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Gene Review

GDNF  -  glial cell derived neurotrophic factor

Homo sapiens

Synonyms: ATF, ATF1, ATF2, Astrocyte-derived trophic factor, Glial cell line-derived neurotrophic factor, ...


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Disease relevance of GDNF


Psychiatry related information on GDNF


High impact information on GDNF

  • Alternative splicing in exon 4 of human GDNF gene produces GDNF-α long isoform of 185 amino acids and GDNF-β short isoform of 159 amino acids. The deleted 26 amino acid peptide is located in the pre-pro-regions of GDNF-α long isoform. GDNF-αL mRNA was expressed several fold higher than that of the GDNF-βS across brain regions and peripheral tissues [6] [12].
  • The pro-domain of GDNF-α long isoform encodes a peptidase cleaved and activated short 11-mer peptide, neuron stimulating peptide-11 (DNSP-11). In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons and in vivo, DNSP-11 increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of Parkinson disease [13] [14].
  • Glial-derived neurotrophic factor (GDNF), secreted by skeletal muscle, triggers expression of the ETS transcription factor Pea3 in a subset of motor neurons in the spinal cord [15].
  • In this issue, find that this retrograde GDNF-Pea3 signal controls dendrite patterning and assembly of a sensory-motor reflex circuit [15].
  • N-CAM has now been identified as a receptor for glial cell line-derived neurotrophic factor (GDNF) [16].
  • These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor [17].
  • These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases [18].

Chemical compound and disease context of GDNF


Biological context of GDNF


Anatomical context of GDNF

  • These effects were relatively specific; GDNF did not increase total neuron or astrocyte numbers nor did it increase transmitter uptake by gamma-aminobutyric-containing and serotonergic neurons [2].
  • In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake [2].
  • Persephin also supports the survival of motor neurons in culture and in vivo after sciatic nerve axotomy and, like GDNF, promotes ureteric bud branching [26].
  • These results, and recent studies implicating GDNF and ET-3 in the patterning of the enteric nervous system, suggest that specific pairing of endothelins and neurotrophic factors may be used in distinct target organs to coordinate neuronal migration, differentiation, and survival [27].
  • Expression of nerve fibres positive for GDNF (p=0.001) and tyrosine kinase A (p=0.002) was also increased, as were cell bodies of the submucosal ganglia immunoreactive to CGRP (p=0.0009) [28].

Associations of GDNF with chemical compounds

  • Persephin, like GDNF and NTN, promotes the survival of ventral midbrain dopaminergic neurons in culture and prevents their degeneration after 6-hydroxydopamine treatment in vivo [26].
  • Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells [5].
  • Imaging analysis showed that the size of acetylcholine receptor clusters at synapses increased in muscle cells overexpressing GDNF [29].
  • DNA sequences of all the RET/GDNF/NTN coding regions were determined using a direct DyeDeoxy Terminator Cycle method [30].
  • C6 cells revealed the highest expression levels of 2,837 +/- 813 pg/g, whereas mouse 3T3 fibroblasts showed no detectable GDNF protein [21].
  • GDNF reverses this ethanol-mediated adaptation by inhibiting the interaction of TH with HSP90 [31].

Physical interactions of GDNF

  • An initial step in the activation of signaling via the GDNF family of ligands (GFLs) is their binding to their cognate co-receptor GFR alpha [32].
  • In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells [33].
  • The neurotrophic activities of GDNF are mediated by binding to GFRalpha1 and further interaction of the GDNF-GFRalpha1 complex with a coreceptor tyrosine kinase encoded by the c-Ret protooncogene [34].
  • Of these, paxillin and p130Cas interacted with Crk proteins in GDNF-treated neuroblastoma cells [35].
  • These results suggest that the assembly of stable multiprotein complexes containing Tax, CREB/ATF-1, and CBP/p300 on the 21-bp repeats is the principal mechanism employed by Tax to preclude nucleosome formation at the HTLV-1 enhancer/promoter [36].

Co-localisations of GDNF

  • Calcitonin gene-related peptide and GAP43 immunoreactivity significantly increased and co-localized in cervicothoracic dorsal horn laminae I-III following C17.2 and C17.2/GDNF transplantation [37].

