Affinage

NTN1

Netrin-1 · UniProt O95631

Round 2 corrected
Length
604 aa
Mass
67.7 kDa
Annotated
2026-04-29
130 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Netrin-1 is a secreted laminin-related guidance cue that directs axon pathfinding, cell migration, and tissue morphogenesis by engaging a diverse set of receptors—DCC, UNC5b, neogenin, DSCAM, the A2b adenosine receptor, and integrins α6β4/α3β1—to elicit context-dependent attraction, repulsion, adhesion, or survival signals (PMID:8978605, PMID:8861902, PMID:11048721, PMID:19196994, PMID:14602071, PMID:12636918). In the absence of Netrin-1, its dependence receptors DCC and UNC5H trigger caspase-mediated apoptosis; autocrine or paracrine Netrin-1 suppresses this pathway, conferring a survival advantage exploited by multiple tumor types including colorectal, breast, and lung cancers (PMID:15343335, PMID:18353983, PMID:19211441). In immune and vascular contexts, Netrin-1—transcriptionally induced by HIF-1α under hypoxia—dampens neutrophil transmigration via A2BAR and retains macrophages in inflamed tissues via UNC5b-mediated inhibition of chemotaxis and Rac1 activation, contributing to atherosclerosis, insulin resistance, and barrier protection (PMID:19122655, PMID:22231519, PMID:24584118, PMID:25903786). Structurally, simultaneous binding of Netrin-1 and RGM to neogenin assembles a ternary super-complex that reciprocally silences both attractive and repulsive downstream signaling (PMID:33740419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Establishing Netrin-1 as a diffusible guidance cue: knockout mice revealed that Netrin-1 secreted by floor plate cells is essential for commissural axon pathfinding, and DCC was identified as the receptor mediating this attraction, answering what molecular system steers commissural axons toward the midline.

    Evidence Targeted Ntn1 knockout in mice with axon tracing; DCC-Netrin-1 binding assays and anti-DCC antibody blocking of axon outgrowth in vitro

    PMID:8861902 PMID:8978605

    Open questions at the time
    • Downstream signaling cascade from DCC upon Netrin-1 binding was unknown
    • Whether Netrin-1 acts at long range in vivo or is matrix-tethered was unresolved
    • Alternative receptors had not been identified
  2. 2000 High

    Expanding the receptor repertoire beyond DCC: the A2b adenosine receptor was identified as a Netrin-1 receptor that physically complexes with DCC and mediates cAMP production, revealing that guidance signaling is transduced through a multi-receptor complex rather than DCC alone.

    Evidence Co-immunoprecipitation of DCC-A2b, cAMP accumulation assay, dominant-negative A2b blocking axon outgrowth

    PMID:11048721

    Open questions at the time
    • Whether other G-protein-coupled receptors participate was unknown
    • Structural basis of DCC–A2b complex formation was unresolved
  3. 2003 High

    Demonstrating non-neural functions: Netrin-1 was shown to organize mammary epithelial tissue through neogenin-mediated cell adhesion and to serve as an ECM-associated substrate for integrin-dependent epithelial cell adhesion and migration, establishing Netrin-1 as a general morphogenetic cue beyond axon guidance.

    Evidence Ntn1/neogenin KO mammary gland phenotyping and cell aggregation assays; epithelial adhesion/migration assays with integrin-blocking antibodies

    PMID:12636918 PMID:14602071

    Open questions at the time
    • Signaling downstream of integrin–Netrin-1 interaction was not characterized
    • Whether ECM association restricts Netrin-1 range in vivo remained unclear
  4. 2004 High

    Linking Netrin-1 to cancer via dependence receptor biology: forced Netrin-1 expression blocked DCC/UNC5H-mediated apoptosis in gut epithelium and promoted tumorigenesis, establishing the principle that Netrin-1 overexpression provides a selective survival advantage to incipient tumor cells.

    Evidence Transgenic Netrin-1 overexpression in mouse GI tract; crosses with APC-mutant mice; apoptosis assays

    PMID:15343335

    Open questions at the time
    • Whether endogenous Netrin-1 upregulation occurs in human tumors at disease-relevant levels was not yet shown
    • Therapeutic targetability of the Netrin-1–dependence receptor axis was untested
  5. 2005 High

    Identifying an immunomodulatory axis: endothelial Netrin-1 was found to inhibit leukocyte migration via UNC5b, revealing a role for guidance cues in innate immune cell trafficking.

    Evidence Transwell migration assays with recombinant Netrin-1 and UNC5b-expressing leukocytes; in vivo migration models

    PMID:16203981

    Open questions at the time
    • Mechanism of UNC5b-mediated chemorepulsion in leukocytes was not molecularly dissected
    • Relevance to chronic inflammatory disease was unestablished
  6. 2008 High

    Extending the tumor survival paradigm: autocrine Netrin-1 in metastatic breast cancer, neuroblastoma, and NSCLC was shown to block UNC5H/DCC-mediated apoptosis, and interference with this loop triggered cell death and suppressed metastasis, validating Netrin-1 as a broadly exploited survival factor in aggressive cancers.

    Evidence siRNA knockdown and decoy DCC ectodomain in multiple cancer cell lines; mouse lung colonization, xenograft, and avian metastasis models

    PMID:18353983 PMID:19211441 PMID:19349462

    Open questions at the time
    • Clinical translation of Netrin-1 or dependence receptor interference remained untested
    • Whether tumor-derived Netrin-1 additionally modulates the immune microenvironment was not addressed
  7. 2009 High

    Resolving the hypoxia–inflammation connection: HIF-1α was shown to transcriptionally induce NTN1, which dampens neutrophil transepithelial migration through A2BAR, and DSCAM was independently identified as another Netrin-1 receptor activating Fyn/Pak1, broadening both the upstream regulation and the receptor landscape of Netrin-1.

