double KO, NMR/SPR/ITC for GAG binding, and functional collapse assays

    PMID:24898499 PMID:25358863 PMID:27803639

    Open questions at the time
    • Whether ADAM-mediated NRP1 shedding regulates adult contexts (e.g., tumor angiogenesis) untested
    • GAG-binding contribution to in vivo gradient formation not established
  11. 2018 High

    Expanding the signaling toolkit: PlexinA1 Rap1 GAP activity was shown to suppress supernumerary axon formation; ROCK2/MLC2 was identified as a regeneration-inhibitory branch; and an NRP1-independent engineered SEMA3A mutant demonstrated that direct PlexinA4 engagement suffices for anti-angiogenic activity.

    Evidence Rap1 activity assays in hippocampal neurons, ROCK2 inhibitor in optic nerve crush, and structure-guided protein engineering with mouse tumor/AMD models

    PMID:29794061 PMID:30353093 PMID:31733191

    Open questions at the time
    • Whether Rap1 GAP and ROCK2 branches operate in parallel or sequentially not resolved
    • Long-term efficacy and specificity of NRP1-independent SEMA3A variants in vivo unknown
  12. 2019 High

    Establishing osteocyte autocrine survival signaling and muscle progenitor guidance: estrogen-induced Sema3A signals back on osteocytes via NRP1-sGC-cGMP to promote survival; and Sema3A expressed by slow-twitch fibers repels Twist2+ progenitors to fast-twitch fibers via NRP1.

    Evidence Osteocyte-specific Sema3a and Nrp1 conditional KOs with cGMP pharmacology; stripe migration and chimeric fusion assays with transgenic mice

    PMID:30661929 PMID:31474563

    Open questions at the time
    • Whether cGMP pathway converges with canonical PlexinA signaling in osteocytes unknown
    • Nrp1 co-receptor (Plexin identity) in Tw2+ progenitors not determined
  13. 2021 High

    Structural resolution of the holoreceptor architecture: the 3.7 Å cryo-EM structure of the Sema3A/PlexinA4/NRP1 2:2:2 complex revealed how NRP1 bridges Sema3A to PlexinA4 across multiple interfaces and positions PlexinA4 intracellular domains for active dimerization.

    Evidence Cryo-EM structure determination of near-intact extracellular complex

    PMID:34039996

    Open questions at the time
    • Intracellular GAP domain activation mechanism not visualized
    • Full-length receptor in lipid bilayer not yet resolved
    • How K108 contributes at the structural level not explicitly shown
  14. 2024 Medium

    Linking SEMA3A to mechanotransduction: PIEZO1 in odontoblasts drives SEMA3A expression via Ca²⁺/PI3K-Akt, and sensory neuron-derived SEMA3A maintains mitochondrial dynamics in periodontal ligament cells under mechanical load through ROCK2.

    Evidence Conditional Piezo1 KO, Ca²⁺ imaging, PI3K-Akt inhibition, exogenous Sema3A rescue, mechanical stimulation assays

