Affinage

CNTF

Ciliary neurotrophic factor · UniProt P26441

Length
200 aa
Mass
22.9 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNTF is a secreted neural cytokine, originally purified from sciatic nerve, that signals through a cytokine-type receptor rather than a receptor tyrosine kinase (PMID:2587985, PMID:1617725). It assembles a tripartite receptor by first binding the ligand-specific, GPI-anchored CNTFRα and then recruiting gp130 and LIFRβ, whose heterodimerization (distinct from the gp130 homodimerization used by IL-6) drives signaling (PMID:8390097, PMID:7852997); CNTFRα is both necessary and sufficient to confer CNTF responsiveness on otherwise unresponsive cells (PMID:8381290). Distinct surface determinants on CNTF mediate these contacts — a D-helix region (Gln167) for CNTFRα and residues F152/K155 for LIFRβ — and mutations combining enhanced CNTFRα affinity with disrupted LIFRβ binding yield a competitive antagonist (PMID:7621819, PMID:8799186). Because CNTFRα can be shed as a soluble form that forms a 1:1 complex with CNTF and reconstitutes signaling on cells lacking membrane receptor, CNTF activity can be extended in a paracrine manner, including following nerve injury (PMID:7681218, PMID:8180210). The dimerized beta receptors activate constitutively associated JAK/TYK kinases, which in turn activate STAT3; maximal STAT3 transcriptional activity additionally requires Ser727 phosphorylation contributed by mTOR, alongside PI3K/AKT and MAPK/ERK outputs (PMID:8272873, PMID:7852997, PMID:10660304, PMID:19332123). Through these cascades CNTF supports motoneuron survival, retinal ganglion cell axon regeneration, oligodendrocyte myelination, and adult neurogenesis, and it acts peripherally on skeletal muscle to activate AMPK and reverse insulin resistance (PMID:8793295, PMID:17971355, PMID:12417647, PMID:22960105, PMID:16604088). Several CNTF effects are relayed indirectly through induced mediators — Reg-2 in motoneurons, FGF2 in the subventricular zone, and a CCL5–CCR5 axis engaging immune cells during optic nerve regeneration (PMID:11146655, PMID:22960105, PMID:33627402). CNTFRα additionally serves as a shared receptor component for other ligands including the CLF/CLC complex and humanin, and CNTFRα-null mice die perinatally with motoneuron deficits far exceeding those of CNTF-null mice, indicating an essential CNTFRα ligand beyond CNTF itself (PMID:7585948, PMID:10966616, PMID:19386761). A human CNTF null mutation is common in some populations yet is not causally linked to neurological disease, consistent with genetic redundancy among CNTF, LIF, and CT-1 in trophic support of motoneurons (PMID:8075647, PMID:8793295, PMID:15716414).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1989 High

    Establishing CNTF's molecular identity was the prerequisite to any mechanistic work; purification and cloning defined it as a distinct neural effector protein unrelated to known neurotrophins.

    Evidence Protein purification from rabbit sciatic nerve, cDNA cloning, and functional expression

    PMID:2587985

    Open questions at the time
    • Did not define the receptor or signaling pathway
    • No structural model of the protein
  2. 1992 High

    Resolved the class of receptor CNTF uses, showing it signals via a shared cytokine receptor component (gp130) rather than a tyrosine kinase receptor like neurotrophins.

    Evidence Tyrosine phosphorylation and gene activation assays comparing CNTF, LIF and IL-6 in neuronal and hematopoietic cell lines

    PMID:1617725

    Open questions at the time
    • Did not yet resolve full receptor subunit composition
    • Downstream transcription factors unidentified
  3. 1993 High

    Defined the tripartite receptor architecture and the specificity-determining subunit, showing CNTFRα plus heterodimerized gp130/LIFRβ form the functional complex and that CNTFRα alone confers responsiveness.

    Evidence Receptor reconstitution, co-immunoprecipitation, transfection, and cell-based response assays

    PMID:8381290 PMID:8390097

    Open questions at the time
    • Order of subunit assembly not yet established
    • Cytoplasmic kinases not yet linked
  4. 1993 High

    Showed CNTFRα is GPI-anchored and can act as a diffusible soluble cofactor, explaining how CNTF responsiveness can be extended beyond cells bearing membrane receptor, including after nerve injury.

    Evidence Cell-based responsiveness assays with soluble CNTFRα, CSF analysis, and muscle denervation model

    PMID:7681218

    Open questions at the time
    • In vivo physiological role of shed receptor not quantified
    • Stoichiometry not yet defined
  5. 1994 High

    Connected receptor dimerization to the intracellular signaling machinery, showing gp130/LIFRβ constitutively associate with JAK/TYK kinases activated upon ligand-induced dimerization, and biochemically defined stepwise complex assembly.

    Evidence Co-immunoprecipitation of receptor–kinase complexes, kinase activation assays, biochemical assembly analysis

    PMID:7852997 PMID:8272873

    Open questions at the time
    • Cell-type-specific differences in kinase usage not mechanistically explained
    • STAT specificity not detailed
  6. 1994 High

    Defined the precise binding stoichiometry of soluble CNTFRα with CNTF, confirming a 1:1 complex that faithfully reconstitutes receptor activity and specificity.

