Affinage

GDNF

Glial cell line-derived neurotrophic factor · UniProt P39905

Round 2 corrected
Length
211 aa
Mass
23.7 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDNF is a secreted, disulfide-bonded homodimeric neurotrophic factor of the TGF-β superfamily that promotes survival, differentiation, and morphogenesis of dopaminergic neurons, motor neurons, enteric neurons, and kidney epithelium by binding the GPI-anchored co-receptor GFRα1, which recruits and activates the RET receptor tyrosine kinase to engage PI3K/AKT, MAPK/ERK, and NF-κB signaling cascades (PMID:8493557, PMID:8657309, PMID:25822020). In cells lacking RET, the GDNF–GFRα1 complex signals alternatively through NCAM (activating Fyn and FAK) to drive Schwann cell migration and axonal growth, or through syndecan-3 (activating Src) to promote cortical neuron migration and neurite outgrowth (PMID:12837245, PMID:21200028). GDNF is retrogradely transported from target tissues to neuronal cell bodies to propagate survival signals, and its signaling amplitude is regulated by endosomal sorting through SorLA, which directs GDNF to lysosomal degradation while recycling GFRα1 (PMID:15485769, PMID:23333276). Germline GDNF deficiency causes complete absence of the enteric nervous system and kidneys in mice, and GDNF loss-of-function mutations have been identified in Hirschsprung disease patients in combination with RET mutations (PMID:8657308, PMID:8896568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Identification of GDNF as a novel TGF-β superfamily member answered the question of whether a specific trophic factor exists for midbrain dopaminergic neurons, establishing the founding member of a new neurotrophic factor family.

    Evidence Purification from B49 cell conditioned medium, cloning, and dopamine uptake assay in embryonic midbrain cultures

    PMID:8493557

    Open questions at the time
    • Receptor identity unknown
    • In vivo relevance to dopaminergic neuron survival unproven
    • Processing and secretion pathway not characterized
  2. 1995 High

    Demonstration that GDNF protects and restores dopaminergic neurons in MPTP models and rescues motor neurons from programmed cell death in vivo established GDNF as a potent neuroprotective agent with therapeutic potential beyond dopaminergic neurons.

    Evidence Intracerebral GDNF injection in mouse MPTP model with neurochemical analysis; chick embryo motor neuron survival and axotomy rescue experiments

    PMID:7830766 PMID:7830769

    Open questions at the time
    • Signaling receptor unknown
    • Mechanism of neuroprotection not defined at molecular level
    • Human relevance unconfirmed
  3. 1996 High

    Discovery of GFRα1 as the GDNF-binding co-receptor and RET as the signal-transducing kinase resolved the long-standing question of how GDNF signals, establishing a two-component receptor system: GPI-anchored GFRα1 for ligand binding and RET for kinase activation.

    Evidence Expression cloning of GFRα1, Co-IP of GFRα1–RET complex, RET phosphorylation assays, soluble GFRα1 reconstitution, Ret-knockout mouse explants

    PMID:8657282 PMID:8657309 PMID:8674117

    Open questions at the time
    • Downstream signaling pathways not yet mapped
    • Whether alternative receptors exist was unknown
    • Crystal structure of the complex not available
  4. 1996 High

    GDNF knockout mice revealed essential non-neuronal roles: complete kidney agenesis and absence of the enteric nervous system demonstrated that GDNF is an obligate morphogen for renal and enteric development, broadening its biology far beyond dopaminergic neurons.

    Evidence Germline GDNF-null mice with histological analysis; organ culture showing GDNF induces ureteric bud branching

    PMID:8657307 PMID:8657308

    Open questions at the time
    • Downstream effectors in kidney morphogenesis not identified
    • Relative contributions of RET-dependent vs. RET-independent signaling in these tissues unknown
  5. 1996 Medium

    GDNF was linked to human Hirschsprung disease when GDNF mutations were identified co-occurring with RET mutations in a patient, supporting a digenic model of enteric nervous system agenesis.

