Affinage

GDNF

Glial cell line-derived neurotrophic factor · UniProt P39905

Length
211 aa
Mass
23.7 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDNF is a secreted neurotrophic factor that orchestrates neuronal survival, epithelial branching morphogenesis, and stem cell maintenance by engaging a multicomponent receptor system in which it binds with high affinity to the GPI-anchored co-receptor GFRα1, and this complex then recruits and induces tyrosine phosphorylation of the RET receptor tyrosine kinase as the signaling component (PMID:8657309, PMID:8657282, PMID:8657281). RET activation requires recruitment into lipid rafts together with Src, and drives downstream MAPK, PI3K, and CREB outputs (PMID:11106404). In vivo, GDNF is essential for development of the enteric nervous system, kidneys, and multiple peripheral neuron populations (PMID:8657308). In RET-expressing epithelia, GDNF functions as a chemoattractant that reorganizes the actin cytoskeleton and directs migration (PMID:9732293), and during kidney development GDNF/RET signaling shapes ureteric bud branching through PI3K/PTEN-regulated chemotaxis (PMID:17540362) and through induction of the ETS transcription factors Etv4 and Etv5, which control downstream targets including Cxcr4, Myb, Met, and Mmp14 (PMID:19898483). GDNF also signals independently of RET: via GFRα1 it activates Src-family kinases and, in complex with NCAM, activates Fyn and FAK (PMID:10601639, PMID:12953054), while GDNF-bound GFRα1 mediates trans-homophilic adhesion that drives presynaptic differentiation in hippocampal neurons and supports adult-born granule cell dendritic maturation through CREB (PMID:17310246, PMID:31875542). In hepatic stellate cells GDNF binds directly to ALK5 to activate Smad2/3 signaling independently of GFRα1, promoting fibrosis (PMID:31171625). GDNF maintains spermatogonial stem cell self-renewal by blocking differentiation through selective AKT3 phosphorylation, with peritubular myoid and Sertoli cells serving as cyclically and hormonally regulated sources (PMID:26831079, PMID:29440301, PMID:28051360). The SorLA sorting receptor controls GDNF turnover by routing the GDNF/GFRα1 complex to endosomes, targeting GDNF for lysosomal degradation while recycling GFRα1 and routing RET to endosomes (PMID:23333276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1996 High

    Established the molecular logic of GDNF signaling by resolving that GDNF does not act on a single receptor but uses a GPI-anchored ligand-binding co-receptor (GFRα1) coupled to the orphan kinase RET as the transducer.

    Evidence Binding assays, co-IP of GDNFR-alpha with RET, and RET tyrosine phosphorylation in responsive cells, plus RET transfection conferring GDNF responsiveness to fibroblasts and Ret-deficient explant analysis

    PMID:8657281 PMID:8657282 PMID:8657309

    Open questions at the time
    • Stoichiometry and structural geometry of the GDNF/GFRα1/RET complex not resolved
    • Did not address RET-independent signaling modes later discovered
  2. 1996 High

    Defined the physiological necessity of GDNF by showing knockout abolishes whole organ systems, fixing its in vivo role in enteric nervous system and renal development.

    Evidence GDNF knockout mouse phenotyping at P0

    PMID:8657308

    Open questions at the time
    • Does not separate developmental requirement from maintenance roles
    • Cell-type-specific sources of GDNF not defined
  3. 1997 High

    Showed the GFRα co-receptor family encodes ligand selectivity, with GFRα2 favoring neurturin over GDNF, explaining how related TGF-β ligands achieve specificity through a shared RET kinase.

    Evidence Transfection of GFRα2/RET into fibroblasts with dose-response signaling comparison

    PMID:9182803

    Open questions at the time
    • In vitro reconstitution may not reflect native co-receptor expression contexts
  4. 1998 High

    Revealed that GDNF/RET acts as a directional chemoattractant for epithelial cells, providing a cellular mechanism for branching morphogenesis rather than mere survival signaling.

    Evidence Chemotaxis and migration assays with actin imaging in RET-transfected MDCK cells

    PMID:9732293

    Open questions at the time
    • Intracellular effectors linking RET to cytoskeletal remodeling not fully mapped here
  5. 1999 Medium

    Demonstrated GDNF can signal without RET by activating Src-family kinases through GFRα1, expanding the receptor model beyond RET dependence.