    Evidence Size-exclusion chromatography, gel-shift assay, and TF-1 cell survival assays

    PMID:8180210

    Open questions at the time
    • No crystal structure of the complex
    • Affinities of subsequent gp130/LIFRβ recruitment not measured here
  7. 1994 High

    Tested whether CNTF is a non-redundant trophic factor in humans; a common null mutation produces no functional protein yet causes no neurological disease, revealing functional redundancy.

    Evidence Genomic sequencing, minigene transfection, mRNA analysis, and population genotyping

    PMID:8075647

    Open questions at the time
    • Did not identify the redundant ligands
    • Possible subtle phenotypes not assessed
  8. 1995 High

    Genetically dissociated CNTFRα from CNTF, showing CNTFRα-null mice die perinatally with motoneuron loss absent in CNTF-null mice, implying an essential second CNTFRα ligand.

    Evidence Comparative phenotyping of CNTF-/- versus CNTFRα-/- knockout mice

    PMID:7585948

    Open questions at the time
    • Identity of the developmental ligand not established here
    • Mechanism of perinatal lethality unresolved
  9. 1995 High

    Mapped the CNTFRα-binding surface of CNTF and demonstrated affinity could be engineered, identifying the D-helix/Gln167 as a functional receptor-contact site.

    Evidence Phage display affinity maturation with in vitro binding and cell-based bioactivity assays

    PMID:7621819

    Open questions at the time
    • LIFRβ and gp130 contact sites not yet defined
    • Structural basis of enhanced affinity not resolved
  10. 1996 High

    Identified the distinct LIFRβ-binding determinant (F152/K155) on CNTF and exploited it to engineer a competitive receptor antagonist, separating receptor-binding functions.

    Evidence Alanine-scanning mutagenesis with binding and bioactivity assays

    PMID:8799186

    Open questions at the time
    • gp130 contact residues not mapped
    • Antagonist in vivo efficacy not tested here
  11. 1996 High

    Uncovered cryptic ligand redundancy in motoneuron support, showing LIF provides trophic support unmasked only when CNTF is also absent.

    Evidence CNTF-/-/LIF-/- double knockout with quantitative motoneuron and grip-strength analysis

    PMID:8793295

    Open questions at the time
    • Did not include all family ligands
    • Cellular source of compensatory LIF not defined
  12. 2000 High

    Identified a true second ligand for CNTFRα, the secreted CLF/CLC complex, that activates the same receptor and supports motoneuron survival.

    Evidence Co-secretion assays, STAT3 activation, receptor specificity tests, motoneuron survival assays

    PMID:10966616

    Open questions at the time
    • Whether CLF/CLC is the developmental ligand causing CNTFRα-null lethality not confirmed
    • In vivo CLC sources not mapped
  13. 2000 High

    Resolved the kinase responsible for the activating STAT3 Ser727 phosphorylation, showing mTOR rather than MAPK or PKC mediates maximal STAT3 transcriptional output downstream of CNTF.

    Evidence In vitro mTOR kinase assay, rapamycin and pathway inhibitors, dominant-negative mTOR, STAT3 Ser727Ala reporter

    PMID:10660304

    Open questions at the time
    • Cell-context generality not established
    • Link between receptor activation and mTOR engagement not detailed
  14. 2000 High

    Identified an obligatory downstream mediator of CNTF motoneuron survival, showing Reg-2 acts as an autocrine/paracrine effector through PI3K-Akt-NF-κB.

    Evidence Antisense adenovirus knockdown and purified Reg-2 survival assays with pathway inhibitors in cultured motoneurons

    PMID:11146655

    Open questions at the time
    • Reg-2 receptor not identified
    • In vivo requirement of Reg-2 not tested
  15. 2002 Medium

    Extended CNTF function to glial maturation, showing it promotes oligodendrocyte myelination via gp130 and JAK.

    Evidence Oligodendrocyte myelination index assays with JAK pathway pharmacological blockade

    PMID:12417647

    Open questions at the time
    • Single-lab cell culture study without genetic validation
    • STAT effector not identified
  16. 2003 Medium

    Defined a species difference and receptor-substitution capacity, showing human CNTF can use IL-6Rα in place of CNTFRα but cannot engage gp130/LIFRβ without an alpha receptor.

    Evidence Cell-based signaling and receptor competition assays with chimeric constructs

    PMID:12643274

    Open questions at the time
    • Single-lab functional assays
    • Physiological relevance of IL-6Rα usage unclear
  17. 2006 High

    Established a peripheral metabolic role, showing CNTF acts directly on skeletal muscle via CNTFRα-IL-6R-gp130 to activate AMPK and reverse insulin resistance independent of the brain.

