Affinage

NRTN

Neurturin · UniProt Q99748

Length
197 aa
Mass
22.4 kDa
Annotated
2026-06-10
96 papers in source corpus 32 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRTN is a secreted GDNF-family neurotrophic factor that signals by binding the GPI-anchored co-receptor GFRα2, which then recruits and dimerizes the RET receptor tyrosine kinase to trigger downstream signaling (PMID:31535977, PMID:31392261, PMID:17953664). Structural studies define the assembly: NRTN and GFRα2 impose a specific RET dimerization mode that juxtaposes two kinase domains for cross-phosphorylation, with the RET cysteine-rich domain contacting NRTN and the RET calcium-binding site contacting GFRα2 domain 3; the resulting dimeric complex further packs into a tetramer that regulates RET endocytosis, and a heparan sulfate-binding site on NRTN participates in complex assembly and modulates in vivo exposure (PMID:31535977, PMID:31392261, PMID:29414779). Downstream of RET, NRTN activates PI3K and MAPK and, in an isoform-specific manner (GFRα2c/RET9), drives serine-727 phosphorylation of mitochondrially localized STAT3 to support neurite outgrowth through a transcription-independent route (PMID:23872421, PMID:18673446). Physiologically, NRTN functions as a target-derived retrograde trophic factor transported in a GFRα coreceptor-specific manner and required for postnatal survival and target innervation of parasympathetic neurons—including lacrimal, cardiac, and penile populations—as well as sensory neurons and retinal horizontal/amacrine cells (PMID:10531437, PMID:14507865, PMID:19176599, PMID:18417692, PMID:10770848, PMID:11069590). Beyond classical neurotrophism, NRTN acts as a muscle-secreted myokine that retrogradely promotes slow motor neuron identity while raising muscle oxidative metabolism (PMID:34592133), supports a sympathetic-cholinergic neuro-osteocyte survival interface in bone (PMID:35276096), and dampens pro-inflammatory cytokine release from interferon-primed lung macrophages (PMID:33020210). Its striatal production is controlled by Hedgehog signaling in primary cilia, linking pathogenic LRRK2 mutations to reduced NRTN output and dopaminergic vulnerability (PMID:40591712). NRTN/GFRα2/RET signaling is also co-opted by pancreatic, colorectal, hepatocellular, and acute myeloid leukemia cells to drive proliferation, invasion, and survival (PMID:24067900, PMID:37211171, PMID:29654265, PMID:35114191).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Established that NRTN is a target-derived factor delivered by retrograde axonal transport and that its uptake is coreceptor-specific rather than shared with GDNF, defining how peripheral neurons distinguish GDNF-family ligands.

    Evidence In vivo sciatic nerve retrograde transport with cross-competition in dorsal root ganglion neuron populations

    PMID:10531437

    Open questions at the time
    • Did not resolve the molecular transport machinery
    • Receptor isoform usage not dissected at structural level
  2. 2000 High

    Genetic loss of GFRα2 separated NRTN's role from GDNF's: NRTN/GFRα2/RET is dispensable for early gangliogenesis but essential for postnatal parasympathetic survival and target innervation.

    Evidence GFRα1, GFRα2, and RET knockout mouse histology and innervation analysis; penile retrograde transport plus GFRα2-knockout phenotyping

    PMID:10770848 PMID:11069590

    Open questions at the time
    • Downstream signaling events not assayed
    • Mechanism of selective postnatal dependence unresolved
  3. 2003 High

    Defined a concrete physiological output of NRTN signaling—parasympathetic innervation of the lacrimal gland and ocular surface homeostasis—through systematic knockout phenotyping.

    Evidence NRTN knockout mouse tear function, ocular surface inflammation, and innervation readouts

    PMID:14507865

    Open questions at the time
    • Cell-autonomous vs systemic effects not separated
    • Signaling pathway within neurons not addressed
  4. 2007 Medium

    Showed NRTN promotes ciliary neuron survival exclusively through GFRα2 and, unlike GDNF, independently of TGFβ, distinguishing the two ligands' receptor-recruitment requirements.

    Evidence Receptor-specific neutralizing antibodies, radioligand binding, and neuronal survival assays in ciliary ganglion neurons

    PMID:17953664

    Open questions at the time
    • Single-lab finding
    • Molecular basis of GFRα2 membrane recruitment not defined
  5. 2008 High

    Identified the specific retinal and intracellular signaling targets of NRTN—horizontal/amacrine cells via PI3K and MAPK rather than photoreceptors—clarifying which cell types carry the receptor complex.

    Evidence NRTN/RET knockout and conditional mice with electroretinography; chick retinosphere PI3K/MAPK pathway analysis

    PMID:18417692 PMID:18673446

    Open questions at the time
    • Connection between pathway activation and specific functional output incomplete
    • Retinosphere is an in vitro model
  6. 2009 High

    Quantified NRTN's requirement for presynaptic cardiac cholinergic innervation and vagal control of heart rate, localizing its action to neuron maintenance rather than postsynaptic responsiveness.