    PMID:38238300 PMID:38910430

    Open questions at the time
    • Whether PIEZO1-SEMA3A axis operates in non-dental tissues unknown
    • Mechanosensory-to-SEMA3A transcriptional regulation not fully resolved
    • Single-lab findings for both studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include how the intracellular PlexinA GAP domain is structurally activated upon dimerization, how SEMA3A achieves pathway bifurcation (repulsion vs. attraction) in the same cell type, and the structural basis of SEMA3A's direct Kv4.3 channel inhibition.
  • No intracellular PlexinA activation structure available
  • Mechanism of pathway switch between repulsion and attraction unresolved
  • SEMA3A–Kv4.3 binding interface not structurally characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4
Partners
CHL1CRMP1FARP2KV4.3L1CAMNRP1PLXNA1PLXNA4
Complex memberships
NRP1/L1CAM co-receptor complexSema3A/NRP1/PlexinA4 holoreceptor (2:2:2)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cryo-EM structure of the Sema3A/PlexinA4/Neuropilin-1 tripartite extracellular complex resolved at 3.7 Å, revealing a symmetric 2:2:2 assembly in which Sema3A, PlexinA4, and Nrp1 make multiple interfaces; the two PlexinA4 molecules are poised to form an intracellular active dimer for signaling, and a previously unknown interface between the Nrp1 a2b1b2 module and the Sema domain of Sema3A was identified. Cryo-EM structure determination Nature communications High 34039996
2000 L1 CAM forms a stable complex with neuropilin-1 (NP-1) through direct extracellular domain association and acts as a component of the Sema3A receptor complex; L1-deficient cortical axons lose Sema3A repulsion, and addition of soluble L1Fc converts Sema3A repulsion to attraction in wild-type axons. Co-immunoprecipitation, coculture repulsion assay, genetic (L1-deficient mice) Neuron High 10985345
2005 FARP2, a FERM domain-containing Rac GEF, directly associates with PlexinA1 in the presence of neuropilin-1; Sema3A binding to neuropilin-1 induces FARP2 dissociation from PlexinA1, activating FARP2's Rac GEF activity, recruiting Rnd1 to PlexinA1, downregulating R-Ras, and sequestering PIPKIγ661 from talin to suppress its kinase activity—all required for growth cone repulsion. Pulldown, co-immunoprecipitation, GEF activity assay, mutagenesis, collapse assay Nature neuroscience High 16286926
1999 Sema3A-induced growth cone collapse is mediated by Rac1 amino acids 17–32; cell-permeable peptides spanning this region bind PAK, WASP, 3BP-1, and p85β-PI3K and compete with activated Rac1, blocking Sema3A-induced collapse; a PAK CRIB peptide (but not N-WASP CRIB) similarly inhibits collapse correlating with Rac1 binding. Cell-permeable peptide competition assay, growth cone collapse assay, direct binding assay Current biology High 10508610
2006 PTEN is required for Sema3A-mediated growth cone collapse: Sema3A suppresses PI3K signaling and activates GSK-3 in a PTEN phosphatase-dependent manner; following Sema3A exposure, PTEN rapidly accumulates at the growth cone membrane where it colocalizes with microtubules. Live-cell imaging, phospho-PTEN/GSK-3 immunoblot, pharmacological inhibition, PTEN localization by immunofluorescence Journal of cell science High 16495486
2014 Filamin-A interacts with CRMP1 through both its actin-binding domain and its last immunoglobulin-like repeat; phosphorylation-mimicking CRMP1(Ser522Asp) enhances Sema3A repulsion and weakens F-actin gelation crosslinked by Filamin-A, as shown by atomic-force microscopy; alanine mutants of either protein suppress Sema3A repulsion. Co-IP, in vitro binding, atomic-force microscopy, mutagenesis, neuronal collapse/repulsion assay Nature communications High 25358863
2014 ADAM10 and ADAM17 metalloprotease-mediated cleavage of Neuropilin-1 (Nrp1) promotes developmental loss of sensory axon sensitivity to Sema3A; genetic ablation of ADAM10/ADAM17 maintains Nrp1 on sensory axons and preserves Sema3A repulsive response; Nrp1 overexpression reverses desensitization but is blocked by a cleavage-susceptible Nrp1 mutant. Genetic knockout (ADAM10/17 double KO), in vitro collapse assay, Nrp1 overexpression/mutagenesis, immunofluorescence Nature communications High 24898499