    Evidence In vivo skeletal muscle AMPK activation and central-versus-peripheral pathway dissection

    PMID:16604088

    Open questions at the time
    • Long-term metabolic effects not addressed here
    • Endogenous physiological trigger unclear
  18. 2007 High

    Identified astrocyte-derived CNTF as a key mediator of injury-induced retinal ganglion cell protection and axon growth, acting through STAT3.

    Evidence Intravitreal CNTF neutralization, JAK inhibition, STAT3 immunostaining, and CNTF-/- comparison in vivo

    PMID:17971355

    Open questions at the time
    • Did not separate direct from indirect effects on RGCs
    • Relative contribution of multiple inflammatory mediators not resolved
  19. 2009 High

    Demonstrated CNTF uses distinct signaling cascades for different outcomes and amplifies its own expression, with JAK/STAT3 and PI3K/AKT driving RGC axon growth and exogenous CNTF inducing endogenous astrocytic CNTF via MAPK/ERK.

    Evidence In vitro neurite outgrowth with pathway inhibitors, CNTF-/- mice, and MAPK/ERK inhibition in vivo

    PMID:19332123

    Open questions at the time
    • Mechanism coupling receptor to ERK-driven autoinduction not detailed
    • Quantitative contribution of autoinduction unclear
  20. 2009 Medium

    Showed CNTFRα is co-opted by humanin to form a CNTFRα-WSX-1-gp130 neuroprotective receptor, broadening CNTFRα's ligand repertoire.

    Evidence In vitro reconstituted binding, siRNA knockdown, and receptor overexpression protection assays

    PMID:19386761

    Open questions at the time
    • Single-lab study on a secondary ligand
    • In vivo relevance not established
  21. 2009 Medium

    Extended CNTF protection to non-neural and lower-vertebrate contexts, showing JAK2/STAT3-dependent islet protection and divergent MAPK-versus-STAT3 use for photoreceptor protection versus Müller glia proliferation.

    Evidence Pharmacological pathway inhibition and morpholino knockdown in rat islets and adult zebrafish retina

    PMID:19272793 PMID:19450453

    Open questions at the time
    • Single-lab pharmacological studies without genetic confirmation in mammals
    • Cross-species generality uncertain
  22. 2012 High

    Identified endogenous CNTF as a driver of injury-induced adult neurogenesis acting through FGF2 induction.

    Evidence CNTF-/- mice, BrdU proliferation, MCAO stroke model, and FGF2/EGF/Notch1 expression analysis

    PMID:22960105

    Open questions at the time
    • Direct versus FGF2-mediated effect not fully separated
    • Receptor-bearing target cell not defined
  23. 2013 High

    Defined how CNTF expression is held in check, showing neuronal contact represses astrocytic CNTF via αvβ5 integrin-FAK-JNK signaling and FAK-mediated inhibitory STAT3 Ser727 phosphorylation, with STAT3 binding the CNTF promoter.

    Evidence Integrin antibodies, FAK/JNK inhibitors, co-culture, STAT3 ChIP, and in vivo FAK inhibitor microinjection

    PMID:23693126

    Open questions at the time
    • Interplay between activating and inhibitory STAT3 phosphorylation not fully reconciled
    • Thy1 receptor partner not defined
  24. 2018 High

    Revealed a volume-transmission neuroendocrine role, showing CRH-driven CNTF release into the ventricular system activates locus coeruleus norepinephrine synthesis via sequential ERK1 and tyrosine hydroxylase phosphorylation gated by secretagogin.

    Evidence Tract tracing, conditional CNTF/secretagogin ablation, phosphorylation and behavioral assays, human tissue validation

    PMID:30209240

    Open questions at the time
    • Receptor subunits mediating this CNS action not specified
    • Generality across stress paradigms not exhausted
  25. 2020 High

    Established CNTF as a propagator of peripheral neuroinflammation and pain, showing Schwann-cell CNTF drives STAT3-dependent IL-6 induction transmitted from periphery to spinal cord.

    Evidence CNTF-/- mice, recombinant CNTF application, pain behavior, STAT3 and IL-6 quantification in DRG and spinal cord

    PMID:32433966

    Open questions at the time
    • Cellular target of CNTF in DRG not fully defined
    • Therapeutic window not addressed
  26. 2021 High

    Showed that CNTF's regenerative effect can be largely indirect and immune-mediated, since RGC-specific CNTFRα deletion did not block optic nerve regeneration whereas a CCL5-CCR5 axis engaging immune cells did.