    Evidence Nrtn knockout cardiac neuron counts, ACh measurement, vagal stimulation, and isolated atria pharmacology

    PMID:19176599

    Open questions at the time
    • Trophic mechanism vs developmental specification not separated
  7. 2013 Medium

    Resolved an isoform-specific, transcription-independent signaling route: NRTN drives serine-727 STAT3 phosphorylation localized to mitochondria to support neurite outgrowth.

    Evidence Isoform-specific expression, dominant-negative STAT3 mutants, subcellular fractionation, and neurite outgrowth assays

    PMID:23872421

    Open questions at the time
    • Single-lab finding
    • Mechanism by which mitochondrial P-Ser-STAT3 promotes outgrowth unresolved
  8. 2018 High

    Provided the first three-domain GFRα2 structure with NRTN and identified a heparan sulfate-binding site that modulates functional affinity through avidity and controls in vivo exposure.

    Evidence X-ray crystallography of NRTN and NRTN/GFRα2, mutagenesis, biophysical binding, and in vivo pharmacokinetics

    PMID:29414779

    Open questions at the time
    • RET engagement not captured in this structure
    • Role of heparan sulfate in cellular signaling output not directly tested
  9. 2019 High

    Determined the architecture of the complete NRTN/GFRα2/RET extracellular complex, revealing the specific contacts and RET dimerization mode that enable kinase cross-phosphorylation, plus a tetramer that regulates RET endocytosis.

    Evidence Two independent cryo-EM structures of the reconstituted ternary complex with cell-based endocytosis assays

    PMID:31392261 PMID:31535977

    Open questions at the time
    • Dynamics of tetramer formation in cells not fully resolved
    • Link between endocytosis and signaling duration not defined
  10. 2021 High

    Expanded NRTN beyond classical neurotrophism by establishing it as a muscle-secreted myokine that retrogradely specifies slow motor neuron identity while reprogramming muscle toward oxidative metabolism.

    Evidence Muscle-specific HSA-NRTN transgenic mice with RNA-seq of motor neuron somas and metabolic phenotyping; differential enteric neuron regulation by calcium imaging

    PMID:33444816 PMID:34592133

    Open questions at the time
    • Receptor-level signaling mediating motor neuron specification not detailed
    • Whether endogenous NRTN performs this role at physiological levels untested
  11. 2022 Medium

    Identified non-neuronal trophic and immunomodulatory roles—an NRTN-dependent sympathetic-cholinergic/osteocyte survival interface in bone and dampening of macrophage inflammation downstream of interferon-induced receptor upregulation.

    Evidence Conditional/global knockout mice with micro-CT and exercise models in bone; human lung macrophage cultures with IFN stimulation and cytokine measurement

    PMID:33020210 PMID:35276096

    Open questions at the time
    • Single-lab findings
    • Direct NRTN signaling readouts in macrophages and osteocytes limited
  12. 2024 Medium

    Demonstrated that NRTN signaling is hijacked across multiple cancers to drive proliferation, invasion, EMT, angiogenesis, and survival via GFRα2/RET and PI3K/AKT/mTOR.

    Evidence Knockdown/overexpression functional assays, xenograft/metastasis models, RET inhibition, and Co-IP across pancreatic, colorectal, hepatocellular, and AML systems

    PMID:24067900 PMID:29654265 PMID:31392261 PMID:35114191 PMID:37211171

    Open questions at the time
    • Single-lab studies per tumor type
    • NRTN's specific contribution vs paracrine RET activation not always separated
  13. 2025 Medium

    Placed NRTN production downstream of Hedgehog/primary cilia signaling in striatal interneurons and astrocytes, connecting pathogenic LRRK2 to reduced NRTN and dopaminergic vulnerability, and identified BHLHE40 as a direct transcriptional repressor of NRTN in macrophages.

    Evidence LRRK2 mutant mice with MLi-2 treatment, cilia immunofluorescence, and Nrtn expression; ChIP-qPCR and luciferase promoter assays with in vivo asthma epistasis

    PMID:40467844 PMID:40591712

    Open questions at the time
    • Causal chain from reduced NRTN to dopaminergic loss not directly tested by rescue
    • Single-lab transcriptional findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NRTN's distinct cellular outcomes (survival, axon outgrowth, metabolic reprogramming, immunosuppression, oncogenic growth) are selected from a shared GFRα2/RET signaling core remains unresolved.
  • No unified model linking signaling complex stoichiometry to context-specific output
  • Endogenous-level contributions in non-neuronal tissues largely inferred from gain-of-function