    Evidence Kinase and phosphorylation assays in Ret-deficient DRG neurons and Ret-negative cell lines

    PMID:10601639

    Open questions at the time
    • Direct membrane transducer for GFRα1-Src coupling not identified in this study
    • Single lab
  6. 2000 Medium

    Localized GDNF signaling to lipid rafts and established Src association as a requirement for effective RET-mediated differentiation and survival.

    Evidence Membrane fractionation, co-IP, and Src association assays

    PMID:11106404

    Open questions at the time
    • Mechanism of raft recruitment of RET not resolved
    • Embedded in review summarizing prior work
  7. 2003 Medium

    Identified a second RET-independent route in which GDNF binds an NCAM/GFRα1 complex to activate Fyn and FAK, defining an adhesion-linked signaling axis.

    Evidence Binding and kinase activation assays in RET-negative NCAM/GFRα1-expressing cells

    PMID:12953054

    Open questions at the time
    • Physiological contexts where NCAM substitutes for RET not delineated
  8. 2003 High

    Characterized the death pathway triggered by GDNF withdrawal in sympathetic neurons as a distinct non-mitochondrial caspase route, separating it mechanistically from NGF-deprivation death.

    Evidence Cytochrome c, caspase, Bax/Bcl-xL, and c-Jun phosphorylation assays in primary sympathetic neurons

    PMID:14657232

    Open questions at the time
    • Upstream sensor linking GDNF loss to MLK activation not identified
  9. 2007 High

    Uncovered a ligand-induced cell adhesion (LICAM) function whereby GDNF drives trans-homophilic GFRα1 binding to promote presynaptic differentiation, adding an adhesion role distinct from kinase signaling.

    Evidence Trans-homophilic binding and aggregation assays, presynaptic differentiation in hippocampal neurons, and Gdnf mutant mouse immunofluorescence

    PMID:17310246

    Open questions at the time
    • Whether RET participates in the adhesion-driven presynaptic effect not fully isolated
  10. 2007 High

    Placed the PI3K/PTEN axis as the spatial regulator of GDNF/RET chemotaxis, linking asymmetric PIP3 localization to ureteric bud branching pattern.

    Evidence Chemotaxis/migration assays with PTEN manipulation, PIP3 imaging, and conditional Pten knockout kidneys

    PMID:17540362

    Open questions at the time
    • How PTEN asymmetry is established downstream of RET not defined
  11. 2009 High

    Identified Etv4/Etv5 as the transcriptional effectors of GDNF/RET branching signaling and named their downstream targets, building the gene-regulatory arm of the pathway.

    Evidence Conditional and double-knockout mouse genetics with expression and epistasis analysis

    PMID:19898483

    Open questions at the time
    • Direct versus indirect regulation of named target genes not fully distinguished
  12. 2013 High

    Defined the trafficking control of GDNF signaling by showing SorLA sorts the GDNF/GFRα1 complex, degrading GDNF while recycling GFRα1 and routing RET, controlling ligand turnover in vivo.

    Evidence Co-IP, endocytosis and degradation assays, and SorLA knockout mouse phenotyping

    PMID:23333276

    Open questions at the time
    • Quantitative contribution of SorLA to signaling output not measured
  13. 2015 High

    Connected GDNF/RET to mitochondrial protection and Parkin biology, showing genetic crosstalk safeguarding dopaminergic neurons via a RET-PI3K-NF-κB axis.

    Evidence Double-mutant mice, mitochondrial and NF-κB assays, PI3K inhibition, and parkin rescue experiments

    PMID:25822020

    Open questions at the time
    • Molecular link between RET signaling and mitochondrial function incompletely defined
  14. 2016 High

    Established peritubular myoid cells as an essential, hormonally regulated GDNF source for spermatogonial stem cell maintenance, defining the niche cell origin in vivo.

    Evidence Cell-type-specific conditional Gdnf knockout, spermatogonial transplantation, and testosterone induction assays

    PMID:26831079

    Open questions at the time
    • Relative contribution of PM versus Sertoli GDNF not quantified
  15. 2017 High

    Defined transcriptional repression of GDNF by showing NOTCH targets HES1/HEY1 directly bind the Gdnf promoter, creating a spermatogonia-driven negative feedback antagonizing FSH/cAMP induction.