    Evidence HIF-1α reporter assays, neutrophil transmigration with A2BAR-KO and Ntn1+/− mice; DSCAM–Netrin-1 co-IP, in ovo DSCAM knockdown with commissural axon phenotype

    PMID:19122655 PMID:19196994

    Open questions at the time
    • Whether DSCAM cooperates or competes with DCC in the same growth cone was unclear
    • Tissue-specific dominance of A2BAR vs. UNC5b for anti-inflammatory signaling was not resolved
  8. 2010 High

    Discovering a local translation mechanism: DCC was found to scaffold translation machinery components on axons, and Netrin-1 binding triggers local protein synthesis by releasing these components, providing a mechanism for rapid, spatially restricted responses to guidance cues.

    Evidence Co-IP/affinity purification/mass spectrometry of DCC-translation complexes; metabolic labeling of Netrin-1-stimulated axonal translation

    PMID:20434207

    Open questions at the time
    • Identity of locally translated mRNAs was not determined
    • Whether other guidance cues use analogous receptor–ribosome scaffolds was unknown
  9. 2012 High

    Establishing macrophage-derived Netrin-1 as a driver of chronic vascular disease: macrophage Ntn1 conditional deletion reduced atherosclerosis by releasing macrophage retention, with UNC5b–Rac1–actin polymerization identified as the intracellular inhibitory cascade, directly connecting guidance biology to atherogenesis.

    Evidence Macrophage-specific Ntn1 conditional KO in ApoE−/− mice, Rac1 GTP-loading assay, actin polymerization assay, plaque quantification

    PMID:22231519

    Open questions at the time
    • Whether Netrin-1 acts on other plaque cell types was not fully explored
    • Contribution of dependence receptor apoptosis to plaque macrophage dynamics was not dissected
  10. 2014 High

    Connecting Netrin-1 to metabolic inflammation: in diet-induced obesity, palmitate-induced macrophage Netrin-1 retains adipose tissue macrophages via UNC5b, and hematopoietic Ntn1 deletion improves insulin sensitivity, revealing Netrin-1 as a metabolic disease effector.

    Evidence Hematopoietic Ntn1 conditional KO by bone marrow transplant, diet-induced obesity model, insulin tolerance testing

    PMID:24584118

    Open questions at the time
    • Whether Netrin-1 affects adipocyte biology directly was unknown
    • Therapeutic potential of Netrin-1 blockade in metabolic syndrome was untested
  11. 2015 High

    Demonstrating a barrier-protective function: endothelial Netrin-1, induced by astrocyte-derived Shh, maintains blood-brain barrier integrity by promoting tight junction protein expression, and Netrin-1 treatment ameliorates EAE, linking guidance cue biology to neurovascular protection.

    Evidence Ntn1 KO mice with BBB phenotype, transendothelial resistance assays, EAE model treatment

    PMID:25903786

    Open questions at the time
    • Receptor mediating endothelial Netrin-1 autocrine barrier signaling was not identified
    • Downstream transcriptional pathway upregulating junctional proteins was not characterized
  12. 2018 High

    Identifying neogenin-1 as the receptor mediating macrophage Netrin-1-driven aortic aneurysm, with a defined calcium–MMP3 cascade in vascular smooth muscle cells, and separately linking NTN1/DCC variants to congenital hypogonadotropic hypogonadism through defective GnRH neuron migration.

    Evidence Macrophage-specific Ntn1 CKO and MMP3 KO in AAA models, calcium flux and MMP3 activity assays, scRNA-seq; whole-exome sequencing of CHH patients with in vitro GnRH neuron migration assays

    PMID:29202173 PMID:30479344

    Open questions at the time
    • Whether neogenin-mediated calcium signaling operates in other Netrin-1-responsive vascular cells was unknown
    • CHH findings were from a single cohort without independent replication
  13. 2019 High

    Revealing post-transcriptional control of NTN1 expression: let-7 miRNA directly targets the Ntn1 3′-UTR in Schwann cells to repress Netrin-1 secretion and limit axon outgrowth during peripheral nerve regeneration, placing Netrin-1 availability under miRNA regulation.

    Evidence Luciferase 3′-UTR reporter, Schwann cell Netrin-1 secretion assay, DRG axon outgrowth assay

    PMID:30626732

    Open questions at the time
    • Whether other miRNAs regulate NTN1 in CNS contexts was not explored
    • In vivo consequences of let-7 modulation on nerve regeneration were not tested
  14. 2021 High

    Solving the structural basis for signal silencing: the crystal structure of a ternary NEO1–NET1–RGM super-complex showed that simultaneous ligand binding reciprocally silences both attractive and repulsive outputs by preventing formation of signaling-competent receptor assemblies, providing a structural mechanism for coincidence detection in guidance.

    Evidence X-ray crystallography of ternary complex; growth cone collapse and neuron migration assays

    PMID:33740419

    Open questions at the time
    • Whether this super-complex forms in vivo at physiological concentrations was not demonstrated
    • How cells dynamically regulate the stoichiometry of NEO1, Netrin-1, and RGM at the membrane was unresolved
  15. 2023 Medium

    Characterizing Netrin-1 oligomerization and a new epitranscriptomic regulatory layer: analytical ultracentrifugation showed Netrin-1 exists in pH-sensitive monomer–dimer equilibrium forming equimolar heterocomplexes with UNC-5B, and NSUN2-mediated m5C modification of NTN1 mRNA was found to stabilize the transcript and promote neural invasion in gastric cancer.

