Affinage

NTN1

Netrin-1 · UniProt O95631

Length
604 aa
Mass
67.7 kDa
Annotated
2026-06-10
19 papers in source corpus 14 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NTN1 (Netrin-1) is a secreted guidance cue that signals through cell-surface receptors to direct neuronal migration, axon outgrowth, and tissue morphogenesis, and that is co-opted in cancer and vascular and inflammatory settings [PMID:39774925, PMID:39399669, PMID:bio_10.1101_2025.07.22.666009]. In cerebellar granule neuron germinal zone exit, Netrin-1-mediated repulsion of maturing neurons is gated by surface availability of the receptor DCC, which is promoted by the polarity protein Pard3 and the adhesion molecule JamC and antagonized by the ubiquitin ligase Siah2 — integrating adhesive and guidance cues with cell polarity (PMID:39774925, PMID:39399669). In peripheral neurons, Netrin-1 secreted by Schwann cells supports axon outgrowth in dorsal root ganglion neurons, and in cell-based assays it promotes migration of GnRH neurons, with rare heterozygous NTN1 variants from congenital hypogonadotropic hypogonadism patients altering intracellular signaling and morphology (PMID:30626732, PMID:29202173). Beyond the nervous system, Netrin-1 acts through distinct receptors in disease contexts: NEO1 signaling activates FAK to drive EMT and stemness during pancreatic tumorigenesis and sympathetic innervation [PMID:bio_10.1101_2025.07.22.666009], and Unc5b-dependent signaling stabilizes the blood-retina barrier [PMID:bio_10.1101_2025.06.14.658755]. NTN1 also functions as a survival factor for inflammatory macrophages downstream of a HIF1α/SIMALR transcriptional circuit (PMID:36546321). NTN1 expression is controlled at multiple levels: transcriptionally through enhancer/promoter elements (PMID:31780810), post-transcriptionally by let-7 binding the 3'-UTR (PMID:30626732), and via NSUN2-mediated m5C methylation that stabilizes NTN1 mRNA to promote gastric cancer neural invasion (PMID:37037818).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2013 Low

    Established that Ntn1 is an inducible target of growth-factor signaling, linking IGF-1 to upregulation of a guidance cue in developing sensory tissue.

    Evidence cDNA microarray, qRT-PCR, and pharmacological inhibition of PI3K/Akt and MEK/ERK pathways in neonatal murine cochlea

    PMID:24333914

    Open questions at the time
    • Indirect mRNA-level readout without identification of the responsible transcription factor
    • Does not establish a functional consequence for cochlear development
  2. 2018 Medium

    Connected NTN1 to GnRH neuron biology and human disease by showing it promotes GnRH neuron migration and that patient-derived variants perturb signaling.

    Evidence GN11 cell migration assays and in vitro characterization of rare variants from congenital hypogonadotropic hypogonadism patients

    PMID:29202173

    Open questions at the time
    • Migration assayed in an immortalized cell line, not in vivo GnRH neuron tracts
    • Receptor mediating the migratory effect not defined
  3. 2019 Medium

    Defined a post-transcriptional brake on NTN1, showing let-7 directly represses Ntn1 to limit axon outgrowth.

    Evidence 3'-UTR luciferase reporter, qRT-PCR, and DRG axon outgrowth assays in Schwann cells

    PMID:30626732

    Open questions at the time
    • Does not address upstream regulation of let-7 itself
    • Single-lab functional readout
  4. 2019 Medium

    Identified cis-regulatory control of NTN1 and an in vivo developmental role, linking a risk allele to reduced enhancer activity and craniofacial phenotypes.

    Evidence Luciferase enhancer reporter, CRISPR/Cas9 ntn1a knockout zebrafish, cell cycle and apoptosis assays

    PMID:31780810

    Open questions at the time
    • Transcription factor binding the disrupted motif not conclusively identified
    • Zebrafish phenotype not mechanistically tied to receptor signaling
  5. 2022 Medium

    Placed NTN1 downstream of a HIF1α/lncRNA transcriptional circuit and established it as a macrophage survival factor.

    Evidence RIP, NTN1 promoter luciferase reporter, siRNA knockdown, Annexin V apoptosis, and recombinant NTN1 rescue in stimulated macrophages

    PMID:36546321

    Open questions at the time
    • Receptor transducing the survival signal in macrophages not defined
    • In vitro stimulation model only
  6. 2023 Medium

    Revealed epitranscriptomic control of NTN1, with NSUN2-deposited m5C stabilizing NTN1 mRNA to drive cancer neural invasion.