    Evidence Luciferase reporter, ChIP-qPCR, double-mutant mice, and co-culture

    PMID:28051360

    Open questions at the time
    • Integration of NOTCH repression with cyclic GDNF expression not fully resolved
  16. 2018 High

    Resolved the downstream selectivity of GDNF in spermatogonial self-renewal, showing it blocks differentiation via isoform-specific AKT3 phosphorylation rather than driving proliferation.

    Evidence Stage-specific transgenic overexpression, EdU labeling, busulfan model, and isoform-specific AKT western blots

    PMID:29440301

    Open questions at the time
    • Mechanism conferring AKT3 isoform selectivity not identified
  17. 2019 High

    Demonstrated a direct GFRα1-independent GDNF-ALK5 binding mode driving Smad2/3 activation in hepatic stellate cells, establishing a profibrotic signaling axis distinct from canonical RET signaling.

    Evidence SPR, docking, mutagenesis, co-IP, adenoviral and CRISPR manipulation, and primary HSC cultures in mice

    PMID:31171625

    Open questions at the time
    • Whether ALK5 binding occurs in other tissues not addressed
  18. 2019 High

    Extended GDNF/GFRα1 function to adult hippocampal neurogenesis, linking it via CREB to dendritic maturation and behavioral pattern separation, and to exercise-driven plasticity.

    Evidence Conditional GFRα1 knockout mice, dendritic morphology, behavioral testing, and exercise paradigm with CREB phosphorylation

    PMID:31875542

    Open questions at the time
    • RET involvement in this neurogenic effect not separated from GFRα1 adhesion function
  19. 2019 Medium

    Identified a role for GDNF/Ret in muscle stem cell quiescence and self-renewal, with Gas1 acting as a counteracting suppressor of Ret signaling.

    Evidence Gas1 gain/loss-of-function, Ret signaling assays, and muscle regeneration assays in mice

    PMID:32021964

    Open questions at the time
    • Source of GDNF in the muscle niche not defined
    • Single lab
  20. 2020 Medium

    Described an epigenetic mechanism driving high GDNF transcription in glioblastoma via pCREB-coordinated DNA methylation and histone acetylation crosstalk between GDNF regulatory elements.

    Evidence ChIP, reporter assays with promoter mutations, CREB manipulation, and pharmacological inhibition in GBM cell lines

    PMID:32183903

    Open questions at the time
    • Whether this epigenetic mechanism operates in normal tissues not established
    • Single lab
  21. 2021 Medium

    Identified enteric glial cells as a GDNF source maintaining intestinal epithelial barrier integrity through RET on epithelial cells, extending GDNF function to mucosal protection.

    Evidence EGC isolation, co-culture, GDNF knockdown, neutralizing antibody, RET blockade, organoids, and TEER measurements

    PMID:33672854

    Open questions at the time
    • In vivo requirement of EGC-derived GDNF for barrier function not genetically confirmed
    • Single lab
  22. 2021 Medium

    Showed GDNF and neurturin acutely and differentially modulate myenteric neuron activity and gut motility according to Gfra1/Gfra2 subtype expression, revealing an acute neuromodulatory role beyond trophic support.

    Evidence Single-cell RNA-seq, calcium imaging with ligand application, and immunohistochemistry