    Evidence Direct sequencing of GDNF in 106 HSCR patients with haplotype analysis

    PMID:8896568

    Open questions at the time
    • GDNF mutations alone insufficient to cause HSCR—penetrance and modifier landscape undefined
    • Functional impact of specific GDNF variants not tested in vitro
    • Only a single patient carried both mutations
  6. 1997 High

    Identification of GFRα2 and GFRα3 as additional co-receptors with differential ligand preferences established that GDNF signals through a family of GPI-linked co-receptors with hierarchical specificity (GFRα1 preferring GDNF, GFRα2 preferring neurturin), explaining tissue-specific responses.

    Evidence Receptor cloning, quantitative dose-response binding assays, RET phosphorylation in transfected cells

    PMID:9182803 PMID:9407096

    Open questions at the time
    • GFRα3 ligand not yet identified at this time
    • In vivo cross-signaling between ligands and non-preferred receptors not quantified
  7. 2000 High

    RET was shown to function as a dependence receptor—inducing caspase-mediated apoptosis in the absence of GDNF—reframing GDNF not merely as a survival factor but as an essential suppressor of constitutive RET-mediated death signaling.

    Evidence Cell transfection apoptosis assays, caspase inhibition, Hirschsprung-associated RET mutant analysis

    PMID:10921886

    Open questions at the time
    • Identity of the RET pro-apoptotic cleavage fragment's downstream effectors unknown
    • Whether dependence receptor function operates in vivo in adult neurons untested
  8. 2003 High

    Discovery that GDNF/GFRα1 signals through NCAM via Fyn/FAK in RET-negative cells answered whether GDNF has functions in cells lacking RET, establishing a RET-independent signaling pathway that mediates Schwann cell migration and axonal growth.

    Evidence Reciprocal Co-IP of NCAM–GFRα1, kinase assays, migration and axon outgrowth assays in RET-null cells

    PMID:12837245

    Open questions at the time
    • Relative physiological contribution of NCAM vs. RET pathway in vivo not established
    • Structural basis of NCAM–GFRα1 interaction unknown
    • Full downstream transcriptional program via NCAM not mapped
  9. 2004 High

    Demonstration of GDNF retrograde transport in compartmentalized neuron cultures—with differential kinase activation at axon tips (RET, AKT, ERK) versus cell bodies (RET, AKT but not ERK)—established the mechanism by which target-derived GDNF communicates survival signals over long distances.

    Evidence Compartmentalized sympathetic neuron cultures, radiolabeled GDNF transport assay, phospho-specific western blots

    PMID:15485769

    Open questions at the time
    • Identity of the retrograde signaling endosome cargo complex not fully defined
    • Whether the transport-associated complex differs between neuron types unknown
  10. 2009 High

    Identification of ETS transcription factors Etv4/Etv5 as essential downstream effectors of GDNF/RET in ureteric bud branching—with double-KO phenocopying kidney agenesis—connected GDNF receptor signaling to a defined transcriptional network controlling morphogenesis.

    Evidence Conditional and germline Etv4/Etv5 KO mice, gene expression profiling of ureteric bud tips

    PMID:19898483

    Open questions at the time
    • Direct regulation of Etv4/5 by specific MAPK/ERK branch not fully dissected
    • How Etv4/5 targets (Cxcr4, Met, Mmp14) are individually required for branching untested
  11. 2011 High

    Syndecan-3 was established as a third GDNF receptor, mediating cortical neuron migration and neurite outgrowth through Src kinase activation—syndecan-3-null mice phenocopied GDNF-null cortical GABAergic neuron deficits, demonstrating a RET- and NCAM-independent signaling route.

    Evidence Binding assays, neurite outgrowth and cell spreading assays, syndecan-3 KO mouse phenotyping, Src kinase activity measurement

    PMID:21200028

    Open questions at the time
    • Whether syndecan-3 and NCAM pathways are redundant or additive in vivo not resolved
    • Structural basis of GDNF–heparan sulfate interaction on syndecan-3 not determined
  12. 2013 High

    SorLA was identified as a sorting receptor that directs GDNF/GFRα1 complexes to lysosomes for GDNF degradation while recycling GFRα1, answering how GDNF signaling amplitude is negatively regulated at the endosomal level; SorLA-null mice showed elevated GDNF and behavioral hyperactivity.