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2
Partners
GFRA1GFRA2RETTANGO1
Complex memberships
NRTN/GFRα2/RET ternary signaling complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Cryo-EM structure of the NRTN/GFRα2/RET extracellular ternary complex revealed that NRTN and GFRα2 induce a specific dimerization mode of RET that brings two kinase domains into proximity for cross-phosphorylation. The NRTN/GFRα2/RET dimeric complex further packs into a tetrameric assembly, and cell-based assays showed this tetramer regulates RET endocytosis. Cryo-EM structure determination; cell-based endocytosis assays eLife High 31535977
2019 Cryo-EM structure of the complete extracellular RET signaling complex with NRTN and GFRα2 (5.7 Å) identified two key interaction points: (i) the calcium-binding site in RET contacts GFRα2 domain 3, and (ii) the RET cysteine-rich domain directly interacts with NRTN. This structure provides a model for how ternary complex formation leads to RET dimerization and activation. Cryo-EM structure determination (reconstituted full extracellular complex) Science advances High 31392261
2018 Crystal structure of NRTN alone and in complex with GFRα2 (first structure of a GFRα with all three domains) showed that GFRα2 domain 1 does not interact directly with NRTN but may support interaction with RET/NCAM via a conserved surface. A heparan sulfate-binding site was identified on NRTN, and biophysical data showed relative GFRα2 concentration on cell surfaces affects NRTN functional affinity through avidity. A NRTN mutant with reduced heparan sulfate affinity showed increased in vivo exposure. X-ray crystallography; biophysical binding assays; mutagenesis; in vivo pharmacokinetic studies The Journal of biological chemistry High 29414779
1999 After sciatic nerve injection, NRTN was retrogradely transported by two populations of dorsal root ganglion sensory neurons: a major population of small, RET+/IB4+/non-TrkA neurons that also transport GDNF, and a minor calretinin-expressing population that does not transport GDNF. Cross-competition studies showed only limited competition between NRTN and GDNF, indicating GFRα coreceptor-specific transport in vivo. In vivo retrograde transport assay; immunohistochemistry; competition experiments The Journal of neuroscience High 10531437
2001 GDNF and NRTN are target-derived factors for developing ciliary ganglion neurons. GDNF and NRTN are secreted from eye muscle (the target tissue) during the period of ciliary axon innervation. In vitro and in vivo function-blocking of GDNF at early embryonic ages suppressed ciliary axon outgrowth. After GDNF expression declines in the target, GFRα1 and RET (but not GFRα2) are downregulated in innervating neurons, suggesting target-derived GDNF regulates coreceptor expression. In vitro and in vivo function-blocking antibody assays; in situ hybridization; immunohistochemistry Development High 11585803
2013 NRTN signals through GFRα2c and RET9 isoforms specifically to induce serine-727 (but not tyrosine-705) phosphorylation of STAT3 in neurons. A serine-dominant-negative STAT3 mutant impaired NRTN-induced neurite outgrowth, while a tyrosine-dominant-negative mutant did not. Mitochondrially localized P-Ser-STAT3 was identified as the downstream mediator of NRTN-induced neurite outgrowth (transcription-independent mechanism). Isoform-specific expression; dominant-negative mutagenesis; phospho-specific immunoblotting; subcellular fractionation; neurite outgrowth assays Biochimica et biophysica acta Medium 23872421
2007 In ciliary ganglion neurons, NRTN promotes survival exclusively via its cognate receptor GFRα2 (demonstrated by receptor-specific neutralizing antibodies), and unlike GDNF, NRTN-mediated survival and signaling does not require TGFβ. TGFβ does not promote recruitment of GFRα2 to the plasma membrane (in contrast to GFRα1), and disruption of TGFβ signaling does not impair NRTN-mediated survival. Receptor-specific neutralizing antibody assays; radioligand binding; immunocytochemistry; neuronal survival assays Journal of neurochemistry Medium 17953664
2003 NRTN-deficient (NRTN−/−) mice show reduced aqueous tear production, corneal sensation, mucin expression, and goblet cell density, with increased ocular surface inflammation (elevated IL-1β, TNF-α, MMP-9), demonstrating NRTN is required for parasympathetic innervation of the lacrimal gland and maintenance of ocular surface homeostasis. Knockout mouse phenotyping; tear function assays; immunofluorescence; ELISA; zymography; RT-PCR Investigative ophthalmology & visual science High 14507865