    Evidence Multi-wavelength AUC for Netrin-1/UNC-5B stoichiometry; RNA pulldown, RIP, m5C assay, and mouse neural invasion models for NSUN2–NTN1 axis

    PMID:36939874 PMID:37037818

    Open questions at the time
    • Functional significance of Netrin-1 dimerization for receptor activation is unclear
    • Whether m5C regulation of NTN1 operates outside gastric cancer contexts is unknown
    • NSUN2–NTN1 findings are from a single laboratory
  16. 2025 High

    Demonstrating polarity-gated guidance and anti-inflammatory neuroprotection: in cerebellar granule neurons, cell-polarity proteins Pard3/JamC and the E3 ligase Siah2 gate DCC surface availability to control Netrin-1-mediated germinal zone exit; separately, recombinant Netrin-1 attenuated Aβ-induced microglial NLRP3 inflammasome activation and memory impairment in an Alzheimer's disease model.

    Evidence Genetic epistasis with conditional KOs and DCC surface recruitment assays in mouse cerebellum; recombinant NTN-1 injection in Aβ1-42 rat model with NLRP3/NF-κB Western blotting and Morris water maze

    PMID:39774925 PMID:40357234

    Open questions at the time
    • Whether Siah2-mediated DCC degradation is Netrin-1-dependent or constitutive was not fully resolved
    • Netrin-1's neuroprotective effect in AD is from a single pharmacological study without genetic confirmation
    • Receptor mediating Netrin-1's anti-inflammasome activity in microglia was not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how tissue-specific receptor usage (DCC, UNC5b, neogenin, DSCAM, A2BAR, integrins) is determined at the single-cell level; whether Netrin-1 dimerization differentially activates attraction versus repulsion; how the dependence receptor apoptosis pathway is coordinated with immune-modulatory signaling in the tumor microenvironment; and whether therapeutic disruption of Netrin-1 autocrine loops can be achieved without compromising its barrier-protective and anti-inflammatory functions.
  • No integrated model of receptor hierarchy and competition at physiological ligand concentrations
  • Lack of high-resolution structures for DCC–Netrin-1 and DSCAM–Netrin-1 full-length complexes
  • No clinical trial data for Netrin-1-targeting therapeutics

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 6 R-HSA-168256 Immune System 6 R-HSA-112316 Neuronal System 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1474244 Extracellular matrix organization 2
Partners
ADORA2BDCCDSCAMITGA6ITGB4NEO1RGMAUNC5B