    Evidence Co-IP, endosomal fractionation, receptor trafficking assays, SorLA KO mouse behavioral and neurochemical analysis

    PMID:23333276

    Open questions at the time
    • Whether SorLA interacts with other GDNF family ligands untested
    • Mechanism of SorLA recruitment to the GDNF/GFRα1/RET complex at the molecular level unknown
  13. 2015 High

    Convergence of Parkin and GDNF/RET signaling on mitochondrial integrity via the NF-κB/PI3K axis explained how loss of either pathway alone may be tolerated but combined deficiency accelerates dopaminergic degeneration, linking GDNF to Parkinson's disease-associated mitochondrial quality control.

    Evidence Parkin/Ret double-KO mouse, mitochondrial morphology assays, NF-κB reporter, PI3K inhibition, reciprocal rescue experiments

    PMID:25822020

    Open questions at the time
    • Whether GDNF directly promotes mitophagy or only supports general mitochondrial health unknown
    • Relevance to sporadic Parkinson's disease not addressed
  14. 2019 High

    GDNF/RET signaling was shown to promote muscle stem cell self-renewal by counteracting Gas1-mediated Ret suppression, extending GDNF's trophic role beyond the nervous system and kidney to stem cell maintenance in skeletal muscle, particularly during aging.

    Evidence Gas1 overexpression/KO in MuSCs, Ret signaling assays, muscle regeneration in aged mice