2006 SEMA3A selectively inhibits the Kv4.3 (Ito) potassium channel by direct binding interaction (co-immunoprecipitation), reducing peak Kv4.3 current density in HEK293 cells and human iPSC-derived cardiomyocytes without altering surface expression; disruption of the putative toxin-binding domain on Kv4.3 or Brugada syndrome-associated SEMA3A missense mutations abolish this inhibition, resulting in Kv4.3 gain-of-function. Whole-cell patch clamp, co-immunoprecipitation, site-directed mutagenesis, human iPSC-derived cardiomyocytes Circulation research High 24963029
2010 A forward genetic screen identified Sema3A(K108N) as a loss-of-function allele that retains neuropilin-1 binding but cannot signal through the Npn-1/PlexinA holoreceptor; K108N protein fails to repel or collapse DRG axons and phenocopies Sema3A-null mice, demonstrating that the K108 residue is critical for holoreceptor activation. Forward genetic screen, in vitro collapse/repulsion assay, in silico modeling, binding assay, mouse genetics The Journal of neuroscience High 20410128
2014 Plexin-A2 is specifically required for Sema3B (but not Sema3A) signaling in endothelial and glioblastoma cells; Sema3A signaling depends on neuropilin-1, plexin-A1, and plexin-A4; overexpression of plexin-A2 can functionally substitute for plexin-A1 or plexin-A4, but plexin-A4 overexpression cannot restore Sema3B signaling in plexin-A2-silenced cells. siRNA knockdown, overexpression, migration/signaling assay Journal of cell science Medium 25335892
2009 Sema3A promotes hippocampal dendrite extension via a pathway requiring integrin engagement and focal adhesion kinase (FAK) phosphorylation; conditional inactivation of β1 integrin or FAK blocks dendrite growth stimulation but not axonal growth cone collapse, demonstrating mechanistically distinct pathways for the two opposing responses. Conditional gene knockout, FAK phosphorylation assay, neuron culture Journal of cell science High 19454481
2010 FAK is required downstream of Sema3A signaling in hippocampal axon remodeling: Sema3A differentially phosphorylates FAK at Tyr397, Tyr861, Tyr925 (increased) and Tyr407, Tyr861 (decreased); FAKY925 reduces FAK-Paxillin interaction and promotes disassembly of adhesion contacts; conditional FAK ablation abolishes Sema3A-induced axon remodeling. Conditional gene knockout, phospho-specific immunoblot, co-immunoprecipitation, neuronal remodeling assay Molecular and cellular neurosciences Medium 20159040
2018 A rationally designed NRP1-independent SEMA3A point mutant binds PlexinA4 with nanomolar affinity (unlike wild-type Sema3A which requires NRP1 co-receptor) and normalizes tumor vasculature, inhibits tumor growth, and reduces retinal neovascularization in mouse models. Protein engineering, binding assay, in vitro endothelial cell assay, mouse xenograft/AMD models Science translational medicine High 29794061
2013 Hypoxia-induced Sema3A attracts tumor-associated macrophages (TAMs) by triggering VEGFR1 phosphorylation through the Nrp1/PlexinA1/PlexinA4 holoreceptor; in hypoxic conditions where Nrp1 is downregulated, Sema3A retains TAMs via Nrp1-independent PlexinA1/PlexinA4-mediated stop signals; Nrp1 gene deletion in macrophages traps them in normoxic areas, abating pro-angiogenic and immunosuppressive functions. Gene deletion (macrophage-specific Nrp1 KO), phospho-VEGFR1 assay, in vivo tumor models Cancer cell High 24332039
2013 Neuron-derived (not osteoblast-derived) Sema3A regulates bone mass by modulating sensory nerve innervation of trabecular bone; neuron-specific Sema3A knockout mice have low bone mass with reduced sensory but not sympathetic innervation, and sensory nerve ablation phenocopies the bone loss without further reducing bone mass in Sema3A-deficient mice. Cell-type-specific conditional knockout mice, histomorphometry, nerve ablation Nature High 23644455
2019 Estrogen induces osteocyte expression of Sema3A, which signals back onto osteocytes via neuropilin-1 to promote their survival; postnatal global and osteocyte-specific deletion of Sema3a or Nrp1 in osteoblastic cells causes severe osteoporosis with reduced osteocyte numbers; soluble guanylate cyclase-cGMP signaling mimics Sema3A survival action. Conditional knockout (global, osteocyte-specific Sema3a and Nrp1), pharmacological cGMP stimulation, histomorphometry Cell metabolism High 30661929
2007 Sema3A, expressed in Purkinje fibers, establishes cardiac sympathetic innervation patterning; Sema3A-null mice lack the epicardial-to-endocardial sympathetic gradient and show stellate ganglia malformation causing sinus bradycardia; cardiac-specific Sema3A overexpression reduces sympathetic innervation and causes ventricular tachycardia via catecholamine supersensitivity and prolonged action potential. Constitutive knockout, cardiac-specific transgenic overexpression, electrophysiology, sympathetic innervation mapping Nature medicine High 17417650