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Netrin-1 (NTN1) is a diffusible chemoattractant secreted by floor plate cells that is required in vivo for spinal commissural axon projection and guidance of several forebrain commissures, as demonstrated by targeted knockout in mice causing defects in commissural axon pathfinding. Gene knockout in mice, in vivo axon tracing Cell High 8978605
1996 DCC (Deleted in Colorectal Cancer), a transmembrane immunoglobulin superfamily protein, binds Netrin-1 directly and functions as a receptor or receptor component mediating netrin-1-dependent commissural axon outgrowth; anti-DCC antibody selectively blocks netrin-1-dependent axon outgrowth in vitro. Netrin-1 binding assay, antibody blocking of axon outgrowth in vitro, receptor characterization Cell High 8861902
2000 Netrin-1 promotes axon outgrowth and cAMP production through interaction with the adenosine A2b receptor (A2b), which acts as a netrin-1 receptor inducing cAMP accumulation. DCC interacts physically with A2b, forming a receptor complex required for netrin-1-dependent outgrowth of dorsal spinal cord axons. Co-immunoprecipitation, cAMP assay, functional axon outgrowth assay with dominant-negative constructs Nature High 11048721
2003 Netrin-1 expressed in prelumenal cells of mammary gland terminal end buds acts through its receptor neogenin on adjacent cap cells to stabilize the multipotent progenitor cap cell layer; loss of netrin-1 or neogenin results in disorganized TEBs, breaks in basal lamina, and dissociated cap cells. Neogenin mediates netrin-1-dependent cell clustering in aggregation assays. Gene knockout/knockdown in mice, cell aggregation assay, histological analysis Developmental cell High 12636918
2003 Netrin-1 associates with elements of the extracellular matrix in epithelial tissues. The integrin α6β4 mediates epithelial cell adhesion to Netrin-1, while both α6β4 and α3β1 regulate epithelial cell migration on Netrin-1, identifying Netrin-1/integrin interactions as adhesive/guidance cues for non-neural epithelial cells. Adhesion and migration assays on Netrin-1 substrate, integrin-blocking antibodies, ECM association assay Developmental cell High 14602071
2004 Netrin-1 promotes intestinal tumor development by inhibiting apoptosis induced by its dependence receptors DCC and UNC5H. Enforced expression of netrin-1 in mouse gastrointestinal tract leads to spontaneous hyperplastic and neoplastic lesions, and in APC mutant background leads to aggressive adenocarcinomas, establishing a tumor-promoting role via cell survival regulation. Transgenic mouse overexpression, APC mutant cross, tumor histology, apoptosis assays Nature High 15343335
2005 Netrin-1 expressed on vascular endothelium acts as a potent inhibitor of leukocyte migration in vitro and in vivo via UNC5b receptor on leukocytes, inhibiting migration in response to diverse chemotactic stimuli. Endothelial netrin-1 expression is regulated by infection and inflammatory cytokines. Transwell migration assays, in vivo migration models, receptor expression analysis, cytokine treatment Proceedings of the National Academy of Sciences of the United States of America High 16203981
2008 Netrin-1 expression in metastatic breast cancer cells confers a survival advantage by blocking proapoptotic activity of dependence receptors DCC and UNC5H. Interference with netrin-1 via siRNA or decoy DCC ectodomain triggers apoptosis in netrin-1-expressing tumor cell lines and prevents metastasis in mouse models. siRNA knockdown, decoy receptor treatment, apoptosis assays, mouse lung colonization and spontaneous metastasis models Proceedings of the National Academy of Sciences of the United States of America High 18353983
2009 HIF-1α transcriptionally induces Netrin-1 (NTN1) expression in hypoxic epithelia. Netrin-1 attenuates hypoxia-elicited neutrophil transepithelial migration by engaging the A2B adenosine receptor (A2BAR) on neutrophils. Exogenous netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not A2BAR-deficient mice; Ntn1+/- mice showed enhanced inflammation. HIF-1α-dependent luciferase reporter assay, neutrophil transmigration assay, A2BAR knockout mice, Ntn1 heterozygous mice Nature immunology High 19122655
2009 DSCAM (Down syndrome cell adhesion molecule) binds Netrin-1 and functions as a netrin-1 receptor on commissural axons. DSCAM mediates netrin-1 signaling by activating phosphorylation of Fyn and Pak1 independently of DCC, and its knockdown in ovo causes commissural axon projection defects. Co-immunoprecipitation (DSCAM-Netrin-1 interaction), siRNA knockdown, in vitro axon outgrowth and turning assays, in ovo knockdown Proceedings of the National Academy of Sciences of the United States of America High 19196994
2009 Autocrine netrin-1 production in aggressive neuroblastoma blocks the proapoptotic activity of UNC5H dependence receptors, conferring a selective advantage for tumor growth and dissemination. Disruption of the netrin-1 autocrine loop triggers neuroblast cell death in vitro and inhibits NB metastasis in avian and mouse models. siRNA knockdown, decoy receptor treatment, apoptosis assays, avian and mouse metastasis models The Journal of experimental medicine High 19349462
2009 Netrin-1 interference via decoy DCC ectodomain or siRNA in NSCLC cell lines induces UNC5H-mediated cell death in vitro and inhibits or reverses tumor growth in xenografted nude mice, demonstrating that netrin-1 promotes lung cancer cell survival through its dependence receptor UNC5H. siRNA knockdown, decoy receptor protein treatment, caspase-3 assay, xenograft mouse model Journal of the National Cancer Institute High 19211441
2010 The transmembrane receptor DCC forms a physical complex with multiple translation machinery components (eukaryotic initiation factors, ribosomal subunits, monosomes) in neuronal axons. Netrin-1 binding to DCC promotes translation and disassociation of translation components from DCC, establishing a mechanism for extracellular ligand-regulated local protein synthesis. Co-immunoprecipitation, affinity purification, mass spectrometry, metabolic labeling of newly synthesized protein, fluorescence colocalization in axons Cell High 20434207
2010 Netrin-1 dampens pulmonary inflammation and neutrophil infiltration during acute lung injury via the A2B adenosine receptor (A2BAR). Ntn1+/- mice showed enhanced ALI; exogenous netrin-1 reduced neutrophil influx and cytokine production in an A2BAR-dependent manner. The netrin-1 promoter contains an NF-κB-dependent element mediating LPS-induced repression. Mouse ALI model (LPS inhalation, mechanical ventilation), Ntn1+/- and A2BAR-/- mice, luciferase reporter assay, cytokine ELISA American journal of respiratory and critical care medicine High 20075388
2012 Netrin-1, secreted by macrophages in atherosclerotic plaques, promotes atherosclerosis by retaining macrophages in the artery wall. Acting via its receptor UNC5b, netrin-1 inhibits macrophage migration toward chemokines CCL2 and CCL19, suppresses Rac1 activation and actin polymerization. Macrophage-targeted deletion of Ntn1 reduced atherosclerosis and promoted macrophage emigration from plaques. Macrophage-specific Ntn1 conditional knockout, macrophage migration assays, Rac1 GTP-loading assay, actin polymerization assay, atherosclerosis quantification Nature immunology High 22231519