2009 NRTN knockout mice contain only 35% the normal number of cardiac cholinergic neurons (15% smaller), with 87% reduction in cholinergic nerve density at the sinoatrial node, substantially lower atrial acetylcholine, and reduced vagal bradycardia. Post-junctional sensitivity to muscarinic agonists was normal, placing NRTN's role specifically in maintaining presynaptic cholinergic innervation and cholinergic control of heart rate. Nrtn knockout mouse; immunohistochemistry; confocal microscopy; quantitative image analysis; ACh measurement; vagal nerve stimulation; isolated atria pharmacology Cardiovascular research High 19176599
2008 NRTN deficiency (knockout mice) led to diminished scotopic and photopic electroretinogram responses, thinning of the outer plexiform layer, reduction in horizontal cell dendrites and axons, and mislocalized synaptic complexes. GFRα2 expression was restricted to a subset of amacrine and ganglion cells; photoreceptors and Müller cells did not express GFRα1, GFRα2, or RET, indicating NRTN/RET signaling acts on horizontal and amacrine cells rather than photoreceptors. Electroretinography; NRTN/RET knockout and conditional mice; fluorescence reporter expression mapping; morphologic analysis The Journal of neuroscience High 18417692
2000 NRTN mRNA is expressed in smooth muscle of penile blood vessels and corpus cavernosum; GFRα2 and RET mRNAs are expressed in virtually all major pelvic ganglion neurons. 125I-NRTN injected into the penis was retrogradely transported to major pelvic and dorsal root ganglia. GFRα2-deficient mice had significantly fewer NOS-containing nerve fibers in penile nerves, establishing NRTN as a target-derived trophic factor for penile erection-inducing parasympathetic neurons via GFRα2/RET. In situ hybridization; radioligand retrograde transport assay; GFRα2 knockout immunohistochemistry Journal of neurobiology Medium 10770848
2000 GFRα2-deficient mice show normal early gangliogenesis in cranial parasympathetic ganglia but postnatal amplification of neuron loss and atrophy in submandibular and otic ganglia, accompanied by complete loss of target innervation. Sphenopalatine neurons were not reduced numerically despite complete loss of target innervation. This establishes that NRTN/GFRα2/RET signaling is essential for the development and maintenance of parasympathetic target innervation (distinct from GDNF/GFRα1/RET, which is required for early gangliogenesis). GFRα1, GFRα2, and RET knockout mouse histology; in situ hybridization; immunohistochemistry The European journal of neuroscience High 11069590
2021 Muscle-derived NRTN acts as a myokine that signals retrogradely to motor neurons to promote slow motor neuron identity (RNA sequencing of motor neuron somas from HSA-NRTN transgenic mice). In muscle, NRTN increased capillary density, oxidative capacity, and induced transcriptional reprogramming toward fatty acid metabolism. HSA-NRTN mice phenocopied muscle-specific PGC-1α1 overexpression. Muscle-specific NRTN transgenic mice; RNA sequencing of motor neuron somas; metabolic phenotyping; immunohistochemistry Cell metabolism High 34592133
2021 Calcium imaging combined with differential Gfra1 and Gfra2 expression analysis in enteric neurons showed that GDNF and NRTN acutely and differentially regulate activity of ~50% of myenteric neurons, with distinct effects on smooth muscle contractions. Single-nucleus/single-cell RNA-seq; calcium imaging; immunohistochemistry; conditional knockout mice Cellular and molecular gastroenterology and hepatology Medium 33444816
2022 Sympathetic cholinergic nerve fibers establish a neurotrophic dependency with bone-embedded osteocytes via NRTN/GFRα2. An IL-6-induced cholinergic switch in sympathetic fibers occurs postnatally upon bone contact, and osteocytes require cholinergic innervation for survival and connectivity. Loss of cholinergic skeletal innervation caused osteopenia and impaired skeletal adaptation to exercise, establishing a NRTN-dependent neuro-osteocyte interface. Conditional and global knockout mice; lineage tracing; immunohistochemistry; micro-CT; exercise models Cell stem cell Medium 35276096
2013 In pancreatic cancer cells, NRTN promoted proliferation and invasion via GFRα2. siRNA silencing of NRTN limited PCC proliferation and invasion. Depletion of NRTN from cancer tissue extracts and PCC supernatants decreased axonal sprouting in neuronal cultures. Paradoxically, NRTN silencing in PCCs boosted neural invasion. siRNA knockdown; MTT viability assay; Matrigel invasion assay; in vitro neuroplasticity assay; 3D neural migration assay; immunohistochemistry; qRT-PCR; immunoblotting Carcinogenesis Medium 24067900