    PMID:33444816

    Open questions at the time
    • Signaling pathway mediating acute neuronal activity changes not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GDNF integrates its multiple receptor modes (RET, GFRα1-NCAM, GFRα1 homophilic adhesion, ALK5) into context-specific outputs, and what determines the isoform/effector selectivity (e.g. AKT3, ALK5 residue usage) across tissues, remains unresolved.
  • No unified structural model of GDNF in its alternative receptor complexes
  • Determinants of tissue-specific effector selection unknown
  • Relative in vivo contribution of RET-independent modes not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9609507 Protein localization 1
Partners
ALK5GFRA1GFRA2NCAM1RETSORL1SRC
Complex memberships
GDNF/GFRα1/NCAM complexGDNF/GFRα1/RET receptor complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 GDNF signals through a multicomponent receptor system: it binds with high affinity to a novel GPI-linked protein (GDNFR-alpha/GFRα1), and this complex then promotes physical association with and tyrosine phosphorylation of the orphan receptor tyrosine kinase RET, making GFRα1 the ligand-binding component and RET the signaling component. Binding assays, co-immunoprecipitation of GDNFR-alpha with RET, tyrosine phosphorylation assays in GDNF-responsive cells Nature High 8657281 8657282 8657309
1996 RET is a functional receptor for GDNF: GDNF binds to and induces tyrosine phosphorylation of the RET proto-oncogene product in motor neuron cell lines; transfection of RET into naive fibroblasts confers GDNF-binding ability and mediates survival/growth responses to GDNF. Radioligand binding, tyrosine phosphorylation assay, transfection of RET into fibroblasts with functional survival assay, Xenopus embryo bioassay, Ret-deficient mouse explant cultures Nature High 8657281 8657282
1996 GDNF-deficient mice completely lack the enteric nervous system, ureters, and kidneys, and have deficits in dorsal root ganglion, sympathetic, and nodose neurons, establishing that GDNF is essential in vivo for development/survival of enteric neurons and the renal system. GDNF knockout mouse analysis (postnatal day 0 phenotyping) Nature High 8657308
1997 A second GPI-linked co-receptor, TrnR2 (GFRα2), can mediate both neurturin and GDNF signaling through RET in vitro, but shows ~30-fold higher sensitivity to neurturin than GDNF, while TrnR1 (GFRα1)-expressing cells respond equivalently to both factors, indicating distinct ligand preferences among GFRα co-receptors. Transfection of fibroblasts with TrnR2 and RET followed by dose-response signaling assays; homology cloning and GPI-linkage characterization Neuron High 9182803
1999 GDNF can activate Src-family tyrosine kinase(s) via GPI-linked GFRα1 independently of RET, subsequently triggering phosphorylation of MAPK, CREB, and PLCγ in RET-deficient neurons and cell lines. Kinase activity assays and phosphorylation blotting in Ret-deficient mouse DRG neurons and two Ret-negative cell lines FEBS letters Medium 10601639
2000 GFRα1 is localized to lipid rafts in the plasma membrane; GDNF binding to GFRα1 recruits RET to lipid rafts and triggers association with Src, which is required for effective downstream signaling leading to differentiation and neuronal survival. Membrane fractionation, co-immunoprecipitation, Src association assays European journal of biochemistry Medium 11106404
2003 GDNF can signal through GFRα1 in a RET-independent manner: in cells lacking RET, GDNF binds with high affinity to a complex of NCAM and GFRα1, activating Fyn and FAK kinases. Binding assays and kinase activation assays in RET-negative cells expressing NCAM and GFRα1 Journal of cell science Medium 12953054
2003 GDNF-deprived sympathetic neurons die via a novel non-mitochondrial caspase-dependent pathway that requires MLK kinases, c-Jun phosphorylation (at Ser73 but not Ser63), and caspase-2 and -7, but does not involve cytochrome c release, Bax, caspase-9, or Bcl-xL—distinct from the NGF-deprivation death pathway. Cytochrome c release assay, caspase activity assays, Bax/Bcl-xL overexpression, c-Jun phosphorylation analysis, electron microscopy of mitochondria, primary sympathetic neuron cultures The Journal of cell biology High 14657232