2014 Netrin-1 promotes adipose tissue macrophage retention and insulin resistance during obesity via UNC5b receptor. Palmitate induces netrin-1 expression in macrophages; netrin-1 via UNC5b blocks macrophage migration. Hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration, reduces inflammation, and improves insulin sensitivity. Hematopoietic Ntn1 conditional knockout (bone marrow transplant), macrophage migration assays, diet-induced obesity model, insulin tolerance test Nature medicine High 24584118
2015 Netrin-1, induced in brain endothelial cells by astrocyte-derived sonic hedgehog, supports blood-brain barrier integrity by upregulating endothelial junctional protein expression via autocrine signaling. Netrin-1 knockout mice display disorganized tight junction proteins and barrier breakdown. During inflammation, upregulated endothelial netrin-1 prevents junctional breach. Netrin-1 treatment during EAE reduced blood-brain barrier disruption and clinical disease severity. Netrin-1 KO mice, in vitro transendothelial resistance and permeability assays, EAE mouse model, tight junction protein immunostaining Brain : a journal of neurology High 25903786
2018 Macrophage-derived netrin-1, acting through its receptor neogenin-1, promotes abdominal aortic aneurysm formation. Neogenin-1 binding triggers intracellular calcium flux in vascular smooth muscle cells, leading to transcriptional upregulation and persistent catalytic activation of MMP3, driving ECM degradation. Macrophage-specific Ntn1 deletion protects mice from AAA; MMP3 deficiency similarly reduces ECM damage and AAA susceptibility. Single-cell RNA-seq, macrophage-specific Ntn1 conditional KO, calcium flux assays, MMP3 activity assays, MMP3 KO mice, AAA mouse model Nature communications High 30479344
2018 DCC/NTN1 mutations identified in congenital hypogonadotropic hypogonadism (CHH/Kallmann syndrome) patients impair GnRH neuron development. In vitro studies of rare sequence variants showed altered intracellular signaling and defects in cell morphology. Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells), establishing a role for the NTN1-DCC pathway in GnRH neuron ontogeny. Whole-exome sequencing, in vitro cell morphology and migration assays with RSVs, GN11 cell migration assay Human molecular genetics Medium 29202173
2019 The microRNAs let-7 and miR-9 directly repress Ntn1 (Netrin-1) and Dcc, respectively, during peripheral nerve regeneration. Let-7 binds the Ntn1 3'-UTR, represses Ntn1 expression and reduces secretion of Netrin-1 protein from Schwann cells, decreasing axon outgrowth. A regulatory network involving let-7, Lin28, and NF-κB modulates Netrin-1 levels during nerve regeneration. qRT-PCR, luciferase reporter assay with 3'-UTR constructs, Schwann cell Ntn1 protein secretion assay, DRG axon outgrowth assay The Journal of biological chemistry High 30626732
2021 Simultaneous binding of Netrin-1 (NET1/NTN1) and repulsive guidance molecule (RGM) to neogenin (NEO1) forms a ternary NEO1-NET1-RGM super-complex ('trimer-of-trimers') in the cell membrane. This super-assembly reciprocally silences downstream signaling: it inhibits RGMA-NEO1-mediated growth cone collapse and both RGMA- and NET1-NEO1-mediated neuron migration, by preventing formation of signaling-compatible RGM-NEO1 complexes and blocking NET1-induced NEO1 ectodomain clustering. X-ray crystallography (NEO1-NET1-RGM structure), cell-based growth cone collapse assay, neuron migration assay, membrane complex analysis Cell High 33740419
2022 The human macrophage lncRNA SIMALR suppresses inflammatory macrophage apoptosis via NTN1 (Netrin-1). SIMALR knockdown in LPS/IFNγ-stimulated macrophages reduces NTN1 expression; NTN1 knockdown alone induces apoptosis. Recombinant NTN1 rescues SIMALR knockdown-induced apoptosis. SIMALR interacts with HIF1α to regulate NTN1 promoter activity, placing NTN1 downstream of SIMALR-HIF1α in a macrophage survival pathway. Antisense oligonucleotide knockdown, RNA-seq, Western blot (cleaved PARP/caspase), luciferase NTN1 promoter assay, RNA immunoprecipitation (SIMALR-HIF1α), recombinant NTN1 rescue Arteriosclerosis, thrombosis, and vascular biology Medium 36546321
2023 The lncRNA DIAPH2-AS1 stabilizes NSUN2 from ubiquitin-proteasomal degradation by masking its K577 and K579 residues. NSUN2 in turn enhances NTN1 mRNA stability through m5C modification, promoting neural invasion of gastric cancer. This DIAPH2-AS1-NSUN2-NTN1 axis was validated by pulldown and RNA immunoprecipitation assays and in vivo mouse models. RNA pulldown, RNA immunoprecipitation, ubiquitination assay, m5C RNA modification assay, in vivo mouse sciatic nerve and lung metastasis models Cell death & disease Medium 37037818
2023 Netrin-1 (NET-1/NTN1) and its receptor UNC-5B interact to form equimolar heterocomplexes. Sedimentation velocity experiments show that Netrin-1 exists in a monomer-dimer equilibrium, forming a pH-sensitive anti-parallel dimer. UNC-5B forms equimolar heterocomplexes with both monomeric and dimeric Netrin-1. Multi-wavelength analytical ultracentrifugation (AUC), sedimentation velocity experiments, fluorophore-labeled UNC-5B European biophysics journal : EBJ Medium 36939874
2025 In cerebellar granule neuron germinal zone exit, Netrin-1 (Ntn1) signals via DCC receptor are gated by cell polarity. The Pard3 polarity protein and JamC adhesion molecule promote DCC surface recruitment to enable Netrin-1-mediated repulsion from the germinal zone, while the Siah2 ubiquitin ligase inhibits DCC surface recruitment. Genetic epistasis demonstrates that this Pard3/JamC-Siah2-DCC coincidence detection circuit integrates adhesion and guidance cues for GZ exit. Genetic epistasis in mouse cerebellum, conditional knockouts, live imaging, DCC surface recruitment assays Nature communications High 39774925
2025 Netrin-1 (NTN-1) attenuates Aβ1-42-induced microglial neuroinflammation and memory impairment in a rat Alzheimer's disease model by inhibiting microglial proliferation, NLRP3 inflammasome activation, proinflammatory cytokine (IL-1β and IL-18) release, and NF-κB signaling upstream activation in the hippocampus and cortex. Microinjection of recombinant NTN-1 in Aβ1-42 rat model, Morris water maze, Western blotting for NLRP3/caspase-1/NF-κB pathway components, immunohistochemistry Frontiers in aging neuroscience Medium 40357234
2001 Netrin-1 is expressed by neurons and oligodendrocytes throughout the adult rat spinal cord. In adult spinal cord white matter, the majority of netrin-1 protein is not freely soluble but is membrane-associated or ECM-associated, and is enriched in fractions containing periaxonal myelin and axolemma rather than compact myelin, suggesting a short-range function in axon-oligodendroglial interactions in the mature CNS. In situ hybridization, immunofluorescence colocalization with cell-type markers, subcellular fractionation of white matter, Western blot The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 11356879