    PMID:32021964

    Open questions at the time
    • Whether GDNF is the physiological RET ligand in MuSCs or whether other GFLs contribute is unclear
    • Source of GDNF in the muscle stem cell niche not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for how GDNF selects among GFRα1, NCAM, and syndecan-3 receptors in vivo; the relative contributions of RET-dependent versus RET-independent pathways in each physiological context; and whether modulating GDNF signaling amplitude (e.g. via SorLA) can be therapeutically exploited for neurodegeneration or cancer perineural invasion.
  • No high-resolution structure of the full GDNF/GFRα1/RET ternary signaling complex
  • In vivo quantification of RET vs. NCAM vs. syndecan-3 pathway contributions lacking
  • Therapeutic window for GDNF modulation in human disease undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 2
Partners
GFRA1GFRA2NCAM1PRKNRETSDC3SORL1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GDNF was purified and cloned as a glycosylated, disulfide-bonded homodimer that is a distant member of the TGF-β superfamily. It promotes survival and morphological differentiation of embryonic midbrain dopaminergic neurons and increases their high-affinity dopamine uptake in culture. Protein purification, cloning, embryonic midbrain neuron culture with dopamine uptake assay Science High 8493557
1995 GDNF protects and repairs the nigrostriatal dopamine system in vivo: injection over substantia nigra or striatum before MPTP potently protects dopamine neurons (cell bodies, terminal density, dopamine levels), and post-MPTP administration restores dopamine levels and fiber densities. In vivo mouse MPTP model, intracerebral GDNF injection, neurochemical and histological analysis Nature High 7830766
1995 GDNF rescues developing avian spinal motor neurons from naturally occurring programmed cell death in vivo and promotes survival of cultured enriched motor neurons. GDNF also prevents axotomy-induced death and atrophy of avian and mouse motor neurons. In vivo chick embryo injection, motor neuron culture survival assay, axotomy model Nature High 7830769
1996 GDNF requires a novel GPI-linked protein GDNFR-alpha (GFRα1) as a high-affinity ligand-binding component: GDNF binds GDNFR-alpha with high affinity, and GDNF promotes formation of a physical complex between GDNFR-alpha and the orphan receptor tyrosine kinase RET, inducing RET tyrosine phosphorylation. GDNFR-alpha and RET function as ligand-binding and signaling components, respectively. Expression cloning, Co-IP, receptor binding assays, RET phosphorylation assay Nature High 8657309
1996 GDNF signals through the RET receptor tyrosine kinase: Xenopus embryo bioassay demonstrated GDNF signaling via RET, and explant cultures from Ret-deficient mouse embryos showed that normal c-ret function is required for GDNF signaling in the peripheral nervous system. Xenopus embryo bioassay, Ret knockout mouse explant cultures Nature High 8657282
1996 GDNFR-alpha (GFRα1) is a GPI-anchored cell surface receptor that binds GDNF specifically and mediates activation of the RET protein-tyrosine kinase. Soluble GDNFR-alpha can also activate RET in cells lacking endogenous GDNFR-alpha when combined with GDNF, and this is blocked by soluble Ret-Fc fusion protein, establishing a stepwise complex formation model: GDNF → GDNFR-alpha → RET. Expression cloning, cell-based binding assays, RET autophosphorylation assay, soluble receptor competition Cell High 8674117
1996 GDNF-deficient mice completely lack the enteric nervous system, ureters, and kidneys at P0, and have deficits in dorsal root ganglion, sympathetic, and nodose neurons, establishing GDNF as essential for development/survival of enteric, sympathetic, and sensory neurons and the renal system. Germline GDNF knockout mouse, histological and anatomical analysis Nature High 8657307 8657308
1996 GDNF-null mice exhibit kidney agenesis/dysgenesis and defective enteric innervation. GDNF induces ureteric bud formation and branching during metanephros development in organ culture, establishing GDNF as a mesenchyme-derived signal for ureteric bud induction. Germline KO mouse, in vitro organ culture ureteric bud branching assay Nature High 8657307
1996 Functional recovery in parkinsonian rhesus monkeys treated with intracerebral GDNF: improvements in bradykinesia, rigidity, and postural instability; dopamine levels in midbrain and globus pallidus were twice as high on the lesioned side, and nigral dopamine neurons were 20% larger with increased fiber density. MPTP non-human primate model, intracerebral GDNF injection, behavioral and neurochemical analysis Nature High 8637574