    Evidence Conditional CRISPR CNTFRα/CCR5 knockout, neutrophil/monocyte depletion, recombinant CCL5, and CCR5 antagonist with axon regeneration quantification

    PMID:33627402

    Open questions at the time
    • Relative split between direct and indirect mechanisms not quantified
    • Cell type releasing CCL5 in response to CNTF not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the essential developmental CNTFRα ligand responsible for the perinatal lethality of CNTFRα-null mice, and how its signaling differs from CNTF's, remains unresolved.
  • No single ligand has been shown to fully account for the CNTFRα-null phenotype
  • In vivo deconvolution of CNTF, CLC/CLF and humanin contributions through shared CNTFRα is incomplete

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:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
CNTFRCRLF1IL6RIL6STJAK1LIFRMTORSTAT3
Complex memberships
CNTFRα–WSX-1–gp130 humanin receptor complexCNTFRα–gp130–LIFRβ tripartite receptor complexCNTF–soluble CNTFRα 1:1 ligand complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CNTF was purified from rabbit sciatic nerve and cloned; biologically active CNTF was expressed from a cDNA clone, establishing it as a distinct neural effector protein with no significant sequence homology to previously known proteins including NGF. Protein purification, cDNA cloning, transient expression assay Science High 2587985
1992 CNTF and LIF share signaling pathways in neuronal cells that involve the IL-6 signal transducing receptor component gp130; CNTF induces the same tyrosine phosphorylations and gene activations as LIF and IL-6 in hematopoietic cells, demonstrating that CNTF signals via a cytokine-type receptor rather than a receptor tyrosine kinase. Tyrosine phosphorylation assays, gene activation assays, receptor component characterization in neuronal and hematopoietic cell lines Cell High 1617725
1993 The CNTF receptor complex is tripartite, consisting of the CNTF-specific binding protein CNTFRα plus LIFR-β and gp130; CNTF and LIF both trigger association of initially separate receptor components leading to tyrosine phosphorylation of receptor subunits; signaling requires heterodimerization of gp130 with LIFRβ (unlike IL-6 which uses gp130 homodimerization). Receptor reconstitution, co-immunoprecipitation, tyrosine phosphorylation assays, cell-based signaling assays Science High 8390097
1993 CNTFRα is a required receptor component that confers CNTF responsiveness; transfection of CNTFRα into hematopoietic cells normally responsive only to LIF was sufficient to render them CNTF-responsive, demonstrating CNTFRα is necessary and sufficient for CNTF target cell specification. Gene transfection, cell-based CNTF response assay, immunolocalization Neuron High 8381290
1993 CNTFRα is anchored by a GPI linkage and can be released as a soluble form; soluble CNTFRα can function as part of a heterodimeric ligand with CNTF to activate cells lacking membrane-bound CNTFRα, and is present in cerebrospinal fluid and released from skeletal muscle upon peripheral nerve injury. Cell-based responsiveness assays with soluble CNTFRα, CSF analysis, muscle denervation model Science High 7681218
1994 The beta receptor components gp130 and LIFRβ constitutively associate with Jak/Tyk family cytoplasmic tyrosine kinases; ligand-induced dimerization of these receptor beta components activates the kinases; CNTF receptor utilizes all known members of the Jak/Tyk family but induces distinct phosphorylation patterns in different cell lines. Co-immunoprecipitation of receptor–kinase complexes, tyrosine phosphorylation assays, kinase activation assays Science High 8272873
1994 CNTF assembles its tripartite receptor in a stepwise fashion: CNTF first binds CNTFRα, then recruits gp130, and finally complexes with LIFRβ; heterodimerization of the beta components activates JAK/TYK kinases that are preassociated with beta components in an inactive state, which in turn activate STAT family transcription factors. Biochemical receptor assembly assays, kinase activation analysis, signaling pathway characterization Journal of neurobiology High 7852997
1994 Human CNTF null mutation (G to A transition creating a new splice acceptor site) produces only aberrant mRNA and no functional protein; 2.3% of Japanese individuals are homozygous for this mutation, but CNTF deficiency is not causally related to neurological diseases. Genomic sequencing, minigene transfection into cultured cells, mRNA analysis, population genotyping Nature genetics High 8075647
1994 Recombinant soluble CNTFRα forms a 1:1 stoichiometric complex with CNTF; soluble CNTFRα reconstitutes active complexes on the surface of cells lacking membrane CNTFRα with the same relative ligand specificity and affinity as the cell-surface receptor. Size-exclusion chromatography, protein gel-shift assay, cell-based survival assays with TF-1 cells Biochemistry High 8180210
1995 Mice lacking CNTFRα die perinatally with severe motor neuron deficits, whereas mice lacking CNTF itself have no notable developmental neurological abnormalities, demonstrating that CNTFRα serves as receptor for a second developmentally important CNTF-like ligand distinct from CNTF. Gene knockout (null mutation), comparative phenotypic analysis of CNTF-/- vs CNTFRα-/- mice Cell High 7585948