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1996 Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 1084 8978605
1999 Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 1005 10102268
1996 Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell 873 8861902
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2009 Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nature immunology 350 19122655
1999 Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell 335 10219245
2012 The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nature immunology 305 22231519
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nature genetics 275 22863734
2004 Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 247 15343335
2005 Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 235 16203981
2003 Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis. Developmental cell 233 12636918
2004 Netrin-1 and its receptors in tumorigenesis. Nature reviews. Cancer 220 15573119
2014 Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nature medicine 216 24584118
1999 Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Molecular and cellular biology 215 9858595
2010 Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 195 20434207
2008 Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer. Proceedings of the National Academy of Sciences of the United States of America 191 18353983
2003 Recognition of the neural chemoattractant Netrin-1 by integrins alpha6beta4 and alpha3beta1 regulates epithelial cell adhesion and migration. Developmental cell 191 14602071
2000 Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature 174 11048721
2005 Support for association between ADHD and two candidate genes: NET1 and DRD1. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 159 15717291
2015 Netrin 1 regulates blood-brain barrier function and neuroinflammation. Brain : a journal of neurology 156 25903786
2018 Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nature communications 141 30479344
2009 DSCAM functions as a netrin receptor in commissural axon pathfinding. Proceedings of the National Academy of Sciences of the United States of America 137 19196994
2001 Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 129 11356879
2010 Netrin-1 dampens pulmonary inflammation during acute lung injury. American journal of respiratory and critical care medicine 122 20075388
2013 Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. Human genetics 120 23512105
2009 Netrin-1 acts as a survival factor for aggressive neuroblastoma. The Journal of experimental medicine 116 19349462
2009 Interference with netrin-1 and tumor cell death in non-small cell lung cancer. Journal of the National Cancer Institute 115 19211441
2001 Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit. Molecular cell 111 11511359
2011 Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 95 21986943
2001 The activity of guanine exchange factor NET1 is essential for transforming growth factor-beta-mediated stress fiber formation. The Journal of biological chemistry 93 11278519
2008 NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer. British journal of cancer 87 18827818
2011 The small GTPase RhoA localizes to the nucleus and is activated by Net1 and DNA damage signals. PloS one 85 21390328
1996 Isolation of a novel oncogene, NET1, from neuroepithelioma cells by expression cDNA cloning. Oncogene 79 8649828
2002 The Rho exchange factor Net1 is regulated by nuclear sequestration. The Journal of biological chemistry 67 11839749
2006 Net1 and Myeov: computationally identified mediators of gastric cancer. British journal of cancer 66 16552434
2005 PAK1 negatively regulates the activity of the Rho exchange factor NET1. The Journal of biological chemistry 64 15684429
2001 Characterization of the Net1 cell cycle-dependent regulator of the Cdc14 phosphatase from budding yeast. The Journal of biological chemistry 64 11274204
2002 Cdc5 influences phosphorylation of Net1 and disassembly of the RENT complex. BMC molecular biology 63 11960554
2011 The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage. PloS one 62 21373644
2011 Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. British journal of anaesthesia 60 21857017
2002 Mass spectrometry-based methods for phosphorylation site mapping of hyperphosphorylated proteins applied to Net1, a regulator of exit from mitosis in yeast. Molecular & cellular proteomics : MCP 60 12096118
2008 A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage. PloS one 58 18509476
2002 Budding yeast Cdc5 phosphorylates Net1 and assists Cdc14 release from the nucleolus. Biochemical and biophysical research communications 57 12056824
2014 Propofol and bupivacaine in breast cancer cell function in vitro - role of the NET1 gene. Anticancer research 56 24596379
2013 Regulation of focal adhesion kinase activation, breast cancer cell motility, and amoeboid invasion by the RhoA guanine nucleotide exchange factor Net1. Molecular and cellular biology 52 23689132
2019 The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration. The Journal of biological chemistry 47 30626732
2010 Smad3 regulates Rho signaling via NET1 in the transforming growth factor-beta-induced epithelial-mesenchymal transition of human retinal pigment epithelial cells. The Journal of biological chemistry 45 20547485
2023 Long noncoding RNA DIAPH2-AS1 promotes neural invasion of gastric cancer via stabilizing NSUN2 to enhance the m5C modification of NTN1. Cell death & disease 42 37037818
2007 The nuclear RhoA exchange factor Net1 interacts with proteins of the Dlg family, affects their localization, and influences their tumor suppressor activity. Molecular and cellular biology 42 17938206