2012 In chronic pancreatitis, NRTN/GFRα2 axis is activated (upregulated mature multimeric NRTN and elevated GFRα2). Depletion of NRTN from chronic pancreatitis tissue extracts using blocking antibodies reduced neurotrophic effects on DRG neurons in vitro (decreased axonal sprouting), while NRTN depletion did not affect glial cell density, establishing NRTN as a key mediator of reactive neural alterations in chronic pancreatitis. Immunohistochemistry; immunoblotting; qRT-PCR; in vitro neuroplasticity assay with NRTN depletion American journal of physiology. Gastrointestinal and liver physiology Medium 22961804
2013 NRTN overexpression in keratinocytes (NRTN-OE mice) increased density of PGP9.5-positive free nerve endings, hypertrophied GFRα2-immunopositive sensory neuron somas, increased mRNAs for GFRα2, RET, P2X3, ASIC2a, and TRPM8 in sensory ganglia, and elevated behavioral sensitivity to mechanical stimuli, cool temperature, and menthol. The increase in cool/menthol sensitivity correlated directly with elevated TRPM8 expression. Transgenic NRTN overexpression; immunohistochemistry; electron microscopy; RT-PCR; behavioral testing; calcium imaging The Journal of neuroscience High 23365243
2006 In adult mouse heart, NRTN mRNA is expressed in atrial and ventricular tissue, and >90% of cardiac parasympathetic ganglion neurons express both RET and GFRα2 (the NRTN receptor complex). GFRα2 is present in most cholinergic nerve fibers and Schwann cells, with some cholinergic sinoatrial node fibers also expressing RET, suggesting ongoing neurotrophic support of adult cardiac cholinergic innervation by NRTN. RT-PCR; immunohistochemistry; confocal microscopy Cell and tissue research Medium 16708241
2007 In chick embryo liver development, NRTN is expressed in endothelial cells of the ductus venosus while GFRα2 is expressed in the liver bud. Inhibition of GFRα2 signaling suppressed liver bud elongation along the ductus venosus without affecting cell proliferation or apoptosis. Ectopic NRTN expression perturbed directional migration. In vitro, liver buds selectively migrated toward NRTN-soaked beads, establishing NRTN as a chemoattractant for GFRα2-expressing liver bud cells. In situ hybridization; GFRα2 signaling inhibition in ovo; ectopic NRTN expression; in vitro bead chemotaxis assay Developmental biology Medium 17509555
2000 Seizure activity regulates GFRα2 gene expression in limbic structures, and mice lacking GFRα2 show markedly suppressed epileptogenesis in the hippocampal kindling model, with lower hyperexcitability at 6–8 weeks post-kindling. This places NRTN signaling through GFRα2 as a modulator of seizure susceptibility, potentially via hilar neuropeptide Y-containing interneurons and entorhinal cortical afferents. GFRα2 knockout mice; hippocampal kindling electrophysiology; in situ hybridization Proceedings of the National Academy of Sciences of the United States of America Medium 11050250
2011 After peripheral nerve injury, GFRα2-positive cutaneous sensory neurons (normally NRTN-responsive) switch phenotype: GFRα2 immunoreactivity is rapidly lost and neurons begin expressing GFRα3 and TRPV1. NRTN failed to prevent neuronal death or ATF3 upregulation in vitro, while NGF and ARTN succeeded, correlating with the loss of GFRα2. This switch was correlated with downregulation of the transcription factor Runx1. Retrograde labeling; nerve cut injury; in vitro survival/ATF3 assays with GFL treatment; immunohistochemistry; RT-PCR PloS one Medium 22216140
2020 Human lung-resident macrophages express GFRα2 and RET; type I interferon upregulates RET on macrophages. Epithelial-derived NRTN binding to the GFRα2/RET complex on macrophages dampens pro-inflammatory cytokine release and modulates matrix metalloproteinase production in response to viral stimuli, establishing a non-neuronal immunomodulatory role for NRTN in lung macrophages. Human lung macrophage cultures; cytokine measurement (ELISA); type I IFN stimulation; receptor expression analysis Life science alliance Medium 33020210
2023 TANGO1 interacts with NRTN in hepatocellular carcinoma cells (validated by endogenous Co-IP and confocal colocalization), and both proteins promote HCC progression by activating the PI3K/AKT/mTOR signaling pathway. Endogenous Co-immunoprecipitation; confocal colocalization; RNA-seq; knockdown functional assays Biochemical pharmacology Medium 37211171