1995 The D-helix region of CNTF (particularly Gln167) is important for CNTFRα binding; phage display-selected variants with substitutions at Gln167 showed greatly increased CNTFRα affinity and enhanced neurotrophic activity via CNTFRα, but did not potentiate CNTFRα-independent receptor actions, demonstrating this region is a functional site for CNTFRα interaction. Phage display affinity maturation, in vitro binding assays, cell-based biological activity assays The EMBO journal High 7621819
1996 Residues F152 and K155 in the D1 motif of human CNTF are essential for interaction with LIFRβ; alanine substitution of either residue specifically inhibited CNTF interaction with LIFR without affecting binding to CNTFRα or gp130; combined F152A/K155A substitution abolished biological activity; combining these with CNTFRα-affinity enhancing mutations in the D-helix generated a potent competitive CNTF receptor antagonist. Alanine-scanning mutagenesis, in vitro binding assays, cell-based bioactivity assays PNAS High 8799186
1996 Simultaneous inactivation of both CNTF and LIF genes in mice produces more extensive and earlier-appearing motoneuron degeneration than CNTF knockout alone, accompanied by reduced grip strength, revealing cryptic physiological trophic support by LIF for motoneurons that is unmasked only when CNTF is also absent. Double gene knockout (CNTF-/- / LIF-/-), quantitative motoneuron analysis, functional grip strength testing Current biology High 8793295
2000 CLC (cardiotrophin-like cytokine) forms a stable secreted heteromeric complex with the soluble receptor CLF; CLF expression is required for CLC secretion; the CLF/CLC complex acts only on cells expressing functional CNTF receptors, activates gp130, LIFRβ, and STAT3, and supports motor neuron survival, identifying it as a second ligand for CNTFRα. Co-expression/secretion assays, cell-based signaling assays (STAT3 activation), motor neuron survival assays, receptor specificity tests Nature neuroscience High 10966616
2000 CNTF-induced serine phosphorylation of STAT3 at Ser727 (required for maximal STAT3 transcriptional activation) is mediated by mTOR, not by MAPK or PKC; mTOR directly phosphorylated a STAT3 Ser727 peptide in a CNTF-dependent manner, and kinase-inactive mTOR mutant failed to do so; rapamycin inhibited this phosphorylation and a STAT3 Ser727Ala mutant reduced reporter activation equivalently. In vitro kinase assay with mTOR, pharmacological inhibition (rapamycin, MAPK inhibitors, PKC inhibitors), dominant-negative mTOR mutant, STAT3 reporter assay with Ser727Ala mutant Current biology High 10660304
2000 Reg-2/PAP I is induced by CNTF-related cytokines in motoneurons and functions as an obligatory intermediate in the CNTF survival signaling pathway; blocking Reg-2 expression via antisense adenovirus specifically abrogated the survival effect of CNTF on cultured motoneurons; Reg-2 itself acts as an autocrine/paracrine neurotrophic factor via PI3K-Akt-NF-κB signaling. Antisense adenovirus knockdown, cultured motoneuron survival assay, purified Reg-2 survival assay, pathway inhibitor studies (PI3K, Akt, NF-κB) Nature cell biology High 11146655
2003 Human CNTF can use both membrane-bound and soluble human IL-6Rα as a substitute for its cognate CNTFRα to widen its target cell spectrum; unlike rat CNTF, human CNTF cannot directly induce a heterodimer of human gp130 and LIFRβ in the absence of an alpha receptor. Cell-based signaling assays, receptor competition assays, chimeric receptor constructs The Journal of biological chemistry Medium 12643274
2005 Triple knockout of CNTF, LIF, and CT-1 in mice reveals cooperative but distinct roles: LIF deficiency leads to pronounced loss of distal axons and motor endplate alterations, whereas CNTF and CT-1 deficiency does not cause significant changes in these structures; triple knockout mice show increased motoneuron cell loss correlating with early postnatal muscle weakness. Triple and combined double knockout mouse models, quantitative motoneuron counting, morphological analysis of axons and motor endplates, grip strength testing The Journal of neuroscience High 15716414
2006 CNTF reverses obesity-induced insulin resistance by signaling through the CNTFRα-IL-6R-gp130β receptor complex in skeletal muscle to activate AMPK, increase fatty-acid oxidation, and reduce insulin resistance independent of central (brain) signaling. In vivo skeletal muscle AMPK activation assays, receptor complex characterization, peripheral (skeletal muscle-specific) vs. central pathway dissection Nature medicine High 16604088
2007 Astrocyte-derived CNTF is a major mediator of the neuroprotective and axon-growth-promoting effects of lens injury (intraocular inflammation) on retinal ganglion cells; CNTF from retinal astrocytes activates STAT3 in RGCs; antibody neutralization of CNTF or JAK inhibition compromised the beneficial effects of lens injury, while anti-oncomodulin was ineffective. Intravitreal antibody neutralization, JAK inhibitor treatment, in vivo RGC regeneration assay, STAT3 phosphorylation immunostaining, CNTF-/- mouse comparison Brain High 17971355