2002 Neuropilin-1-mediated Sema3A signaling regulates arrest, aggregation, and axon fasciculation of sympathetic neuron precursors; neuropilin-1 and Sema3A knockout embryos show displacement of sympathetic neurons and abnormal morphogenesis of the sympathetic trunk; Sema3A suppresses migration of wild-type but not neuropilin-1-null sympathetic neurons in vitro. Targeted gene disruption (neuropilin-1 KO, Sema3A KO), in vitro migration/aggregation assay Development High 11830568
2013 SEMA3A expressed by Purkinje cells regulates cerebellar basket cell axon branching through Neuropilin-1; SEMA3A-induced axon branching requires recruitment of soluble guanylyl cyclase (sGC) to the plasma membrane of basket cells, a process regulated by the Src kinase FYN; fyn-deficient mice show reduced basket axon branching specifically in the Purkinje cell layer. Knockout mice (Sema3A-null, nrp1-sema null, fyn-null), sGC membrane localization assay, immunofluorescence Current biology High 23602477
2017 PTPδ mediates Sema3A-induced cortical basal dendritic arborization by dephosphorylating the C-terminal Tyr527 residue of Fyn kinase; Ptpδ-/- and Sema3a-/- mice show identical basal dendrite arborization defects; double heterozygous Ptpδ+/-;Sema3a+/- mice recapitulate the phenotype, demonstrating genetic interaction. Knockout and double-heterozygous mouse genetics, phospho-Fyn immunoblot, Sema3A stimulation assay The Journal of neuroscience High 28637841
2008 ERM proteins (ezrin, radixin, moesin) are rapidly and transiently inactivated by Sema3A in neocortical growth cones; active ERMs are required for Sema3A-mediated growth cone collapse and guidance; the ERM FERM domain regulates internalization of the Sema3A receptor Npn1 and its co-receptor L1CAM, while the ERM C-terminal domain binds and caps F-actin. Phospho-ERM immunofluorescence, dominant-negative/active ERM expression, receptor internalization assay, growth cone collapse assay The Journal of comparative neurology Medium 18651636
2007 CHL1 recruits ERM proteins to the plasma membrane via a membrane-proximal RGGKYSV cytoplasmic motif; this motif is required for Sema3A-induced growth cone collapse and CHL1-dependent neurite outgrowth/branching, as demonstrated by motif deletion mutants. Cytofluorescence ERM recruitment assay, mutagenesis, growth cone collapse assay, neurite outgrowth assay Journal of neurochemistry Medium 17995939
2019 Sema3a-Nrp1 signaling mediates fast-twitch myofiber specificity of Twist2+ (Tw2+) muscle progenitor cells; Sema3a is expressed by type I and IIa but not IIb myofibers, while Nrp1 marks Tw2+ but not Pax7+ cells; stripe migration and chimeric fusion assays show that Sema3a-Nrp1 chemorepulsion restricts Tw2+ cells to IIb fibers; Sema3a transgenic mice confirm this mechanism in vivo. RNA-seq, immunofluorescence, stripe migration assay, chimeric cell-cell fusion assay, transgenic mouse model Developmental cell High 31474563
2014 Sema3A (via its C-terminal basic region) binds glycosaminoglycans (GAGs) heparin and chondroitin sulfate A with low-micromolar affinity; the peptidomimetic SICHI blocks Sema3A-GAG interaction by competing for GAG binding, thereby inhibiting growth cone collapse. NMR, surface plasmon resonance, isothermal titration calorimetry, fluorescence spectroscopy, axon collapse assay Biophysical journal High 27028639
2011 miR-124 controls the timing of Sema3A sensitivity in Xenopus retinal ganglion cell (RGC) growth cones by targeting CoREST, a co-factor of an NRP1 repressor; loss of miR-124 delays onset of Sema3A sensitivity and NRP1 expression, causing cell-autonomous pathfinding errors. Developmental miRNA profiling, morpholino knockdown, luciferase reporter, axon pathfinding assay Nature neuroscience High 22138647
2000 Sema3A inhibits branching morphogenesis of fetal mouse lung via Neuropilin-1; exogenous Sema3A reduces terminal bud number in explant cultures dose-dependently; a soluble NP-1 ectodomain neutralizes inhibition; lung explants from Nrp1-null mice are insensitive to Sema3A treatment. Fetal lung explant organ culture, exogenous protein addition, soluble receptor neutralization, Nrp1-null mouse lung culture Mechanisms of development High 11025205