    Evidence RNA pulldown, RIP, ubiquitination assays, and in vitro/in vivo invasion models in gastric cancer

    PMID:37037818

    Open questions at the time
    • m5C site mapping on NTN1 mRNA not detailed
    • Downstream receptor signaling driving invasion not addressed
  7. 2025 High

    Resolved how Netrin-1 guidance is spatially gated during neuronal migration, showing cell polarity controls DCC surface availability for germinal zone exit.

    Evidence Genetic epistasis (Pard3, JamC, Siah2, DCC), live imaging, and direct DCC surface recruitment assays in mouse cerebellum

    PMID:39399669 PMID:39774925

    Open questions at the time
    • Molecular mechanism by which Siah2 vs Pard3/JamC differentially route DCC not fully resolved
    • Whether the same gating operates in other migrating neuron populations untested
  8. 2025 Medium

    Defined a NEO1/FAK signaling axis through which NTN1 drives pancreatic tumorigenesis and tumor innervation.

    Evidence KrasG12D organoid screen, Ntn1 KO mouse model, ex vivo axonogenesis assay, neutralizing antibody and Neo1 shRNA (preprint)

    PMID:bio_10.1101_2025.07.22.666009

    Open questions at the time
    • Preprint, not peer-reviewed
    • How NEO1 engages FAK mechanistically not established
  9. 2025 Medium

    Showed NTN1 stabilizes the blood-retina barrier through Unc5b, distinguishing barrier maintenance from angiogenic effects.

    Evidence Genetic NTN1 overexpression in mice, vascular leak assays in OIR and CNV models, Unc5b epistasis (preprint)

    PMID:bio_10.1101_2025.06.14.658755

    Open questions at the time
    • Preprint, not peer-reviewed
    • Endothelial signaling downstream of Unc5b not characterized
  10. 2025 Medium

    Demonstrated faithful NTN1 expression in optic fissure fusion pioneer cells and used a reporter to profile their transcriptome.

    Evidence CRISPR/Cas9 NTN1-T2A-eGFP knock-in chicken reporter, FACS isolation, and RNA-seq

    PMID:40128351

    Open questions at the time
    • Functional requirement of NTN1 for optic fissure fusion not demonstrated
    • Receptor partners in pioneer cells unknown
  11. 2025 Low

    Reported anti-inflammatory and neuroprotective actions of NTN1 in an Alzheimer's model via suppression of NLRP3/NF-κB signaling.

    Evidence Microinjection of recombinant NTN1 in Aβ1-42 rat model, Morris water maze, and Western blotting for inflammasome components

    PMID:40357234

    Open questions at the time
    • No direct molecular mechanism linking NTN1 to NLRP3/NF-κB suppression
    • Receptor mediating the anti-inflammatory effect not identified
  12. 2025 Low

    Suggested NTN1 regulates myoblast proliferation and differentiation through AMPK, but the link is inferential.

    Evidence siRNA knockdown, overexpression, and proliferation/differentiation assays in C2C12 cells

    PMID:31461826

    Open questions at the time
    • AMPK link inferred, not directly confirmed
    • Receptor and signaling intermediates undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NTN1's distinct receptors (DCC, NEO1, UNC5B) and intracellular partners are selected across these diverse contexts to produce migration, survival, barrier, or oncogenic outputs remains unresolved.
  • No unified model linking receptor choice to downstream effector pathways
  • Tissue-specific co-receptor and adaptor requirements largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
DCCMAP1BNEO1UNC5B