2009 Humanin (HN) protects neurons by binding to a receptor complex involving CNTFRα, WSX-1, and gp130; HN induces hetero-oligomerization of these three subunits in vitro; siRNA knockdown of CNTFRα or WSX-1 reduced HN binding and abolished neuroprotection, while overexpression of CNTFRα and/or WSX-1 upregulated HN binding. In vitro reconstituted binding assay, siRNA knockdown, receptor overexpression, loss-of-function cell-based protection assay Molecular biology of the cell Medium 19386761
2009 Exogenous CNTF stimulates RGC axon outgrowth in vitro via JAK/STAT3 and PI3K/AKT signaling pathways; in vivo, exogenously applied CNTF induces endogenous CNTF expression in astrocytes via MAPK/ERK pathway activation; reduction of endogenous CNTF or its absence in CNTF-/- mice markedly reduces the neurite growth-promoting effects of exogenous CNTF. In vitro neurite outgrowth assay with pathway inhibitors, in vivo CNTF-/- mice, MAPK/ERK pathway inhibitors in vivo, endogenous CNTF mRNA quantification Molecular and cellular neurosciences High 19332123
2009 CNTF signals through JAK2/STAT3 cascade in pancreatic islets, increases SOCS3 expression, and protects neonatal rat islets from cytokine-induced apoptosis; these effects were blocked by JAK inhibitor AG490 and STAT3 inhibitor curcumin but not by MAPK or PI3K inhibitors. Pharmacological pathway inhibitors, Western blot for STAT3/Akt/ERK phosphorylation, RT-PCR for SOCS3, apoptosis assays Cytokine Medium 19272793
2012 Endogenous CNTF mediates stroke-induced neurogenesis in the adult mouse SVZ; CNTF-/- mice lack stroke-induced SVZ proliferation; CNTF appears to act on C cell proliferation and by inducing FGF2 expression but not via EGF or Notch1 signaling. CNTF-/- mice, BrdU proliferation assay, middle cerebral artery occlusion model, FGF2/EGF/Notch1 expression analysis Neurobiology of disease High 22960105
2013 CNTF expression in astrocytes is repressed by neuronal contact via an αvβ5 integrin–FAK–JNK signaling pathway; FAK phosphorylates STAT3 on inhibitory Ser-727 to interfere with pro-transcriptional Tyr-705 activity; blockade of FAK or JNK rapidly induces CNTF mRNA and protein; neuronal surface protein Thy1 acts as a neuroglial CNTF repressor; STAT3 binds the CNTF promoter and mediates FAK antagonist-induced CNTF expression. Integrin-specific antibodies, FAK/JNK/ERK/p38 inhibitors, co-culture experiments, STAT3 chromatin immunoprecipitation, microinjection of FAK inhibitor in vivo, neurogenesis assay Cell communication and signaling High 23693126
2018 Hypothalamic CRH neurons innervate ependymal cells of the 3rd ventricle to induce CNTF release; CNTF is transported through the brain's aqueductal system (volume transmission) and binds receptors on locus coeruleus norepinephrinergic neurons; CNTF then initiates sequential phosphorylation of ERK1 and tyrosine hydroxylase (gated by the Ca2+-sensor secretagogin); both CNTF and secretagogin ablation blocked stress-induced cortical norepinephrine synthesis and associated behavioral responses. Neuroanatomical tract tracing, CNTF and secretagogin conditional knockout/ablation, phosphorylation assays (ERK1, tyrosine hydroxylase), behavioral assays, human brain tissue validation The EMBO journal High 30209240
2020 CNTF from Schwann cells mediates neuroinflammation in sensory neurons via STAT3 activation and consequent IL-6 induction, propagating the inflammatory cascade from the periphery to the spinal cord; CNTF deficiency attenuates neuroinflammation in DRG and spinal cord with reduced pain; recombinant CNTF applied to sensory nerves recapitulates this neuroinflammatory cascade. CNTF-/- mice, recombinant CNTF application, pain behavioral assays, STAT3 phosphorylation assays, IL-6 quantification in DRG and spinal cord Cell reports High 32433966
2021 CNTF gene therapy promotes optic nerve regeneration partially indirectly through immune mediators: deletion of CNTFRα specifically in RGCs did not diminish the regeneration-promoting effect of CNTF gene therapy, but neutrophil depletion or suppression of monocyte infiltration did; CNTF gene therapy increased CCL5 expression in immune cells and retinal glia, and CCL5 acting through CCR5 on RGCs mediates much of the regenerative effect. Conditional CNTFRα knockout in RGCs (CRISPR), neutrophil depletion, monocyte infiltration suppression, recombinant CCL5 injection, CRISPR CCR5 knockdown in RGCs, CCR5 antagonist treatment, axon regeneration quantification PNAS High 33627402
2002 CNTF enhances myelination by acting on oligodendrocytes to favor their final maturation; this promyelinating effect is mediated through the gp130 receptor common to the CNTF family and transduced through the JAK kinase pathway. Enzymatic myelination index assay, receptor pathway pharmacological blockade (JAK inhibitor), oligodendrocyte culture assays The Journal of neuroscience Medium 12417647
2009 In adult zebrafish retina, CNTF utilizes a MAPK-dependent signaling pathway (not Stat3 or Akt) for neuroprotection of light-induced photoreceptor cell death, while it uses a Stat3-dependent pathway (not MAPK or Akt) to stimulate Müller glia proliferation; these two CNTF-mediated processes use distinct intracellular signaling cascades. Intraocular injection, pathway-specific inhibitors (MAPK, Stat3, Akt), Stat3 morpholino knockdown, light-damage model, cell proliferation quantification Experimental eye research Medium 19450453