2019 LncRNA CTC-497E21.4 promotes the progression of gastric cancer via modulating miR-22/NET1 axis through RhoA signaling pathway. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 41 31451992
2009 Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 37 19124484
2021 Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling. Cell 36 33740419
2022 Circ_0000745 promotes acute lymphoblastic leukemia progression through mediating miR-494-3p/NET1 axis. Hematology (Amsterdam, Netherlands) 35 34957935
2018 DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Human molecular genetics 35 29202173
1993 Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16. Genomics 35 7905857
2021 Baicalin suppresses lung cancer growth phenotypes via miR-340-5p/NET1 axis. Bioengineered 32 33955315
2016 The guanine nucleotide exchange factor Net1 facilitates the specification of dorsal cell fates in zebrafish embryos by promoting maternal β-catenin activation. Cell research 32 27910850
2013 Insulin-like growth factor 1 induces the transcription of Gap43 and Ntn1 during hair cell protection in the neonatal murine cochlea. Neuroscience letters 31 24333914
2008 Expression and clinical significance of NET-1 and PCNA in hepatocellular carcinoma. Medical oncology (Northwood, London, England) 31 18214716
2014 miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1. The FEBS journal 29 25041463
2009 Interaction of the RhoA exchange factor Net1 with discs large homolog 1 protects it from proteasome-mediated degradation and potentiates Net1 activity. The Journal of biological chemistry 26 19586902
2018 miR‑22‑3p enhances multi‑chemoresistance by targeting NET1 in bladder cancer cells. Oncology reports 25 29620229
2023 AAV-Net1 facilitates the trans-differentiation of supporting cells into hair cells in the murine cochlea. Cellular and molecular life sciences : CMLS 24 36917323
2024 SP1-induced circ_0017552 modulates colon cancer cell proliferation and apoptosis via up-regulation of NET1. Cancer genetics 23 38810361
2018 Contributions of the RhoA guanine nucleotide exchange factor Net1 to polyoma middle T antigen-mediated mammary gland tumorigenesis and metastasis. Breast cancer research : BCR 22 29769144
2013 Inhibition of hepatocellular carcinoma growth and angiogenesis by dual silencing of NET-1 and VEGF. Journal of molecular histology 22 23636606
2011 A functional and transcriptomic analysis of NET1 bioactivity in gastric cancer. BMC cancer 22 21284875
2019 NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells. Oncology research 21 31046876
2011 Meiotic nuclear divisions in budding yeast require PP2A(Cdc55)-mediated antagonism of Net1 phosphorylation by Cdk. The Journal of cell biology 19 21690311
2019 The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate. European journal of human genetics : EJHG 17 31780810
2014 The RhoGEF Net1 is required for normal mammary gland development. Molecular endocrinology (Baltimore, Md.) 17 25321414
2013 Rho GTPase-independent regulation of mitotic progression by the RhoGEF Net1. Molecular biology of the cell 16 23864709
2012 Neuroepithelial transforming gene 1 (Net1) binds to caspase activation and recruitment domain (CARD)- and membrane-associated guanylate kinase-like domain-containing (CARMA) proteins and regulates nuclear factor κB activation. The Journal of biological chemistry 16 22343628
2022 Human Macrophage Long Intergenic Noncoding RNA, SIMALR, Suppresses Inflammatory Macrophage Apoptosis via NTN1 (Netrin-1). Arteriosclerosis, thrombosis, and vascular biology 15 36546321
2021 NET1 promotes HCC growth and metastasis in vitro and in vivo via activating the Akt signaling pathway. Aging 14 33839702
2020 Hog1 activation delays mitotic exit via phosphorylation of Net1. Proceedings of the National Academy of Sciences of the United States of America 14 32265285
2019 Evaluation of therapeutic effect of targeting nanobubbles conjugated with NET-1 siRNA by shear wave elastography: an in vivo study of hepatocellular carcinoma bearing mice model. Drug delivery 13 31544556
2012 The effect of NET-1 on the proliferation, migration and endocytosis of the SMMC-7721 HCC cell line. Oncology reports 13 22378020
2024 Visible-light-driven net-1,2-hydrogen atom transfer of amidyl radicals to access β-amido ketone derivatives. Chemical science 12 39664809
2019 The C-terminal region of Net1 is an activator of RNA polymerase I transcription with conserved features from yeast to human. PLoS genetics 12 30802237
2019 Cdc14 activation requires coordinated Cdk1-dependent phosphorylation of Net1 and PP2A-Cdc55 at anaphase onset. Cellular and molecular life sciences : CMLS 12 30927017
2014 The possible involvement of genetic variants of NET1 in the etiology of attention-deficit/hyperactivity disorder comorbid with oppositional defiant disorder. Journal of child psychology and psychiatry, and allied disciplines 12 24942521
2011 RhoC and guanine nucleotide exchange factor Net1 in androgen-unresponsive mouse mammary carcinoma SC-4 cells and human prostate cancer after short-term endocrine therapy. The Prostate 12 22095553
2007 The nucleolar Net1/Cfi1-related protein Dnt1 antagonizes the septation initiation network in fission yeast. Molecular biology of the cell 12 17538026
2020 The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis. Cell cycle (Georgetown, Tex.) 11 32794416
2018 Regulation of RhoA activation and cell motility by c-Jun N-terminal kinases and Net1. Small GTPases 11 30332929
2019 Inhibition of NET-1 suppresses proliferation and promotes apoptosis of hepatocellular carcinoma cells by activating the PI3K/AKT signaling pathway. Experimental and therapeutic medicine 10 30867719
2017 Association between PAX7 and NTN1 gene polymorphisms and nonsyndromic orofacial clefts in a northern Chinese population. Medicine 10 28489749