1998 Activation of the RET pathway by GDNF in MDCK renal epithelial cells results in increased cell motility, dissociation of cell-cell adhesion, formation of lamellipodia and filopodia, actin cytoskeleton reorganization, and directed migration toward a localized GDNF source, demonstrating that GDNF acts as a chemoattractant for RET-expressing epithelial cells. Cell migration assay, chemotaxis assay toward GDNF gradient, actin cytoskeleton staining, MDCK cells transfected with RET The Journal of cell biology High 9732293
2007 GDNF triggers trans-homophilic binding between GFRα1 molecules on opposing cell surfaces, mediating ligand-induced cell adhesion (LICAM); in the presence of GDNF, GFRα1 induces localized presynaptic differentiation in hippocampal neurons (clustering of vesicular proteins, neurotransmitter transporters, and activity-dependent vesicle recycling); Gdnf mutant mice show reduced synaptic localization of presynaptic proteins and decreased density of presynaptic puncta. Trans-homophilic binding assay, cell aggregation assay, presynaptic differentiation assay in hippocampal neurons with GFRα1 loss-of-function, immunofluorescence in Gdnf mutant mice Nature neuroscience High 17310246
2009 ETS transcription factors Etv4 and Etv5 are positively regulated downstream of GDNF/RET signaling in ureteric bud tips; double knockout of Etv4/Etv5 causes renal agenesis or severe hypodysplasia; downstream targets of this pathway include Cxcr4, Myb, Met, and Mmp14, placing Etv4/Etv5 as key nodes in the GDNF→RET→branching morphogenesis pathway. Conditional mouse knockouts, gene expression analysis, genetic epistasis Nature genetics High 19898483
2007 PTEN suppresses RET-mediated cell migration and chemotaxis downstream of GDNF; RET activation results in asymmetric localization of phosphatidylinositol triphosphates; conditional loss of PTEN alters the pattern of ureteric bud branching morphogenesis in developing mouse kidneys, demonstrating that the PI3K/PTEN axis shapes epithelial branching in response to GDNF/RET. Cell culture chemotaxis and migration assays with PTEN overexpression/loss, lipid second messenger localization (PI(3,4,5)P3 immunofluorescence), conditional Pten knockout kidney phenotyping Developmental biology High 17540362
2013 SorLA acts as a sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes; through this mechanism GDNF is targeted to lysosomes for degradation while GFRα1 recycles; SorLA/GFRα1 complex also targets RET for endocytosis (but not degradation); SorLA-deficient mice have elevated GDNF levels, altered dopaminergic function, marked hyperactivity, and reduced anxiety. Co-immunoprecipitation, receptor trafficking/endocytosis assays, GDNF degradation assays, SorLA knockout mouse phenotyping Cell reports High 23333276
2015 Parkin and RET/GDNF signaling exhibit genetic crosstalk in protecting dopaminergic neurons: double parkin/RET knockout mice show accelerated dopaminergic cell loss compared to single knockouts; GDNF stimulation rescues mitochondrial defects in parkin-deficient cells via RET-PI3K-NF-κB pathway activation; parkin expression restores mitochondrial function in GDNF/RET-deficient cells through the same NF-κB pathway. Double-mutant mouse models, mitochondrial function assays, NF-κB pathway analysis, PI3K inhibition, transgenic parkin expression rescue experiments The Journal of clinical investigation High 25822020
2016 Peritubular myoid (PM) cells are an essential source of GDNF for spermatogonial stem cell (SSC) development in vivo: conditional knockout of Gdnf specifically in PM cells causes infertility due to collapse of spermatogenesis and loss of undifferentiated spermatogonia, and testosterone induces GDNF expression in PM cells. Conditional Gdnf knockout in PM cells, spermatogonial transplantation assay, in vitro testosterone treatment of PM cells co-cultured with neonatal spermatogonia Proceedings of the National Academy of Sciences of the United States of America High 26831079