2018 AML cells activate RET signaling via NRTN/GFRα2 ligand/co-receptor complexes. Downstream, RET activates mTORC1-mediated autophagy suppression, which stabilizes leukemogenic drivers such as mutant FLT3. Genetic or pharmacologic RET inhibition impaired AML growth and was accompanied by upregulation of autophagy and FLT3 depletion. Functional genomic screen; co-receptor expression analysis; RET inhibition (genetic and pharmacologic); autophagy and FLT3 assays; mouse AML models; primary patient samples Leukemia Medium 29654265
2008 In chicken retinospheres (3D model), exogenous NRTN activated PI3K and MAPK signaling pathways, with MAPK activation localizing specifically to acetylcholinesterase-positive cells in the innermost rows of the inner nuclear layer. NRTN application increased the number of acetylcholinesterase-positive cells at late culture stages; Müller glia did not express GFRα2 and were not involved in NRTN signaling. 3D retinosphere culture; exogenous NRTN treatment; signaling pathway analysis (phospho-specific antibodies); immunohistochemistry; cell counting Journal of neurochemistry Medium 18673446
2016 NRTN and GDNF were identified as proneurogenic ligands in the embryonic cortex: cortical neurons (but not neural precursor cells) secrete factors promoting NPC differentiation, and NRTN promotes neurogenic differentiation of NPCs in vivo. Transcriptome profiling; cell-surface mass spectrometry; computational modeling; in vivo neurogenesis assays Neuron Low 27545711
2025 Pathogenic LRRK2 mutations inhibit primary cilia formation in striatal cholinergic/parvalbumin interneurons and astrocytes, blocking Hedgehog signaling and reducing GDNF and NRTN production. MLi-2 LRRK2 inhibitor treatment restored primary cilia, Hedgehog-responsive Gdnf and Nrtn expression, and striatal dopaminergic process density. LRRK2 mutant mice; dietary MLi-2 treatment; immunofluorescence for cilia; gene expression analysis; dopaminergic axon density quantification Science signaling Medium 40591712
2025 NRTN when injected intramuscularly alongside tetanus neurotoxin fragment (HcT) to track signaling endosome transport in motor neurons in vivo produced no detectable change in retrograde endosome transport dynamics in either fast or slow motor neurons (negative result), in contrast to CNTF which markedly slowed endosome transport. In vivo intramuscular injection; live imaging of sciatic nerve axonal transport in anaesthetised mice; fluorescent HcT endosome tracking bioRxivpreprint Medium
2017 Subcutaneous NRTN administration to Zucker diabetic fatty rats prevented hyperglycemia, increased pancreatic insulin content and β-cell mass, and preserved islet organization. Acute NRTN treatment did not activate c-Fos in brain feeding centers or directly enhance glucose-stimulated insulin secretion from isolated β-cells, indicating the antidiabetic effect is not mediated through central appetite regulation or direct β-cell insulin secretion. In vivo subcutaneous administration in ZDF rats; c-Fos immunohistochemistry in brain; isolated β-cell glucose-stimulated insulin secretion assay; metabolic phenotyping Diabetes Medium 28408435
2025 BHLHE40 binds to the NRTN promoter (confirmed by ChIP-qPCR and dual luciferase assay) and reduces NRTN transcriptional activity in macrophages. In OVA-challenged asthmatic mice, simultaneous knockdown of Bhlhe40 and Nrtn recovered alternative macrophage activation and rescued the asthma phenotype, placing NRTN as a downstream transcriptional target of BHLHE40 that promotes M2 macrophage activation. Dual luciferase promoter assay; ChIP-qPCR; siRNA knockdown in vivo and in vitro; OVA asthma mouse model; macrophage polarization assays Communications biology Medium 40467844
2022 In colorectal cancer cells, NRTN promoted migration/invasion by upregulating ZEB1 and N-cadherin (EMT markers) and promoted angiogenesis by upregulating VEGF-A. NRTN inhibition prevented CRC metastasis and angiogenesis in vivo. siRNA/overexpression functional assays; migration/invasion assays; endothelial tube formation; in vivo xenograft/metastasis models; Western blotting Experimental cell research Medium 35114191
2001 Targeted overexpression of NRTN in mouse testis caused transient degeneration of spermatids and pachytene spermatocytes between 3–5 weeks of age (in ~20% of transgenic lines), with no defect after 5 weeks and normal fertility, suggesting NRTN may regulate survival/differentiation of spermatocytes and spermatids but is not essential for spermatogenesis. Testis-specific NRTN transgenic mice; histology; phenotypic analysis Molecular and cellular endocrinology Low 11694339