2019 In the PlexinA1/PlexinA4 receptor-mediated osteoclast inhibition pathway, Sema3A binding disrupts the PlexinA1–DAP12 complex and promotes PlexinA1-NRP1 complex formation, suppressing PLCγ2 phosphorylation; in osteoblasts, Sema3A binding to Nrp1/PlexinA1 activates β-catenin nuclear translocation downstream. Co-immunoprecipitation, phospho-PLCγ2 assay, β-catenin nuclear fractionation, antibody blocking Frontiers in pharmacology Medium 27803667
2019 The Plexin-A1 intracellular signaling downstream of Sema3A regulates oligodendrocyte migration and differentiation; a peptidic PlexinA1 antagonist counteracts Sema3A inhibitory effects on oligodendrocytes in vitro and promotes remyelination in the cuprizone mouse model in vivo. In vitro oligodendrocyte migration/differentiation assay, peptide antagonism, cuprizone demyelination model, DTI-MRI, histology EMBO molecular medicine Medium 31566924
2013 Sema3A maintains corneal avascularity by inhibiting VEGF-induced angioblast migration; Sema3A is expressed at higher levels than VEGF in the embryonic lens; blockade of Sema3A (lens removal or synthetic inhibitor) causes ectopic angioblast migration into the cornea; exogenous Sema3A protein inhibits VEGF-induced corneal vascularization; Nrp1-sema mutant mice show corneal vascularization. Surgical lens removal, Sema3A inhibitor injection, exogenous protein bead implantation, Nrp1(Sema-) mutant mouse analysis Developmental biology High 24809797
2006 SEMA3A competitively binds NRP1 with higher affinity than VEGF165, as demonstrated by anti-NRP1 immunoprecipitation showing preferential NRP1-SEMA3A association; exogenous SEMA3A restrains the pro-angiogenic function of multiple myeloma endothelial cells as effectively as anti-VEGFR-2 antibody by counteracting VEGF165 activity. Co-immunoprecipitation with anti-NRP1 antibody, endothelial tube formation assay, proliferation/migration assay Blood Medium 16684957
2018 Sema3A inhibits axonal regeneration of retinal ganglion cells (RGCs) through ROCK2; Sema3A promotes phosphorylation of myosin light chain 2 (MLC2), a specific downstream effector of ROCK2; ROCK2 inhibitor Y-27632 attenuates Sema3A-mediated suppression of optic nerve regeneration. In vivo optic nerve crush, intravitreal injection, ROCK2 inhibitor, MLC2 phospho-immunoblot, axon regeneration markers (GAP43, Sprr1A) Brain research Medium 31733191
2020 Nestin facilitates Sema3A sensitivity in developing cortical neurons by selectively scaffolding doublecortin (DCX) with cdk5/p35, enabling preferential DCX phosphorylation by cdk5; Dcx KO neurons show the same growth cone morphology defects as nestin-manipulated neurons, placing DCX downstream of the nestin-cdk5 scaffold in Sema3A response. Dcx knockout mouse neurons, nestin overexpression/knockdown, phosphorylation assay, growth cone collapse assay The Journal of neuroscience Medium 32273484
2018 Plexin-A1 acts as a GAP for Rap1 GTPases; Sema3A and Plexin-A1 suppress formation of supernumerary axons in hippocampal neurons via Rap1 GTPase inactivation; overactivation of Rap1 promotes supernumerary axon formation that is suppressed by Sema3A/Plexin-A1. Neuronal culture, patterned substrate assay, Rap1 activity assay, Plexin-A1 GAP assay Scientific reports Medium 30353093
2024 Sema3A secreted by sensory neurons activates the ROCK2 pathway to prevent F-actin overstretching from mechanical loads, maintaining mitochondrial dynamics (fusion) in human periodontal ligament cells; Sema3A also exogenously restores osteogenic differentiation suppressed by mechanical overload, acting downstream of Ca2+/PI3K-Akt signaling in odontoblasts. In vitro mechanical stimulation, ROCK2 pathway assay, mitochondrial morphology imaging, neuronal Sema3A ELISA, exogenous Sema3A supplementation, OTM mouse model International journal of oral science Medium 38238300
2024 PIEZO1 in odontoblasts promotes SEMA3A expression via Ca2+/PI3K-Akt signaling; conditional Piezo1 knockout in odontoblasts reduces Sema3A levels and impairs reactionary dentinogenesis after dentin injury; exogenous SEMA3A restores mineralization capacity in PIEZO1-knockdown odontoblast-like cells. Conditional Piezo1 knockout mice, PIEZO1 knockdown, Ca2+ imaging, PI3K-Akt inhibition, exogenous Sema3A rescue, micro-CT/histology Journal of dental research Medium 38910430
2013 Sema3A deletion or PlexinA1/PlexinA3 double knockout disrupts sensory afferent projections of statoacoustic ganglion (SAG) neurons in the inner ear; Sema3A is expressed in the dorsal otocyst and repels SAG axons from dorsal areas through Nrp1/PlexinA1/PlexinA3 receptor complex. Sema3A KO, plexinA1/A3 double KO, genetic epistasis, inner ear immunohistochemistry PloS one Medium 23991118