2018 GDNF is expressed cyclically during spermatogenesis; stage-specific ectopic GDNF expression causes accumulation of GFRA1+ SSCs; GDNF promotes SSC self-renewal by blocking differentiation rather than promoting proliferation; increased GDNF signaling leads to selective phosphorylation of AKT3 (not AKT1 or AKT2) in undifferentiated spermatogonia, independent of RPS6 phosphorylation. Stage-specific transgenic GDNF overexpression, EdU labeling (proliferation assay), busulfan depletion/recovery model, isoform-specific AKT phosphorylation western blotting Development (Cambridge, England) High 29440301
2019 GDNF promotes hepatic stellate cell (HSC) activation and liver fibrosis through ALK5 (at residues His39 and Asp76) and downstream Smad2/3 signaling, independently of GFRα1; this was demonstrated by surface plasmon resonance, molecular docking, mutagenesis and co-immunoprecipitation confirming direct GDNF-ALK5 binding. Surface plasmon resonance (SPR) binding assay, molecular docking, mutagenesis of GDNF binding residues, co-immunoprecipitation, adenoviral GDNF delivery in mice, GDNF CRISPR knockout, blocking antibody experiments, primary HSC cultures Gut High 31171625
2019 GDNF acting through GFRα1 controls dendritic structure and spine density of adult-born granule cells in the hippocampus; conditional GFRα1 mutant mice show deficits in behavioral pattern separation; running increases GDNF in the dentate gyrus and promotes GFRα1-dependent CREB activation and dendrite maturation. Conditional GFRα1 knockout mice, dendritic morphology analysis, behavioral pattern separation test, exercise paradigm with GDNF measurement and CREB phosphorylation assay Cell reports High 31875542
2017 NOTCH signaling in Sertoli cells downregulates GDNF expression: the NOTCH targets HES1 and HEY1 (transcriptional repressors) directly bind the Gdnf promoter to suppress GDNF transcription, antagonizing FSH/cAMP-driven GDNF expression; spermatogonial progenitors activate this negative feedback via JAG1 on their surface. Dual luciferase reporter assay, ChIP-qPCR demonstrating HES1/HEY1 binding to Gdnf promoter, double-mutant mouse model, in vitro co-culture Stem cells and development High 28051360
2019 GDNF/Ret signaling is required for muscle stem cell (MuSC) quiescence and self-renewal; Gas1 reduces Ret signaling and thereby suppresses MuSC self-renewal capacity; exogenous GDNF counteracts Gas1 by stimulating Ret signaling and enhancing MuSC self-renewal and regeneration. Gas1 overexpression and inactivation in MuSCs, Ret signaling assays, muscle regeneration functional assays in mice Nature metabolism Medium 32021964
2020 In glioblastoma cells, pCREB-induced crosstalk between DNA hypermethylation at CRE in GDNF silencer II and histone H3 acetylation at GDNF enhancer II drives high GDNF transcription: hypermethylation at silencer II reduces pCREB binding there, increasing pCREB binding to enhancer II, which recruits CBP (histone acetyltransferase), increasing H3 acetylation and RNA Pol II recruitment at the TSS. ChIP, luciferase reporter assay with promoter II deletions/mutations, CREB overexpression and knockdown, pharmacological inhibition of DNA methylation and histone acetylation in GBM cell lines Clinical epigenetics Medium 32183903
2021 Enteric glial cells (EGCs) produce GDNF in vivo and in vitro; EGC-derived GDNF is required for intestinal epithelial barrier (IEB) maturation and protection from TNFα-induced barrier disruption, acting through the RET receptor on epithelial cells; GDNF depletion from EGC supernatants or RET receptor blockade abrogates EGC-mediated barrier protection. FACS isolation of EGCs from GFAPcre x Ai14 mice, EGC-Caco2 co-culture, GDNF knockdown in EGCs, neutralizing antibody depletion, RET receptor blockade, organoid cultures, TEER measurements International journal of molecular sciences Medium 33672854
2021 GDNF and neurturin acutely and differentially regulate activity of approximately 50% of myenteric neurons, with distinct effects on smooth muscle contractions, as revealed by differential expression of Gfra1 and Gfra2 in neuronal subtypes identified by single-cell RNA-seq. Single-nucleus/single-cell RNA-seq, calcium imaging of myenteric neurons with GDNF/neurturin application, immunohistochemistry Cellular and molecular gastroenterology and hepatology Medium 33444816