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Novel functions and signalling pathways for GDNF. Journal of cell science 477 12953054
1999 Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Experimental neurology 296 10415156
2013 The developmental etiology and pathogenesis of Hirschsprung disease. Translational research : the journal of laboratory and clinical medicine 179 23528997
2008 Treatment of Parkinson's disease with trophic factors. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 123 18394569
2018 Gene Therapy for Parkinson's Disease, An Update. Journal of Parkinson's disease 116 29710735
2020 GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop. Journal of Parkinson's disease 110 32508331
1999 Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRalpha coreceptor-specific. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 10531437
2003 Neurturin-deficient mice develop dry eye and keratoconjunctivitis sicca. Investigative ophthalmology & visual science 94 14507865
2021 scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3. Cellular and molecular gastroenterology and hepatology 86 33444816
2015 Current disease modifying approaches to treat Parkinson's disease. Cellular and molecular life sciences : CMLS 86 26616211
2013 The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. Carcinogenesis 73 24067900
2021 Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Molecular psychiatry 66 34907395
2019 CDNF Protein Therapy in Parkinson's Disease. Cell transplantation 66 30947516
2015 Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease. FEBS letters 63 26450777
2021 Neurotrophic Factors in Parkinson's Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain. Frontiers in cellular neuroscience 62 34149364
2000 Neurturin is a neurotrophic factor for penile parasympathetic neurons in adult rat. Journal of neurobiology 62 10770848
2015 Prospects of Neurotrophic Factors for Parkinson's Disease: Comparison of Protein and Gene Therapy. Human gene therapy 60 26176331
2011 The spinal cord ependymal region: a stem cell niche in the caudal central nervous system. Frontiers in bioscience (Landmark edition) 58 21196217
2019 Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. eLife 55 31535977
2017 Glial Cell Line-Derived Neurotrophic Factor Gene Delivery in Parkinson's Disease: A Delicate Balance between Neuroprotection, Trophic Effects, and Unwanted Compensatory Mechanisms. Frontiers in neuroanatomy 54 28442998
2001 GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development. Development (Cambridge, England) 54 11585803
2022 A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise. Cell stem cell 53 35276096
2018 RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia. Leukemia 53 29654265
2016 Long-Term Safety of Patients with Parkinson's Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. Human gene therapy 51 26711317
2006 Is GAS1 a co-receptor for the GDNF family of ligands? Trends in pharmacological sciences 51 16406089
2011 Properly scaled and targeted AAV2-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease. Neurobiology of disease 47 21704161
2020 Revisiting the Role of Neurotrophic Factors in Inflammation. Cells 45 32252363
2015 The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis. Cancer biology & therapy 45 25975578
2021 Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity. Cell metabolism 41 34592133
2016 Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks. Neuron 37 27545711
2020 The role of glial cell line-derived neurotrophic factor family member artemin in neurological disorders and cancers. Cell proliferation 36 32573073
2000 Distinct roles for GFRalpha1 and GFRalpha2 signalling in different cranial parasympathetic ganglia in vivo. The European journal of neuroscience 36 11069590
2013 Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120). Neurobiology of disease 35 23631873
2002 Caenorhabditis elegans reticulon interacts with RME-1 during embryogenesis. Biochemical and biophysical research communications 34 12054525
2006 Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene. Cell and tissue research 33 16708241
2000 Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor alpha 2. Proceedings of the National Academy of Sciences of the United States of America 33 11050250
2011 Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury. PloS one 32 22216140
2018 Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling. The Journal of biological chemistry 30 29414779
2020 Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson's disease. Cell and tissue research 29 32556722
2019 Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain. Science advances 28 31392261
2009 Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice. Cardiovascular research 26 19176599
2008 Neurturin-mediated ret activation is required for retinal function. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 18417692
2005 Expression and function of GDNF family ligands and receptors in the carotid body. Experimental neurology 25 15629763
2012 Neuronal plasticity in chronic pancreatitis is mediated via the neurturin/GFRα2 axis. American journal of physiology. Gastrointestinal and liver physiology 23 22961804
2013 Neurturin overexpression in skin enhances expression of TRPM8 in cutaneous sensory neurons and leads to behavioral sensitivity to cool and menthol. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 23365243
2012 Translating the therapeutic potential of neurotrophic factors to clinical 'proof of concept': a personal saga achieving a career-long quest. Neurobiology of disease 21 22525569
2007 Specificity in the crosstalk of TGFbeta/GDNF family members is determined by distinct GFR alpha receptors. Journal of neurochemistry 19 17953664
2020 RET receptor expression and interaction with TRK receptors in neuroblastomas. Oncology reports 16 32319659
2012 Human-protein-derived peptides for intracellular delivery of biomolecules. The Biochemical journal 15 22150630
2021 Glial-derived neurotrophic factor in human airway smooth muscle. Journal of cellular physiology 13 34170009
2007 Neurturin-GFRalpha2 signaling controls liver bud migration along the ductus venosus in the chick embryo. Developmental biology 13 17509555
2001 Transient disruption of spermatogenesis by deregulated expression of neurturin in testis. Molecular and cellular endocrinology 13 11694339
2022 The RET gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and RET mutation results in Hirschsprung's disease. AIMS neuroscience 12 35434281