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.) 929 8272873
1992 CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell 688 1617725
1993 LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science (New York, N.Y.) 624 8390097
1989 Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science (New York, N.Y.) 410 2587985
2000 Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Current biology : CB 407 10660304
1993 The alpha component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 397 8381290
1993 Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science (New York, N.Y.) 343 7681218
1991 Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain. The Journal of cell biology 325 1918150
1995 Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 323 7585948
1995 Injury-induced upregulation of bFGF and CNTF mRNAS in the rat retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 287 7472491
1996 The neurotrophins and CNTF: two families of collaborative neurotrophic factors. Annual review of neuroscience 256 8833452
2002 Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Investigative ophthalmology & visual science 250 12356837
2006 CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nature medicine 236 16604088
2006 AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene therapy 222 16708079
2000 CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nature neuroscience 220 10966616
1994 The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines. Journal of neurobiology 213 7852997
2002 Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. The Journal of neuroscience : the official journal of the Society for Neuroscience 204 12417647
2007 Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain : a journal of neurology 203 17971355
2007 ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells. Brain : a journal of neurology 200 18063589
2008 Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Investigative ophthalmology & visual science 185 19060281
2000 Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway. Nature cell biology 183 11146655
1994 A null mutation in the human CNTF gene is not causally related to neurological diseases. Nature genetics 181 8075647
2009 Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Molecular biology of the cell 172 19386761
1992 Effects of ciliary neurotrophic factor (CNTF) and depolarization on neuropeptide expression in cultured sympathetic neurons. Developmental biology 159 1372570
1996 Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF. Current biology : CB 148 8793295
1996 Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 147 8756445
2009 Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF. Molecular and cellular neurosciences 138 19332123
2020 CNTF-STAT3-IL-6 Axis Mediates Neuroinflammatory Cascade across Schwann Cell-Neuron-Microglia. Cell reports 130 32433966
1997 Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina. Experimental eye research 126 9268592
2003 Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. The Journal of biological chemistry 122 12643274
1996 Combined effects of GDNF, BDNF, and CNTF on motoneuron differentiation in vitro. Journal of neuroscience research 112 8723221
1992 The expression of CNTF message and immunoreactivity in the central and peripheral nervous system of the rat. Brain research. Developmental brain research 112 1606686
2015 Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies. Cytokine & growth factor reviews 111 26187860
1991 Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival. Journal of cell science. Supplement 111 1824101
2000 Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Human gene therapy 110 10954906
2000 Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiology of disease 99 10860786
2009 CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina. Experimental eye research 98 19450453
1997 Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone. The Laryngoscope 95 9217144
2001 Cellular and subcellular patterns of expression of bFGF and CNTF in the normal and light stressed adult rat retina. Experimental eye research 91 11311041
1996 Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Human gene therapy 89 8860837
2006 In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration. Molecular therapy : the journal of the American Society of Gene Therapy 83 16872907
2003 Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiology of disease 81 12828933
2005 CNTF/LIF/gp130 receptor complex signaling maintains a VZ precursor differentiation gradient in the developing ventral forebrain. Development (Cambridge, England) 78 15634701
2006 CNTF+BDNF treatment and neuroprotective pathways in the rd1 mouse retina. Brain research 77 17156753
2004 BMP4 and CNTF are neuroprotective and suppress damage-induced proliferation of Müller glia in the retina. Molecular and cellular neurosciences 69 15555930
2002 Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Archives of neurology 69 11890844
2012 Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice. Neurobiology of disease 68 22960105
1998 Continuous exposure to bright light upregulates bFGF and CNTF expression in the rat retina. Current eye research 68 9617544
1997 Cellular delivery of human CNTF prevents motor and cognitive dysfunction in a rodent model of Huntington's disease. Cell transplantation 68 9171158
2003 Adenoviral gene transfer of GDNF, BDNF and TGF beta 2, but not CNTF, cardiotrophin-1 or IGF1, protects injured adult motoneurons after facial nerve avulsion. Journal of neuroscience research 65 12645079
2015 CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa. Molecular therapy : the journal of the American Society of Gene Therapy 64 25896245
2007 Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain : a journal of neurology 64 17898009
2005 Triple knock-out of CNTF, LIF, and CT-1 defines cooperative and distinct roles of these neurotrophic factors for motoneuron maintenance and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 15716414
2005 CNTF and BDNF have similar effects on retinal ganglion cell survival but differential effects on nitric oxide synthase expression soon after optic nerve injury. Investigative ophthalmology & visual science 61 15790921