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 The microRNA let-7 directly targets the 3'-UTR of Ntn1 mRNA, represses Ntn1 expression, and reduces secretion of Ntn1 protein in Schwann cells, thereby reducing axon outgrowth in dorsal root ganglion neurons. Quantitative RT-PCR, biochemical assays, and luciferase reporter gene assay targeting the 3'-UTR of Ntn1 The Journal of biological chemistry Medium 30626732
2018 Netrin-1 (NTN1) promotes migration of immortalized GnRH neurons (GN11 cells), and rare heterozygous NTN1 mutations found in congenital hypogonadotropic hypogonadism patients alter intracellular signaling and cell morphology, consistent with a role in GnRH neuron ontogeny. In vitro migration assay of GN11 cells; in vitro characterization of patient-derived rare sequence variants showing altered intracellular signaling and cell morphology Human molecular genetics Medium 29202173
2023 m5C methylation of NTN1 mRNA by NSUN2 stabilizes NTN1 mRNA; the lncRNA DIAPH2-AS1 protects NSUN2 from ubiquitin-proteasomal degradation (by masking K577/K579 of NSUN2), thereby increasing NTN1 expression and promoting neural invasion of gastric cancer cells. RNA pulldown, RNA immunoprecipitation, ubiquitination assays, in vitro and in vivo invasion/migration models Cell death & disease Medium 37037818
2013 IGF-1 upregulates Ntn1 transcription in the neonatal murine cochlea via both the PI3K/Akt and MEK/ERK pathways, as demonstrated by pathway inhibitor experiments, with the transcriptional response limited to within 12 hours of IGF-1 treatment. cDNA microarray, qRT-PCR, and pharmacological inhibition of PI3K/Akt and MEK/ERK pathways Neuroscience letters Low 24333914
2022 The lncRNA SIMALR partners with HIF1α to regulate NTN1 promoter activity; NTN1 knockdown in LPS/IFNγ-stimulated macrophages induces apoptosis, and the apoptotic phenotype caused by SIMALR knockdown is rescued by recombinant NTN1, establishing NTN1 as a downstream survival factor in inflammatory macrophages. RNA immunoprecipitation, luciferase NTN1 promoter reporter assay, siRNA knockdown, Annexin V apoptosis assay, recombinant NTN1 rescue experiment Arteriosclerosis, thrombosis, and vascular biology Medium 36546321
2019 The rs4791331-T allele in the NTN1 locus disrupts a transcription factor binding motif, reduces NTN1 enhancer/promoter activity (measured by luciferase reporter), lowers NTN1 expression, and exerts anti-apoptotic effects and altered cell cycle progression; ntn1a knockout zebrafish display wider intermaxillary fissures, consistent with a role for NTN1 in craniofacial development. Luciferase enhancer reporter assay, CRISPR/Cas9 ntn1a knockout zebrafish, cell cycle and apoptosis assays, qRT-PCR European journal of human genetics : EJHG Medium 31780810
2025 In cerebellar granule neuron germinal zone exit, Pard3 polarity protein and JamC adhesion molecule promote, while the Siah2 ubiquitin ligase inhibits, surface recruitment of the Netrin-1 receptor DCC; this gating of DCC surface availability controls Netrin-1-mediated repulsion of maturing neurons from the germinal zone, demonstrating that cell polarity integrates adhesive and guidance cues for germinal zone exit. Genetic epistasis analysis in mouse cerebellum, live imaging, loss-of-function and rescue experiments for Pard3, JamC, Siah2, and DCC; direct measurement of DCC receptor surface recruitment Nature communications High 39399669 39774925
2019 NTN1 silencing in C2C12 myoblasts promotes cell proliferation and inhibits differentiation, whereas NTN1 overexpression inhibits proliferation and promotes differentiation; these effects are linked to the AMPK pathway, suggesting NTN1 regulates muscle cell fate via AMPK signaling. siRNA knockdown, gene overexpression, proliferation and differentiation assays in C2C12 cells, Western blotting Animals : an open access journal from MDPI Low 31461826
2025 NTN1 overexpression suppresses apoptosis, inflammation, and ROS in LPS-treated kidney tubular cells (HK-2); mechanistically, NTN1 interacts with MAP1B (identified by co-immunoprecipitation), promotes MAP1B-dependent autophagy (increased Atg5, LC3II/I ratio), and MAP1B in turn interacts with DAPK1 to regulate membrane blebbing and cell survival. Co-immunoprecipitation, Western blotting, MAP1B phosphorylation inhibitors, DAPK1 knockdown/overexpression, ROS measurement Open medicine (Warsaw, Poland) Low 42158103
2025 NTN1 promotes pancreatic tumorigenesis and sympathetic innervation through its receptor NEO1; NTN1/NEO1 signaling activates focal adhesion kinase (FAK) to enhance EMT (ZEB1, SOX9 upregulation) and cancer stemness. NTN1 is upregulated by KrasG12D mutation and β-adrenergic signaling via the MAPK pathway. Ntn1 knockout in KrasG12D mice decreased sympathetic innervation and pancreatic intraepithelial neoplasia. A NTN1-neutralizing antibody or NEO1 knockdown reduced tumor progression in a liver metastasis model. KrasG12D pancreatic organoid qRT-PCR screen; in vivo Ntn1 KO mouse model (Pdx1-Cre;LSL-KrasG12D/+); ex vivo celiac ganglia axonogenesis assay; recombinant NTN1 treatment; NTN1-neutralizing antibody; Neo1 shRNA knockdown; Western blotting for FAK phosphorylation bioRxivpreprint Medium bio_10.1101_2025.07.22.666009
2025 Genetic NTN1 overexpression stabilizes the blood-retina barrier (BRB) in an Unc5b-dependent manner: NTN1 overexpression rescued vascular leak in oxygen-induced retinopathy and laser-induced choroidal neovascularization models, while Unc5b-independent effects on retinal angiogenesis were minimal and transient. Genetic NTN1 overexpression in mice; vascular leak assays in OIR and CNV models; electroretinogram (ERG); genetic epistasis with Unc5b bioRxivpreprint Medium bio_10.1101_2025.06.14.658755
2025 NTN1 is expressed in optic fissure fusion pioneer cells in the chicken embryo, as revealed by a CRISPR/Cas9-generated NTN1-T2A-eGFP reporter line in which GFP faithfully replicated endogenous NTN1 expression; transcriptomic profiling of these pioneer cells identified new optic fissure closure markers and novel pathways for developmental tissue fusion. CRISPR/Cas9 knock-in of T2A-eGFP reporter into NTN1 locus; spectral fluorescence cell-sorting; RNA-seq transcriptomic profiling of pioneer cells Scientific reports Medium 40128351
2025 NTN1 attenuates Aβ1-42-induced neuroinflammation and memory impairment in rats by inhibiting microglial activation, suppressing NLRP3 inflammasome activation, preventing IL-1β and IL-18 release, and blocking NF-κB upstream signaling in the hippocampus and cortex. Microinjection of recombinant NTN1 in Aβ1-42 rat model; Morris water maze; Western blotting for NLRP3, NF-κB pathway components, caspase-1, IL-1β, IL-18 Frontiers in aging neuroscience Low 40357234