1996 Germline mutations in both GDNF and RET were found in a single Hirschsprung disease patient, suggesting that GDNF loss-of-function mutations can cooperate with RET mutations to produce the enteric phenotype, though GDNF mutations alone are insufficient to cause HSCR. Direct sequencing of GDNF in 106 HSCR patients, haplotype analysis Nature genetics Medium 8896568
1997 TrnR2 (GFRα2), a novel GPI-linked receptor 48% identical to GFRα1, mediates both neurturin and GDNF signaling through RET in vitro. Cells expressing GFRα2 and RET are ~30-fold more sensitive to neurturin than to GDNF, whereas GFRα1-expressing cells respond equivalently to both, establishing differential ligand-receptor preferences. Cell-based signaling assay, receptor transfection, dose-response analysis Neuron High 9182803
1997 GFRα2 and GFRα3 are novel receptors for GDNF family ligands. GFRα1 and GFRα2 both bind GDNF and neurturin and mediate Ret phosphorylation; cells expressing GFRα1 bind GDNF more efficiently, while GFRα2-expressing cells preferentially bind neurturin. GFRα3 was cloned but did not respond to known GDNF family members. Receptor cloning, ligand binding assays, RET phosphorylation assay, Northern blot The Journal of biological chemistry High 9407096
1998 Persephin, a GDNF family member (~40% identical to GDNF), promotes survival of ventral midbrain dopaminergic neurons and motor neurons. Unlike GDNF and neurturin, persephin does not support peripheral neurons examined, and fibroblasts expressing Ret with GFRα1 or GFRα2 do not respond to persephin, indicating persephin uses a different receptor component. Cell culture survival assays, 6-OHDA in vivo model, receptor transfection assays Neuron High 9491986
1998 GFRα3 is a GPI-linked glycoprotein that is not expressed in the CNS but is highly expressed in developing and adult PNS sensory and sympathetic ganglia. Fibroblasts expressing Ret and GFRα3 do not respond to GDNF, neurturin, or persephin, establishing GFRα3 as a coreceptor for an unknown GDNF family ligand. Receptor cloning, GPI-linkage characterization, cell-based signaling assay, in situ hybridization PNAS High 9576965
1998 The human GDNF gene promoter is highly GC-rich, lacks canonical CCAT-box and TATA-box motifs, contains >12 binding sites for known transcription factors (including Sp1, CREB, AP2, Zif/268, NFkB, MRE-BP, bHLH), and utilizes a promoter distinct from the rodent GDNF gene. Gene cloning, promoter characterization, sequence analysis of cis-elements Brain research Medium 9729303
2000 RET receptor expression induces apoptosis in the absence of GDNF (dependence receptor behavior), and this pro-apoptotic effect is inhibited by GDNF. RET induces apoptosis via caspase-mediated cleavage, releasing a pro-apoptotic domain. Hirschsprung-associated RET mutations impair GDNF's ability to suppress RET pro-apoptotic activity. Cell transfection, apoptosis assay, caspase inhibition, mutant RET analysis The EMBO journal High 10921886
2000 GDNF prevents ethanol-induced apoptosis in SK-N-SH neuroblastoma cells and specifically blocks ethanol-induced phosphorylation of JNK (a pro-apoptotic MAP kinase), without affecting ERK phosphorylation, demonstrating GDNF gates specific intracellular death pathways. Neuroblastoma cell culture, DNA fragmentation assay, phosphatidylserine externalization, JNK/ERK phosphorylation assay Brain research. Developmental brain research Medium 10675770
2001 Zebrafish GDNF and GFRα1 show conserved correlated expression; ectopic GDNF overexpression in somitic muscle during motor axon outgrowth causes specific perturbations in CaP motor axon growth pattern. GDNF morpholino knockdown demonstrated GDNF is required for zebrafish ENS development but dispensable for kidney and primary motor neuron development. In situ hybridization, ectopic overexpression, morpholino antisense knockdown in zebrafish Developmental biology Medium 11237470
2002 17β-estradiol (E2) increases GDNF expression specifically in neurons (not astrocytes) in developing hypothalamic cultures via non-classical estrogen signaling dependent on intracellular Ca2+ and cAMP/PKA pathways, not nuclear estrogen receptors. Western blotting, competitive RT-PCR, pharmacological inhibitors (ICI 182,780, Ca2+/PKA inhibitors) in hypothalamic cell cultures Endocrinology Medium 12130584
2003 GDNF, in complex with GFRα1, can signal independently of RET by interacting with heparan sulphate glycosaminoglycans to activate the Met receptor tyrosine kinase through cytoplasmic Src-family kinases. In cells lacking RET, GDNF binds with high affinity to NCAM/GFRα1 complex, activating Fyn and FAK. Receptor binding assays, kinase activation assays, RET-deficient cell lines Journal of cell science Medium 12953054