2002 CNTF and CNTF receptor alpha are constitutively expressed by astrocytes in the mouse brain. Glia 61 11870876
1998 Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways. Journal of neuroscience research 61 9788278
2021 Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy. Proceedings of the National Academy of Sciences of the United States of America 60 33627402
2014 Combined suppression of CASP2 and CASP6 protects retinal ganglion cells from apoptosis and promotes axon regeneration through CNTF-mediated JAK/STAT signalling. Brain : a journal of neurology 57 24727569
1992 Peripheral nerve injury down-regulates CNTF expression in adult rat sciatic nerves. Journal of neuroscience research 57 1319503
1995 CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction. The EMBO journal 56 7621819
1999 Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in axotomized facial motoneurons: evidence for a sequential postlesional function of the cytokines. Journal of neurobiology 52 10590179
1997 CNTF and LIF are not required for the target-directed acquisition of cholinergic and peptidergic properties by sympathetic neurons in vivo. Developmental biology 52 9073449
1996 Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists. Proceedings of the National Academy of Sciences of the United States of America 52 8799186
2014 Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation. Bone 51 24721701
2016 AAV-mediated transfer of RhoA shRNA and CNTF promotes retinal ganglion cell survival and axon regeneration. Neuroscience 49 28017835
2011 CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PloS one 46 21912637
2004 CNTF, a pleiotropic cytokine: emphasis on its myotrophic role. Brain research. Brain research reviews 46 15572170
1997 Changes in expression of ciliary neurotrophic factor (CNTF) and CNTF-receptor alpha after spinal cord injury. Journal of neurobiology 46 9058319
2001 IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration. Neuroreport 45 11303750
1996 Physiological effects of CNTF-induced wasting. Cytokine 45 8980880
2000 Green cone opsin and rhodopsin regulation by CNTF and staurosporine in cultured chick photoreceptors. Investigative ophthalmology & visual science 41 11095633
1998 Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha (CNTFR alpha) expression following focal cerebral ischemia. Brain research. Molecular brain research 41 9645962
1997 Aldose reductase inhibition increases CNTF-like bioactivity and protein in sciatic nerves from galactose-fed and normal rats. Diabetes 40 9075806
1993 Rat ciliary neurotrophic factor (CNTF): gene structure and regulation of mRNA levels in glial cell cultures. Glia 40 8294148
1993 The molecular biology of the CNTF receptor. Current opinion in neurobiology 40 8384037
1996 Therapeutic potential of the neurotrophins and neurotrophin-CNTF combinations in peripheral neuropathies and motor neuron diseases. Ciba Foundation symposium 37 8866127
2006 CNTF gene transfer protects ganglion cells in rat retinae undergoing focal injury and branch vessel occlusion. Experimental eye research 36 16831422
2005 CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Experimental eye research 36 16143329
2009 Ciliary neurotrophic factor (CNTF) signals through STAT3-SOCS3 pathway and protects rat pancreatic islets from cytokine-induced apoptosis. Cytokine 35 19272793
2018 Pronounced synergistic neuroprotective effect of GDNF and CNTF on axotomized retinal ganglion cells in the adult mouse. Experimental eye research 34 30237104
2010 Synergistic effects of NGF, CNTF and GDNF on functional recovery following sciatic nerve injury in rats. Advances in medical sciences 34 20494870
1991 Effect of CNTF on low-affinity NGF receptor expression by cultured neurons from different rat brain regions. Journal of neuroscience research 34 1666130
2013 Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression. Cell communication and signaling : CCS 33 23693126
2012 Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance. Diabetologia 33 22349107
1998 Increased expression of CNTF receptor alpha in denervated human skeletal muscle. Journal of neuropathology and experimental neurology 33 9737548
2018 Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress. The EMBO journal 32 30209240
2003 Molecular cloning and characterisation of a carp (Cyprinus carpio) cytokine-like cDNA that shares sequence similarity with IL-6 subfamily cytokines CNTF, OSM and LIF. Developmental and comparative immunology 31 12543126
2003 Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy. Journal of autoimmunity 31 12935781
2007 Polymorphisms in the CNTF and CNTF receptor genes are associated with muscle strength in men and women. Journal of applied physiology (Bethesda, Md. : 1985) 30 17272411
1996 Activating mechanism of CNTF and related cytokines. Molecular neurobiology 30 8884748
2005 Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice. Journal of the neurological sciences 29 15949503
1998 A bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. The Journal of biological chemistry 29 9694834
1997 CNTF induces GFAP in a S-100 alpha brain cell population: the pattern of CNTF-alpha R suggests an indirect mode of action. Brain research. Developmental brain research 29 9051264
1994 Recombinant human CNTF receptor alpha: production, binding stoichiometry, and characterization of its activity as a diffusible factor. Biochemistry 29 8180210
2015 The MAPK and PI3K pathways mediate CNTF-induced neuronal survival and process outgrowth in hypothalamic organotypic cultures. Journal of cell communication and signaling 28 25698661
2006 Intracompartmental delivery of CNTF as therapy for Huntington's disease and retinitis pigmentosa. Current gene therapy 27 16475952
2013 Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology 26 23845766
1991 The neurotrophins and CNTF: specificity of action towards PNS and CNS neurons. Journal de physiologie 26 1818108
2020 Intravitreal Co-Administration of GDNF and CNTF Confers Synergistic and Long-Lasting Protection against Injury-Induced Cell Death of Retinal Ganglion Cells in Mice. Cells 25 32932933
1995 Investigation of a null mutation of the CNTF gene in familial amyotrophic lateral sclerosis. Journal of the neurological sciences 25 8543936

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