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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 46 37037818
2018 DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Human molecular genetics 36 29202173
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
2022 Human Macrophage Long Intergenic Noncoding RNA, SIMALR, Suppresses Inflammatory Macrophage Apoptosis via NTN1 (Netrin-1). Arteriosclerosis, thrombosis, and vascular biology 17 36546321
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
2019 NTN1 Affects Porcine Intramuscular Fat Content by Affecting the Expression of Myogenic Regulatory Factors. Animals : an open access journal from MDPI 10 31461826
2017 Association between PAX7 and NTN1 gene polymorphisms and nonsyndromic orofacial clefts in a northern Chinese population. Medicine 10 28489749
2023 Identification of putative regulatory single-nucleotide variants in NTN1 gene associated with NSCL/P. Journal of human genetics 6 36879001
2018 NLRP1 and NTN1, Deregulated Blood Differentially Methylated Regions in Mild Cognitive Impairment Patients. Journal of molecular neuroscience : MN 6 30397880
2018 NTN1 gene was risk to non-syndromic cleft lip only among Han Chinese population. Oral diseases 5 30506619
2025 Siah2 antagonism of Pard3/JamC modulates Ntn1-Dcc signaling to regulate cerebellar granule neuron germinal zone exit. Nature communications 3 39774925
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 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
2025 A stable NTN1 fluorescent reporter chicken reveals cell specific molecular signatures during optic fissure closure. Scientific reports 2 40128351
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
2026 NTN1 regulates autophagy through the MAP1B/DAPK1 axis to ameliorate acute kidney injury in vitro. Open medicine (Warsaw, Poland) 0 42158103
2025 Therapeutic effects of miR-937-3p by targeting NTN1 expression and regulating apoptosis in an Aβ-induced neuronal cell death. Scientific reports 0 40604203
2024 A Novel De Novo Missense Variant in Netrin-1 (NTN1) Associated With Chorioretinal Coloboma, Sensorineural Hearing Loss and Polydactyly. Clinical genetics 0 39648562

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