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer cell 520 24332039
2000 Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 347 10985345
2013 Sema3A regulates bone-mass accrual through sensory innervations. Nature 331 23644455
2006 A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nature medicine 313 17099709
2005 FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nature neuroscience 186 16286926
2007 Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nature medicine 179 17417650
2007 The CRMP family of proteins and their role in Sema3A signaling. Advances in experimental medicine and biology 173 17607942
2012 SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS genetics 154 22927827
2004 Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes & development 150 15545635
2002 Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system. Development (Cambridge, England) 137 11830568
2019 Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging. Cell metabolism 127 30661929
2023 Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer. European journal of pharmacology 123 37611839
2006 PTEN couples Sema3A signalling to growth cone collapse. Journal of cell science 119 16495486
1999 Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17-32. Current biology : CB 117 10508610
2001 Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 11549731
2008 A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. American journal of human genetics 105 19110214
2012 SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Human reproduction (Oxford, England) 101 22416012
2011 miR-124 acts through CoREST to control onset of Sema3A sensitivity in navigating retinal growth cones. Nature neuroscience 100 22138647
2009 Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. Journal of dermatological science 94 19443185
2003 Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex. The Journal of comparative neurology 90 12454988
2009 Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation. American journal of physiology. Cell physiology 86 19515904
2005 MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO). The Journal of clinical investigation 82 16167086
2000 Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Mechanisms of development 82 11025205
2003 Transient downregulation of Sema3A mRNA in a rat model for temporal lobe epilepsy. A novel molecular event potentially contributing to mossy fiber sprouting. Experimental neurology 76 12821384
2017 Sema3A promotes the resolution of cardiac inflammation after myocardial infarction. Basic research in cardiology 73 28540528
2006 Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 72 16684957
2019 miR-15b-5p ameliorated high glucose-induced podocyte injury through repressing apoptosis, oxidative stress, and inflammatory responses by targeting Sema3A. Journal of cellular physiology 57 31025335
2014 Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism. Pediatric research 56 24522099
2018 Gpr97 Exacerbates AKI by Mediating Sema3A Signaling. Journal of the American Society of Nephrology : JASN 52 29531097
2016 Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages. Cancer research 52 27197153
2007 Effects of different regions of the developing gut on the migration of enteric neural crest-derived cells: a role for Sema3A, but not Sema3F. Developmental biology 51 17362911
2007 CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane. Journal of neurochemistry 50 17995939
2018 A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent. Science translational medicine 48 29794061
2009 The stimulation of dendrite growth by Sema3A requires integrin engagement and focal adhesion kinase. Journal of cell science 47 19454481
2009 Increased proximal bifurcation of CA1 pyramidal apical dendrites in sema3A mutant mice. The Journal of comparative neurology 47 19655386
2014 Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome. Circulation research 46 24963029
2000 SEMA3A regulates developing sensory projections in the chicken spinal cord. Journal of neurobiology 46 11077427
2017 MicroRNA-192-5p Promote the Proliferation and Metastasis of Hepatocellular Carcinoma Cell by Targeting SEMA3A. Applied immunohistochemistry & molecular morphology : AIMM 44 26580097
2021 Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex. Nature communications 43 34039996