2003 NCAM (p140-NCAM) functions as an alternative signaling receptor for GDNF: association of NCAM with GFRα1 downregulates NCAM-mediated cell adhesion and promotes high-affinity GDNF binding to NCAM, resulting in activation of Fyn and FAK in RET-lacking cells. GDNF stimulates Schwann cell migration and axonal growth in hippocampal/cortical neurons via NCAM-Fyn signaling, independently of RET. Co-IP, kinase activity assays, cell migration assay, axonal growth assay, RET-deficient cells Cell High 12837245
2004 GDNF undergoes retrograde signaling in sympathetic neurons: GFRα1 and RET receptors are present at both cell bodies and distal axons. GDNF applied to distal axons activates local RET, AKT, and ERK1/2, and initiates a retrograde signal associated with retrograde transport of radiolabeled GDNF and GFRα1, plus activation of RET and AKT (but not ERK1/2) in cell bodies, leading to neuronal survival and neurite outgrowth. Compartmentalized neuron cultures, radiotracer retrograde transport assay, phospho-specific western blot Molecular and cellular neurosciences High 15485769
2005 GDNF in VTA and SNrm dopaminergic neuron somata is derived by retrograde transport from their striatal targets: after colchicine injection, these neurons lose somatic GDNF immunoreactivity. DA cells projecting to ventral striatum (higher GDNF expression) are more resistant to 6-OHDA than those projecting to dorsal striatum, implicating target-derived GDNF in differential neuroprotection. Retrograde tracer injection, colchicine transport blockade, 6-OHDA lesion model, immunohistochemistry The European journal of neuroscience Medium 15869477
2005 Jagged1 (Notch ligand) and GDNF/Ret/GFRα1 signaling cross-talk during kidney development: exogenous GDNF up-regulates Jag1 in ectopic ureteric buds; transgenic Jag1 overexpression causes persistent Ret/GFRα1 expression in the Wolffian duct and a spectrum of renal defects, rescued by exogenous GDNF in vitro, demonstrating Notch and Ret/GFRα1 pathway crosstalk. Transgenic mouse, organ culture, exogenous factor rescue assay Mechanisms of development Medium 15905075
2005 GFRα1-positive spermatogonial stem cells (SSCs) express RET and proliferate and initiate differentiation in response to rGDNF in vitro. GDNF stimulation induces differential expression of 1124 genes including those involved in early development, differentiation, and cell cycle, establishing a GDNF-driven transcriptional program in SSCs. Cell isolation by GFRα1 expression, GDNF stimulation culture, microarray gene expression analysis Developmental biology Medium 15708562
2007 PTEN suppresses GDNF/RET-mediated cell migration and chemotaxis: RET activation by GDNF results in asymmetric localization of phosphatidylinositol triphosphates (PI3P), and loss of PTEN alters the pattern of ureteric bud branching morphogenesis in developing kidneys, establishing the PI3K/PTEN axis as a critical downstream component of GDNF/RET-mediated epithelial guidance. Cell migration assay, PI3P localization by fluorescent probes, PTEN KO mouse kidney organ culture Developmental biology High 17540362
2007 Adenosine induces GDNF mRNA expression and protein production in primary rat astrocytes via the A2B adenosine receptor, as demonstrated by selective A2B agonist (NECA) mimicry and A2B antagonist (alloxazine) blockade. Primary astrocyte culture, selective agonist/antagonist pharmacology, GDNF ELISA, mRNA analysis Neuroscience research Medium 17920149
2008 GDNF deprivation triggers a mitochondria-independent apoptotic death pathway in cultured embryonic dopaminergic neurons: cytochrome c is not released, Bax is not activated, Bcl-xL does not protect, but caspases (particularly caspase-8, -3, -7) and the death receptor pathway (Fas/FADD) are critically required. Fas ligation induces apoptosis in GDNF-maintained neurons, and Fas-Fc blockade inhibits death of GDNF-deprived neurons. Primary dopaminergic neuron culture, caspase inhibitors, dominant-negative caspase overexpression, Fas-Fc chimera, cytochrome c fractionation The Journal of neuroscience High 18650325
2009 ETS transcription factors Etv4 and Etv5 are positively regulated downstream of GDNF/Ret signaling in ureteric bud tips. Double homozygous Etv4/Etv5 knockout mice have complete kidney agenesis. Etv4/Etv5-dependent genes in the ureteric bud include Cxcr4, Myb, Met, and Mmp14, defining a gene network downstream of GDNF/Ret for branching morphogenesis. Conditional and germline mouse knockouts (Etv4, Etv5), gene expression profiling, in situ hybridization Nature genetics High 19898483
2011 Syndecan-3, a transmembrane heparan sulfate proteoglycan, is a novel receptor for GDNF, neurturin, and artemin (but not persephin): immobilized/matrix-bound GFLs bind syndecan-3 HS chains with high affinity. GFL-syndecan-3 interaction mediates cell spreading and neurite outgrowth via Src kinase activation. GDNF promotes cortical neuron migration in a syndecan-3-dependent manner, and syndecan-3-null mice have reduced cortical GABAergic neurons similar to GDNF-null mice. Binding assays, neurite outgrowth assay, cell spreading assay, syndecan-3 KO mouse, cortical neuron migration assay, Src kinase activity The Journal of cell biology High 21200028