2017 Genetic deletion of the Rho GEF Net1 impairs mouse macrophage motility and actin cytoskeletal organization. Small GTPases 10 29173011
2019 NTN1 Affects Porcine Intramuscular Fat Content by Affecting the Expression of Myogenic Regulatory Factors. Animals : an open access journal from MDPI 9 31461826
2013 Expression and function of NET-1 in human skin squamous cell carcinoma. Archives of dermatological research 9 24196235
2002 A role for the Saccharomyces cerevisiae RENT complex protein Net1 in HMR silencing. Genetics 9 12196389
2017 Short interfering RNA targeting Net1 reduces the angiogenesis and tumor growth of in vivo cervical squamous cell carcinoma through VEGF down-regulation. Human pathology 8 28511963
2021 Cdk1 phosphorylation negatively regulates the activity of Net1 towards RhoA during mitosis. Cellular signalling 7 33465404
2021 Quantitative Proteomics Analysis of FFPE Tumor Samples Reveals the Influences of NET-1 siRNA Nanoparticles and Sonodynamic Therapy on Tetraspanin Protein Involved in HCC. Frontiers in molecular biosciences 7 34041269
2020 Propofol suppresses hepatocellular carcinoma by inhibiting NET1 through downregulating ERK/VEGF signaling pathway. Scientific reports 7 32641699
2020 MiRNA505/NET1 Axis Acts as a CD8+ T-TIL Regulator in Non-Small Cell Lung Cancer. OncoTargets and therapy 7 33061457
2018 A structural study of the complex between neuroepithelial cell transforming gene 1 (Net1) and RhoA reveals a potential anticancer drug hot spot. The Journal of biological chemistry 7 29695506
2015 Inhibition of skin squamous cell carcinoma proliferation and promote apoptosis by dual silencing of NET-1 and survivin. Oncology reports 7 26080853
2013 Real-world experience of carotid artery stenting in Japan: analysis of 7,134 cases from JR-NET1 and 2 nationwide retrospective multi-center registries. Neurologia medico-chirurgica 7 24305031
2013 Study of RNA Interference Targeting NET-1 Combination with Sorafenib for Hepatocellular Carcinoma Therapy In Vitro and In Vivo. Gastroenterology research and practice 7 24307893
2018 VTIQ evaluates antitumor effects of NET-1 siRNA by UTMD in HCC xenograft models. Oncology letters 6 30127877
2018 NLRP1 and NTN1, Deregulated Blood Differentially Methylated Regions in Mild Cognitive Impairment Patients. Journal of molecular neuroscience : MN 6 30397880
2017 A GEF activity-independent function for nuclear Net1 in Nodal signal transduction and mesendoderm formation. Journal of cell science 6 28778986
2024 NET1 is a critical regulator of spindle assembly and actin dynamics in mouse oocytes. Reproductive biology and endocrinology : RB&E 5 38169395
2023 Identification of putative regulatory single-nucleotide variants in NTN1 gene associated with NSCL/P. Journal of human genetics 5 36879001
2018 NTN1 gene was risk to non-syndromic cleft lip only among Han Chinese population. Oral diseases 5 30506619
2025 Multiomics analysis reveals the involvement of NET1 in tumour immune regulation and malignant progression. Scientific reports 4 39747410
2006 [Expression of NET-1 gene and protein in hepatocellular carcinoma and related tissues]. Ai zheng = Aizheng = Chinese journal of cancer 4 16536986
2003 NET1 and HFI1 genes of yeast mediate both chromosome maintenance and mitochondrial rho(-) mutagenesis. Yeast (Chichester, England) 4 12898711
2025 NTN-1 attenuates amyloid-β-mediated microglial neuroinflammation and memory impairment via the NF-κB pathway and NLRP3 inflammasome in a rat model of Alzheimer's disease. Frontiers in aging neuroscience 3 40357234
2023 Investigation of dynamic solution interactions between NET-1 and UNC-5B by multi-wavelength analytical ultracentrifugation. European biophysics journal : EBJ 3 36939874
2023 MicroRNA PC-3p-2869 Regulates Antler Growth and Inhibits Proliferation and Migration of Human Osteosarcoma and Chondrosarcoma Cells by Targeting CDK8, EEF1A1, and NTN1. International journal of molecular sciences 3 37446017
2018 NET-1 promotes invasion, adhesion and growth of hepatocellular carcinoma by regulating the expression of BAX, caspase 3, caspase 8 and BCL2. Cellular and molecular biology (Noisy-le-Grand, France) 3 30301500
2025 Siah2 antagonism of Pard3/JamC modulates Ntn1-Dcc signaling to regulate cerebellar granule neuron germinal zone exit. Nature communications 2 39774925
2025 A stable NTN1 fluorescent reporter chicken reveals cell specific molecular signatures during optic fissure closure. Scientific reports 2 40128351
2024 Conditional Overexpression of Net1 Enhances the Trans-Differentiation of Lgr5+ Progenitors into Hair Cells in the Neonatal Mouse Cochlea. Cell proliferation 2 39675772
2009 [Functions of NET-1 gene in skin squamous cell carcinoma cell line (A431): a siRNA study]. Zhonghua bing li xue za zhi = Chinese journal of pathology 2 20078975
2007 [Expression and significance of NET-1 protein in hepatocellular carcinoma]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2 18478931
2024 Antagonistic action of Siah2 and Pard3/JamC to promote germinal zone exit of differentiated cerebellar granule neurons by modulating Ntn1 signaling via Dcc. Research square 1 39399669
2024 Reduced NET1 adversely affects early embryonic development in mice. Theriogenology 1 39426210
2017 Effect of NET-1 siRNA conjugated sub-micron bubble complex combined with low-frequency ultrasound exposure in gene transfection. Oncotarget 1 29423111
2014 Real-world Experience of Carotid Artery Stentingin Japan: Analysis of 7,134 Cases from JR-NET1 and 2Nationwide Retrospective Multi-center Registries. Neurologia medico-chirurgica 1 26236823
2009 [Participation of SRM5/CDC28, SRM8/NET1, and SRM12/HFI1 genes in checkpoint control in yeast Saccharomyces cerevisiae]. Genetika 1 19507699
2025 Net1 Controls Src Activation to Regulate Breast Cancer Cell Motility and Invasion. Molecular and cellular biology 0 40765140