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The GDNF family: signalling, biological functions and therapeutic value. Nature reviews. Neuroscience 1468 11988777
1996 Renal and neuronal abnormalities in mice lacking GDNF. Nature 1059 8657308
1996 Characterization of a multicomponent receptor for GDNF. Nature 947 8657309
1996 GDNF signalling through the Ret receptor tyrosine kinase. Nature 711 8657282
1996 Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 696 8657281
2013 GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacology & therapeutics 655 23348013
2003 Novel functions and signalling pathways for GDNF. Journal of cell science 477 12953054
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 361 11544105
1997 TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 305 9182803
1999 Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Experimental neurology 296 10415156
1993 Regional and cell-specific expression of GDNF in rat brain. Experimental neurology 260 8287932
2006 GDNF/Ret signaling and the development of the kidney. BioEssays : news and reviews in molecular, cellular and developmental biology 244 16435290
1998 Neurturin and GDNF promote proliferation and survival of enteric neuron and glial progenitors in vitro. Developmental biology 185 9698461
1994 Expression of GDNF mRNA in rat and human nervous tissue. Experimental neurology 184 8033959
2009 Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature genetics 179 19898483
2009 Role of BDNF and GDNF in drug reward and relapse: a review. Neuroscience and biobehavioral reviews 176 19914287
2008 GDNF and GFRalpha: a versatile molecular complex for developing neurons. Trends in neurosciences 170 18597864
2016 Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development. Proceedings of the National Academy of Sciences of the United States of America 147 26831079
2007 GDNF family receptor complexes are emerging drug targets. Trends in pharmacological sciences 147 17218019
1998 Expression of neurturin, GDNF, and their receptors in the adult mouse CNS. The Journal of comparative neurology 145 9703032
2007 GDNF and GFRalpha1 promote formation of neuronal synapses by ligand-induced cell adhesion. Nature neuroscience 136 17310246
1999 Other neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF). Microscopy research and technique 131 10383122
1999 GDNF triggers a novel ret-independent Src kinase family-coupled signaling via a GPI-linked GDNF receptor alpha1. FEBS letters 128 10601639
1998 Neuroprotective and neurorestorative properties of GDNF. Annals of neurology 120 9749583
1998 GFRalpha3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proceedings of the National Academy of Sciences of the United States of America 114 9576965
2020 GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop. Journal of Parkinson's disease 110 32508331
1997 Regulation of GDNF expression in cultured astrocytes by inflammatory stimuli. Neuroreport 110 9351662
2000 GDNF - a stranger in the TGF-beta superfamily? European journal of biochemistry 109 11106404
1998 The RET-glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells. The Journal of cell biology 109 9732293
2020 GDNF, A Neuron-Derived Factor Upregulated in Glial Cells during Disease. Journal of clinical medicine 108 32046031
2015 GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson's disease. Frontiers in neuroanatomy 101 25762899
2017 Neurotrophic Factors (BDNF and GDNF) and the Serotonergic System of the Brain. Biochemistry. Biokhimiia 98 28320272
2019 GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential. Frontiers in physiology 93 30666215
2020 GDNF synthesis, signaling, and retrograde transport in motor neurons. Cell and tissue research 90 32897420
2014 Neurotrophic factor GDNF promotes survival of salivary stem cells. The Journal of clinical investigation 87 25036711
2021 scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3. Cellular and molecular gastroenterology and hepatology 86 33444816
1998 Glial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson's disease. Journal of neurology 84 9808338
2000 Glial-derived neurotrophic factor (GDNF) prevents ethanol-induced apoptosis and JUN kinase phosphorylation. Brain research. Developmental brain research 83 10675770
2000 Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta neuropathologica 81 10672319
2008 Driving GDNF expression: the green and the red traffic lights. Progress in neurobiology 80 18824211
2012 Neuroprotection by GDNF in the ischemic brain. Growth factors (Chur, Switzerland) 77 22670840
2018 Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. Development (Cambridge, England) 76 29440301
2000 RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Human mutation 74 10790203
2006 Evolution of the GDNF family ligands and receptors. Brain, behavior and evolution 70 16912471
2001 Functional analysis of zebrafish GDNF. Developmental biology 70 11237470
2018 Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 29018141
2015 Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. The Journal of clinical investigation 66 25822020
2005 Striatal expression of GDNF and differential vulnerability of midbrain dopaminergic cells. The European journal of neuroscience 66 15869477
2017 The GDNF Family: A Role in Cancer? Neoplasia (New York, N.Y.) 65 29245123
2019 Regulation of GDNF expression in Sertoli cells. Reproduction (Cambridge, England) 60 30620720
2020 Intracellular RET signaling pathways activated by GDNF. Cell and tissue research 58 32816064
2017 The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells. Stem cells and development 58 28051360