2012 Endoneurial macrophages activated by tumor cells secrete elevated GDNF, inducing phosphorylation of RET and downstream ERK activation in pancreatic ductal adenocarcinoma (PDA) cells. Genetic and pharmacological inhibition of GFRα1 and RET abolished macrophage conditioned medium-induced PDA migration, establishing a paracrine GDNF/RET/ERK axis mediating cancer perineural invasion. Conditioned medium assay, cell migration assay, RET/GFRα1 inhibition (genetic and pharmacological), ERK phosphorylation western blot, CCR2 KO in vivo PNI model Cancer research High 22971345
2013 SorLA (sorting protein-related receptor) acts as a sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes for lysosomal degradation of GDNF while GFRα1 recycles. SorLA also targets RET for endocytosis but not degradation. SorLA-deficient mice have elevated GDNF levels, altered dopaminergic function, marked hyperactivity, and reduced anxiety. Co-IP, cell surface binding, endosomal fractionation, SorLA KO mouse behavioral and neurochemical phenotyping, receptor trafficking assays Cell reports High 23333276
2014 Soluble GFRα1 released by nerves enhances cancer cell perineural invasion (PNI) through GDNF-RET signaling: nerve-released GFRα1 potentiates RET phosphorylation and MAPK pathway activity in cancer cells in a dose-dependent fashion. Cancer cells lacking RET (but not those lacking GFRα1) lose the ability to invade nerves in vivo, establishing RET as the obligate signaling component for PNI. In vitro DRG co-culture PNI assay, RET phosphorylation assay, MAPK activity assay, GFRα1+/- mouse DRG co-culture, in vivo murine PNI model with RET/GFRα1 KO cancer cells, tissue microarray PNAS High 24778213
2015 Parkin and GDNF/RET signaling converge to control mitochondrial integrity in dopaminergic neurons: mice lacking both parkin and RET show accelerated dopaminergic degeneration. GDNF stimulation rescues mitochondrial defects in parkin-deficient cells, and parkin expression restores mitochondrial function in RET-deficient cells. Both converge on the NF-κB pathway via RET/PI3K signaling. Double KO mouse model, mitochondrial morphology/function assays, NF-κB reporter, PI3K pathway inhibition, transgenic parkin rescue The Journal of clinical investigation High 25822020
2017 NOTCH signaling in Sertoli cells negatively regulates GDNF expression: HES1 and HEY1 (NOTCH transcriptional repressors) directly bind the Gdnf promoter and downregulate GDNF expression, antagonizing FSH/cAMP. Testicular stem/progenitor cells activate NOTCH in Sertoli cells via surface JAG1, creating a negative feedback loop controlling SSC homeostasis. Double-mutant mouse model, dual luciferase assay, ChIP-qPCR, in vitro co-culture Stem cells and development High 28051360
2018 Vitamin D (1,25(OH)2D3) directly regulates C-Ret expression in dopaminergic neurons via the vitamin D receptor (VDR): ChIP demonstrated VDR binding to the C-Ret locus. VDR overexpression in the absence of ligand suppresses C-Ret; VDR knockdown increases C-Ret. Knocking down C-Ret leads to compensatory increases in GFRα1 expression, revealing an inverse relationship. Developmental vitamin D-deficient rat model, SH-SY5Y transfection, siRNA knockdown, ChIP, qRT-PCR, Western blot FASEB journal Medium 29018141
2019 Gas1 (growth arrest-specific 1) is expressed in muscle stem cells (MuSCs) and reduces their quiescence and self-renewal by suppressing Ret signaling. GDNF counteracts Gas1 by stimulating Ret signaling, thereby enhancing MuSC self-renewal and muscle regeneration in aged mice. Gas1 overexpression and KO in MuSCs, Ret signaling assays, muscle regeneration functional assays in young and aged mice Nature metabolism High 32021964
2020 GDNF is synthesized as a 211 amino acid pro-GDNF precursor; after proteolytic cleavage and processing it becomes the active 134 amino acid mature form. GDNF triggers RET phosphorylation through the GFRα1/RET receptor complex, initiating downstream signaling pathways including PI3K/AKT and MAPK/ERK to promote neuronal health. GDNF can be retrogradely transported from motor nerve terminals to cell bodies. Review synthesizing biochemical characterization, motor neuron culture, retrograde transport studies Cell and tissue research Medium 32897420
2020 GDNF family ligands signal RET-independently through NCAM/GFRα and syndecan-3, mediating neuronal migration, neurite outgrowth, dendrite branching, spine formation, and synaptogenesis. Trans-signaling by soluble GFRα released from one cell can activate RET or NCAM on adjacent cells lacking GPI-anchored GFRα. Review synthesizing prior functional assays, migration assays, morphology analyses Cell and tissue research Medium 32737575