2017 Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 43 28135705
2016 Wedelolactone Enhances Osteoblastogenesis but Inhibits Osteoclastogenesis through Sema3A/NRP1/PlexinA1 Pathway. Frontiers in pharmacology 42 27803667
2014 Amino- and carboxyl-terminal domains of Filamin-A interact with CRMP1 to mediate Sema3A signalling. Nature communications 40 25358863
2014 ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A. Nature communications 38 24898499
2014 The role of the plexin-A2 receptor in Sema3A and Sema3B signal transduction. Journal of cell science 38 25335892
2013 SEMA3A signaling controls layer-specific interneuron branching in the cerebellum. Current biology : CB 38 23602477
2010 A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal. The Journal of neuroscience : the official journal of the Society for Neuroscience 34 20410128
2018 Long non-coding RNA GAS5 reduces cardiomyocyte apoptosis induced by MI through sema3a. International journal of biological macromolecules 33 30099044
2023 miR-196b-5p Regulates Osteoblast and Osteoclast Differentiation and Bone Homeostasis by Targeting SEMA3A. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 31 37221130
2017 Inflammatory milieu cultivated Sema3A signaling promotes chondrocyte apoptosis in knee osteoarthritis. Journal of cellular biochemistry 31 29111592
2015 Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic design. Clinical immunology (Orlando, Fla.) 31 26686462
2011 Growth factor regulation of neural chemorepellent Sema3A expression in satellite cell cultures. American journal of physiology. Cell physiology 31 21865583
2010 Expression by midbrain dopamine neurons of Sema3A and 3F receptors is associated with chemorepulsion in vitro but a mild in vivo phenotype. Molecular and cellular neurosciences 31 20298787
2009 Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration. Cell adhesion & migration 31 19855168
2019 Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development. Scientific reports 30 30862786
2017 Adenovirus-mediated delivery of Sema3A alleviates rheumatoid arthritis in a serum-transfer induced mouse model. Oncotarget 30 29029510
2019 Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination. EMBO molecular medicine 29 31566924
2008 ERM proteins regulate growth cone responses to Sema3A. The Journal of comparative neurology 29 18651636
2017 Protein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 28637841
2024 Sema3A secreted by sensory nerve induces bone formation under mechanical loads. International journal of oral science 25 38238300
2017 Decreased expression of Sema3A, an immune modulator, in blood sample of multiple sclerosis patients. Gene 25 28188869
2017 Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress Glioblastoma Tumor Growth. Cancer research and treatment 25 29129044
2013 Overexpression of Sema3a in myocardial infarction border zone decreases vulnerability of ventricular tachycardia post-myocardial infarction in rats. Journal of cellular and molecular medicine 25 23711091
2018 ALS-related human cortical and motor neurons survival is differentially affected by Sema3A. Cell death & disease 24 29449528
2018 Aberrant Expression of miR-362 Promotes Lung Cancer Metastasis through Downregulation of Sema3A. Journal of immunology research 24 30155491
2018 Sema3a plays a role in the pathogenesis of CHARGE syndrome. Human molecular genetics 23 29432577
2017 SEMA3A partially reverses VEGF effects through binding to neuropilin-1. Stem cell research 23 28636974
2014 Sema3A maintains corneal avascularity during development by inhibiting Vegf induced angioblast migration. Developmental biology 23 24809797
2021 Glucocorticoids suppressed osteoblast differentiation by decreasing Sema3A expression via the PIK3/Akt pathway. Experimental cell research 22 33838126
2017 Sema3A drastically suppresses tumor growth in oral cancer Xenograft model of mice. BMC pharmacology & toxicology 22 28683823
2010 Focal adhesion kinase functions downstream of Sema3A signaling during axonal remodeling. Molecular and cellular neurosciences 22 20159040
2014 CRMP1 Interacted with Spy1 During the Collapse of Growth Cones Induced by Sema3A and Acted on Regeneration After Sciatic Nerve Crush. Molecular neurobiology 21 25526860
2023 Sema3A Drives Alternative Macrophage Activation in the Resolution of Periodontitis via PI3K/AKT/mTOR Signaling. Inflammation 20 36598593