2013 SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET. Cell reports 57 23333276
2003 GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway. The Journal of cell biology 57 14657232
2007 PTEN modulates GDNF/RET mediated chemotaxis and branching morphogenesis in the developing kidney. Developmental biology 56 17540362
2011 GDNF and protection of adult central catecholaminergic neurons. Journal of molecular endocrinology 54 21357726
2019 GDNF and GFRα1 Are Required for Proper Integration of Adult-Born Hippocampal Neurons. Cell reports 53 31875542
2010 High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Molecular and cellular biochemistry 53 20960036
1999 A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. Biochemical pharmacology 53 9890561
2021 Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent. International journal of molecular sciences 51 33672854
2006 Is GAS1 a co-receptor for the GDNF family of ligands? Trends in pharmacological sciences 51 16406089
2022 GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries. Neural regeneration research 49 34472460
1998 GDNF expression is increased in denervated human skeletal muscle. Neuroscience letters 47 9697925
2019 Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling. Gut 45 31171625
2002 Estradiol stimulates GDNF expression in developing hypothalamic neurons. Endocrinology 44 12130584
2014 Deficiency of GDNF Receptor GFRα1 in Alzheimer's Neurons Results in Neuronal Death. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 25253858
2001 Sustained delivery of GDNF: towards a treatment for Parkinson's disease. Brain research. Brain research reviews 43 11690619
2013 GDNF increases cell motility in human colon cancer through VEGF-VEGFR1 interaction. Endocrine-related cancer 41 24165321
2005 Overexpression of NGF or GDNF alters transcriptional plasticity evoked by inflammation. Pain 39 15661434
2004 GDNF gene therapy attenuates retinal ischemic injuries in rats. Molecular vision 39 14961006
2018 GDNF revisited: A novel mammalian cell-derived variant form of GDNF increases dopamine turnover and improves brain biodistribution. Neuropharmacology 38 29857941
1999 GDNF and its receptors in the regulation of the ureteric branching. The International journal of developmental biology 38 10535317
2018 The reversible effects of glial cell line-derived neurotrophic factor (GDNF) in the human brain. Seminars in cancer biology 37 30059726
2001 Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Hearing research 37 11335084
2018 History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair. Brain sciences 36 29899247
2020 Crosstalk between DNA methylation and histone acetylation triggers GDNF high transcription in glioblastoma cells. Clinical epigenetics 35 32183903
2020 RET-independent signaling by GDNF ligands and GFRα receptors. Cell and tissue research 35 32737575
2020 GDNF Gene Therapy to Repair the Injured Peripheral Nerve. Frontiers in bioengineering and biotechnology 34 33251197
2017 MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 34 29224008
2010 Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects cortical neurons from dying following a traumatic brain injury. Restorative neurology and neuroscience 34 20479525
2007 Glial cell line-derived neurotrophic factor (GDNF) therapy for Parkinson's disease. Acta medica Okayama 34 17471304
2014 Expression patterns of gdnf and gfrα1 in rainbow trout testis. Gene expression patterns : GEP 33 24518650
1996 Expression and regulation of glial-cell-line-derived neurotrophic factor (GDNF) mRNA in human astrocytes in vitro. Cell and tissue research 33 8854895
2015 GDNF-induced cerebellar toxicity: A brief review. Neurotoxicology 32 26535469
2005 Crosstalk between Jagged1 and GDNF/Ret/GFRalpha1 signalling regulates ureteric budding and branching. Mechanisms of development 31 15905075
2005 GDNF and addiction. Reviews in the neurosciences 30 16519005
1998 GDNF deficit in Hirschsprung's disease. Journal of pediatric surgery 30 9473110
2013 Glial cell line-derived neurotrophic factor (GDNF) as a novel candidate gene of anxiety. PloS one 29 24324616
2009 Ape1/Ref-1 induces glial cell-derived neurotropic factor (GDNF) responsiveness by upregulating GDNF receptor alpha1 expression. Molecular and cellular biology 29 19188437
2006 GDNF gene delivery via the p75(NTR) receptor rescues injured motor neurons. Experimental neurology 29 16842780
2001 Glial cell line-derived neurotrophic factor (GDNF) and its receptors GFRalpha-1 and GFRalpha-2 in the human testis. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia 29 11732574
1996 Expression and localization of GDNF in developing and adult adrenal chromaffin cells. Cell and tissue research 29 8854896
1999 Differences and developmental changes in the responsiveness of PNS neurons to GDNF and neurturin. Molecular and cellular neurosciences 28 10383828
2019 Muscle stem cell renewal suppressed by Gas1 can be reversed by GDNF in mice. Nature metabolism 27 32021964
2012 GDNF and BDNF gene interplay in chronic tinnitus. International journal of molecular epidemiology and genetics 27 23050055
2003 GDNF and somatostatin in sensory neurones. Current opinion in pharmacology 27 12550740
2022 Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease. Cells 26 35741061
2021 GDNF signaling in subjects with minimal motor deficits and Parkinson's disease. Neurobiology of disease 26 33684514
2005 TAT-GDNF in neurodegeneration and ischemic stroke. CNS drug reviews 26 16614736

Missed literature

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

No submissions yet.