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The sequence of the human genome. Science (New York, N.Y.) 8428 11181995
1993 GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science (New York, N.Y.) 2772 8493557
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2002 The GDNF family: signalling, biological functions and therapeutic value. Nature reviews. Neuroscience 1462 11988777
1995 Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science (New York, N.Y.) 1333 7824938
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1996 Renal and neuronal abnormalities in mice lacking GDNF. Nature 1057 8657308
1996 GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 1026 8674117
1995 Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 983 7830766
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1996 Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 949 8657307
1996 Characterization of a multicomponent receptor for GDNF. Nature 945 8657309
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1996 Functional recovery in parkinsonian monkeys treated with GDNF. Nature 809 8637574
1996 GDNF signalling through the Ret receptor tyrosine kinase. Nature 708 8657282
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature 623 7830769
2003 Novel functions and signalling pathways for GDNF. Journal of cell science 477 12953054
2003 The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 475 12837245
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
1998 Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 401 9491986
2000 The GDNF family ligands and receptors - implications for neural development. Current opinion in neurobiology 383 10679429
2001 The GDNF/RET signaling pathway and human diseases. Cytokine & growth factor reviews 360 11544105
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1997 TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 305 9182803
2005 Isolation of male germ-line stem cells; influence of GDNF. Developmental biology 249 15708562
1996 Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nature genetics 241 8896568
2001 Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 232 11588183
2010 Genome-wide association study of recurrent early-onset major depressive disorder. Molecular psychiatry 219 20125088
2000 The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease. The EMBO journal 195 10921886
1997 GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. The Journal of biological chemistry 194 9407096
2012 Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the current status. The American journal of surgical pathology 192 22510762
1996 Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nature genetics 185 8896569
2009 Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature genetics 178 19898483
2009 Role of BDNF and GDNF in drug reward and relapse: a review. Neuroscience and biobehavioral reviews 174 19914287
2011 Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. The Journal of cell biology 164 21200028
2009 Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut 157 19240061
2012 Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer research 150 22971345
1998 Expression of neurturin, GDNF, and their receptors in the adult mouse CNS. The Journal of comparative neurology 145 9703032
2008 Altered expression of neurotrophic factors in patients with major depression. Journal of psychiatric research 143 18313696
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2014 GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proceedings of the National Academy of Sciences of the United States of America 118 24778213
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2006 Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. The EMBO journal 95 16511568
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2001 Functional analysis of zebrafish GDNF. Developmental biology 70 11237470
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2000 BRCA1 physically and functionally interacts with ATF1. The Journal of biological chemistry 55 10945975
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2018 SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression. Journal of experimental & clinical cancer research : CR 50 29996942
2008 Regulation of TIP60 by ATF2 modulates ATM activation. The Journal of biological chemistry 49 18397884
2015 The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation. Science signaling 47 26645581
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2013 EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice. The Journal of clinical investigation 42 23281395
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2008 Death receptors and caspases but not mitochondria are activated in the GDNF- or BDNF-deprived dopaminergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 18650325
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2007 PIAS3 interacts with ATF1 and regulates the human ferritin H gene through an antioxidant-responsive element. The Journal of biological chemistry 34 17565989
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2014 Expression patterns of gdnf and gfrα1 in rainbow trout testis. Gene expression patterns : GEP 33 24518650
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2007 Adenosine induces expression of glial cell line-derived neurotrophic factor (GDNF) in primary rat astrocytes. Neuroscience research 28 17920149
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2008 Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma. Journal of cutaneous pathology 27 18700251
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2017 The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy. Cancer chemotherapy and pharmacology 25 28120035
2019 Transcription Factor Atf1 Regulates Expression of Cellulase and Xylanase Genes during Solid-State Fermentation of Ascomycetes. Applied and environmental microbiology 24 31604764
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2008 Flavour formation in fungi: characterisation of KlAtf, the Kluyveromyces lactis orthologue of the Saccharomyces cerevisiae alcohol acetyltransferases Atf1 and Atf2. Applied microbiology and biotechnology 23 18309479
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2014 Ecl1 is activated by the transcription factor Atf1 in response to H2O2 stress in Schizosaccharomyces pombe. Molecular genetics and genomics : MGG 20 24696293
2006 Cardiac NGF and GDNF expression during Trypanosoma cruzi infection in rats. Autonomic neuroscience : basic & clinical 20 16854632
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