2025 Single-Cell Transcriptomics Identifies Selective Lineage-Specific Regulation of Genes in Aortic Smooth Muscle Cells in Mice. Arteriosclerosis, thrombosis, and vascular biology 11 39744838
2021 GDNF Therapy: Can We Make It Work? Journal of Parkinson's disease 11 33935108
2019 Focal and dose-dependent neuroprotection in ALS mice following AAV2-neurturin delivery. Experimental neurology 11 31678350
2017 Neurturin and a GLP-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats. Diabetes 11 28408435
2023 TANGO1 interacts with NRTN to promote hepatocellular carcinoma progression by regulating the PI3K/AKT/mTOR signaling pathway. Biochemical pharmacology 10 37211171
2022 Neurturin promotes tumor cell motility and angiogenesis in colorectal cancer. Experimental cell research 10 35114191
2020 Improving therapeutic potential of GDNF family ligands. Cell and tissue research 10 32725425
2013 GDNF family ligand dependent STAT3 activation is mediated by specific alternatively spliced isoforms of GFRα2 and RET. Biochimica et biophysica acta 10 23872421
2005 GDNF family ligand immunoreactivity in the gut of teleostean fish. Anatomy and embryology 9 16193278
2003 Developmental expression of glial cell-line derived neurotrophic factor, neurturin, and their receptor mRNA in the rat urinary bladder. Neurourology and urodynamics 9 12478607
2020 Neurturin regulates the lung-resident macrophage inflammatory response to viral infection. Life science alliance 8 33020210
2014 Effect of neurturin deficiency on cholinergic and catecholaminergic innervation of the murine eye. Experimental eye research 8 24657391
2025 Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson's disease-linked LRRK2-mutant mice. Science signaling 7 40591712
2024 Whole genome sequencing of 4,787 individuals identifies gene-based rare variants in age-related macular degeneration. Human molecular genetics 7 37934784
2023 Multi-omics study of key genes, metabolites, and pathways of periodontitis. Archives of oral biology 7 37285682
2015 Peptide based DNA nanocarriers incorporating a cell-penetrating peptide derived from neurturin protein and poly-L-lysine dendrons. Bioorganic & medicinal chemistry 7 25882529
2025 Deciphering genetic causality between plasma BDNF and 91 circulating inflammatory proteins through bidirectional mendelian randomization. Scientific reports 6 40133606
2025 Lysosomal glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway contributing to Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 6 40737317
2008 Neurturin, a member of the glial cell line-derived neurotrophic factor family, affects the development of acetylcholinesterase-positive cells in a three-dimensional model system of retinogenesis. Journal of neurochemistry 6 18673446
2025 Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived FFPE samples unveils novel paracrine interactions. The Journal of pathology 5 40778592
2023 Expression of Glial-Cell-Line-Derived Neurotrophic Factor Family Ligands in Human Intervertebral Discs. International journal of molecular sciences 5 37958856
2020 Plasma membrane localization of the GFL receptor components: a nexus for receptor crosstalk. Cell and tissue research 5 32767110
2025 Sympathetic cholinergic nerve fibres promote BMSC differentiation into osteoblasts via NRTN secretion: a potential treatment for osteoporosis. Journal of orthopaedic surgery and research 3 40474233
2025 The Role of Gut Microbiota on Idiopathic Pulmonary Fibrosis Mediated by Circulating Inflammatory Proteins: A Two-Step, Two-Sample Mendelian Randomization Study. The clinical respiratory journal 3 40923287
2025 Proteomic Profiling of Inflammatory Protein Dysregulation in HLA-B27-Positive Ankylosing Spondylitis: Molecular Signatures and Potential Biomarkers. Biomolecules 2 40305235
2025 Modulation of Neurturin Expression by Lumbosacral Spinal Stenosis, Lifestyle Factors, and Glycemic Dysregulation. Biomedicines 2 40426929
2025 BHLHE40 contributes to allergic asthma progression in mice through NRTN downregulation in macrophages. Communications biology 2 40467844
2025 Causal network between periodontitis and systemic inflammation: Triangulating evidence from Mendelian randomization and sequencing datasets. Journal of periodontology 2 40627758
2023 Sputum Neurturin Levels in Adult Asthmatic Subjects. Journal of asthma and allergy 2 37671183
2022 Reawakening GDNF's regenerative past in mice and humans. Regenerative therapy 2 35509264
2025 Neurturin gene IVSI-663 polymorphism but not RET variants is associated with increased risk for breast cancer. Laboratory medicine 1 39671698
2025 Identification of immune-associated genes and single-cell sequencing analysis in diagnosing Behçet's disease. Scientific reports 1 40481130
2025 Plasma protein biomarkers of Plasmodium falciparum infection in pregnant women: a high-throughput proteomics study. Frontiers in cellular and infection microbiology 1 40697816
2024 Neurturin GF Enhances the Acute Cytokine Response of Inflamed Skin. The Journal of investigative dermatology 1 39122143
2018 Cellular, Molecular and Non-Pharmacological Therapeutic Advances for the Treatment of Parkinson's Disease: Separating Hope from Hype. Current gene therapy 1 30207219
2026 Gene therapy for Parkinson's disease: current landscape, translational challenges, and future directions. Expert review of neurotherapeutics 0 41837837
2025 Single-Cell Transcriptome Analyses of Four Pain Related Genes in Osteosarcoma. Cancer informatics 0 40686838
2025 Mediating Effects of Plasma Metabolites in Inflammatory Protein-Lymphoma Causality: A Mendelian Randomization Study. Current medicinal chemistry 0 41047677
2025 Inflammatory Proteins Profiling in Tear Fluid in Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 0 41065791
2025 Suppression of HIF-1α alleviates the symptoms associated with diabetic retinopathy in mice. Experimental eye research 0 41224187
2024 The effects of induced type I diabetes on developmental regulation of GDNF, NRTN, and NCAM proteins in the dentate gyrus of male rat offspring. Journal of chemical neuroanatomy 0 38219812
2024 Spatiotemporal regulation of dental pulpal innervation in the rat. Anatomia, histologia, embryologia 0 39056435
2024 Association of MCP-4, NRTN, and PD-L1 with the risk of hepatic fibrosis: A Mendelian randomization study. Medicine 0 39252214

Missed literature

Know a paper Affinage missed for NRTN? Flag it for the maintainers and the community.

No submissions yet.