2020 miR-30b Promotes spinal cord sensory function recovery via the Sema3A/NRP-1/PlexinA1/RhoA/ROCK Pathway. Journal of cellular and molecular medicine 20 32977360
2019 Sema3a-Nrp1 Signaling Mediates Fast-Twitch Myofiber Specificity of Tw2+ Cells. Developmental cell 20 31474563
2018 Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis. Journal of ethnopharmacology 20 29428242
2000 Ectopic adenoviral vector-directed expression of Sema3A in organotypic spinal cord explants inhibits growth of primary sensory afferents. Developmental biology 19 10753505
2024 Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC. Gut 18 38670629
2020 SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD). Frontiers in endocrinology 18 32612575
2019 Sema3A inhibits axonal regeneration of retinal ganglion cells via ROCK2. Brain research 18 31733191
2016 Cationic Peptides and Peptidomimetics Bind Glycosaminoglycans as Potential Sema3A Pathway Inhibitors. Biophysical journal 18 27028639
2021 Knockdown of RMST Impedes Neuronal Apoptosis and Oxidative Stress in OGD/R-Induced Ischemic Stroke Via Depending on the miR-377/SEMA3A Signal Network. Neurochemical research 17 33409855
2020 Nestin Selectively Facilitates the Phosphorylation of the Lissencephaly-Linked Protein Doublecortin (DCX) by cdk5/p35 to Regulate Growth Cone Morphology and Sema3a Sensitivity in Developing Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 32273484
2020 MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression. Open life sciences 17 33817280
2019 Semaphorin 3A (SEMA3A), protocadherin 9 (PCdh9), and S100 calcium binding protein A3 (S100A3) as potential biomarkers of carcinogenesis and chemoresistance of different neoplasms, including ovarian cancer - review of literature. Ginekologia polska 17 31059116
2010 Intrathecally administered Sema3A protein attenuates neuropathic pain behavior in rats with chronic constriction injury of the sciatic nerve. Neuroscience research 17 20888378
2007 Modulating Sema3A signal with a L1 mimetic peptide is not sufficient to promote motor recovery and axon regeneration after spinal cord injury. Molecular and cellular neurosciences 17 17997325
2003 Sema3A and neuropilin-1 expression and distribution in rat white adipose tissue. Journal of neurocytology 17 14724377
2023 Sema3A inactivates the ERK/JNK signalling pathways to alleviate inflammation and oxidative stress in lipopolysaccharide-stimulated rat endothelial cells and lung tissues. Autoimmunity 16 37128697
2018 The Neuropilin-1 Ligand, Sema3A, Acts as a Tumor Suppressor in the Pathogenesis of Acute Leukemia. Anatomical record (Hoboken, N.J. : 2007) 16 30378769
2013 Specific immobilization of biotinylated fusion proteins NGF and Sema3A utilizing a photo-cross-linkable diazirine compound for controlling neurite extension. Bioconjugate chemistry 16 23909702
2021 Cortical expression of IL1-β, Bcl-2, Caspase-3 and 9, SEMA-3a, NT-3 and P-glycoprotein as biological markers of intrinsic severity in drug-resistant temporal lobe epilepsy. Brain research 15 33516813
2020 Sema3A and HIF1α co-overexpressed iPSC-MSCs/HA scaffold facilitates the repair of calvarial defect in a mouse model. Journal of cellular physiology 15 32012286
2019 Sema3a as a Novel Therapeutic Option for High Glucose-Suppressed Osteogenic Differentiation in Diabetic Osteopathy. Frontiers in endocrinology 15 31481931
2018 Sema3a inhibits the differentiation of Raw264.7 cells to osteoclasts under 2Gy radiation by reducing inflammation. PloS one 15 29975739
2013 Deletion of Sema3a or plexinA1/plexinA3 causes defects in sensory afferent projections of statoacoustic ganglion neurons. PloS one 15 23991118
2010 Sema-3A indirectly disrupts the regeneration process of goldfish optic nerve after controlled injury. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 15 20449604
2007 Role of the neuropilin ligands VEGF164 and SEMA3A in neuronal and vascular patterning in the mouse. Novartis Foundation symposium 15 18300426
2024 PIEZO1 Promotes Odontoblast-Mediated Reactionary Dentinogenesis via SEMA3A. Journal of dental research 13 38910430
2021 Long non-coding RNA Gm11974 aggravates oxygen-glucose deprivation-induced injury via miR-122-5p/SEMA3A axis in ischaemic stroke. Metabolic brain disease 13 34338972
2018 The Sema3A receptor Plexin-A1 suppresses supernumerary axons through Rap1 GTPases. Scientific reports 13 30353093