Regulatory relationships of GDNF

  • Although none of the four mutations analyzed appeared to affect the ability of GDNF to activate RET, two of them resulted in a significant reduction in the binding affinity of GDNF for the binding subunit of the receptor complex, GFR(alpha)1 [38].
  • To ascertain whether the biological effects of ret mutations are modulated by GDNF, we have investigated the responsiveness to GDNF of ret mutants in cell lines coexpressing GDNFR-alpha and MEN2A-, MEN2B-, FMTC-, or HSCR-associated ret mutants [39].
  • Tyrosine phosphorylation of paxillin was also induced by GDNF [40].
  • The purpose of this study was to determine whether GDNF regulates the expression and activation of matrix metalloproteinase-9 (MMP-9) in human pancreatic cancer cells [41].
  • We describe herein a sensitive and simple non-radioactive quantitative bioassay for GDNF family proteins based on their ability to induce tyrosine hydroxylase (TH) gene expression [42].

Other interactions of GDNF

  • The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands [43].
  • Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) [44].
  • Neurturin had very similar effects as GDNF [29].
  • Cross-linking experiments have indicated that the RETECD makes direct contacts with both the GDNF ligand and GFR alpha 1 molecule in the complex, although it has low or no detectable affinity for either component alone [45].
  • PSPN, but not other GDNF family ligands, promotes the survival of cultured sympathetic neurons microinjected with GFRA4 [46].

Analytical, diagnostic and therapeutic context of GDNF


  1. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Angrist, M., Bolk, S., Halushka, M., Lapchak, P.A., Chakravarti, A. Nat. Genet. (1996) [Pubmed]
  2. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Lin, L.F., Doherty, D.H., Lile, J.D., Bektesh, S., Collins, F. Science (1993) [Pubmed]
  3. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Woodward, E.R., Eng, C., McMahon, R., Voutilainen, R., Affara, N.A., Ponder, B.A., Maher, E.R. Hum. Mol. Genet. (1997) [Pubmed]
  4. Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. Hishiki, T., Nimura, Y., Isogai, E., Kondo, K., Ichimiya, S., Nakamura, Y., Ozaki, T., Sakiyama, S., Hirose, M., Seki, N., Takahashi, H., Ohnuma, N., Tanabe, M., Nakagawara, A. Cancer Res. (1998) [Pubmed]
  5. Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. Veit, C., Genze, F., Menke, A., Hoeffert, S., Gress, T.M., Gierschik, P., Giehl, K. Cancer Res. (2004) [Pubmed]
  6. Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease. Airavaara, M., Pletnikova, O., Doyle, M.E., Zhang, Y.E., Troncoso, J.C., Liu, Q.R. J. Biol. Chem. (2011) [Pubmed]
  7. Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. Alberch, J., Pérez-Navarro, E., Canals, J.M. Brain Res. Bull. (2002) [Pubmed]
  8. Glial cell line-derived neurotrophic factor promotes sleep in rats and rabbits. Kushikata, T., Kubota, T., Fang, J., Krueger, J.M. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2001) [Pubmed]
  9. GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets. Iravani, M.M., Costa, S., Jackson, M.J., Tel, B.C., Cannizzaro, C., Pearce, R.K., Jenner, P. Eur. J. Neurosci. (2001) [Pubmed]
  10. Glial cell line-derived neurotrophic factor and chronic electrical stimulation prevent VIII cranial nerve degeneration following denervation. Kanzaki, S., Stöver, T., Kawamoto, K., Prieskorn, D.M., Altschuler, R.A., Miller, J.M., Raphael, Y. J. Comp. Neurol. (2002) [Pubmed]
  11. Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo. Ramer, M.S., Bradbury, E.J., Michael, G.J., Lever, I.J., McMahon, S.B. Eur. J. Neurosci. (2003) [Pubmed]
  12. Characterization of the intracellular localization, processing, and secretion of two glial cell line-derived neurotrophic factor splice isoforms. Lonka-Nevalaita, L., Lume, M., Leppänen, S., Jokitalo, E., Peränen, J., Saarma, M. J. Neurosci. (2010) [Pubmed]
  13. Dopamine neuron stimulating actions of a GDNF propeptide. Bradley, L.H., Fuqua, J., Richardson, A., Turchan-Cholewo, J., Ai, Y., Kelps, K.A., Glass, J.D., He, X., Zhang, Z., Grondin, R., Littrell, O.M., Huettl, P., Pomerleau, F., Gash, D.M., Gerhardt, G.A. PLoS. One. (2010) [Pubmed]
  14. Dynamic changes in dopamine neuron function after DNSP-11 treatment: effects in vivo and increased ERK 1/2 phosphorylation in vitro. Fuqua, J.L., Littrell, O.M., Lundblad, M., Turchan-Cholewo, J., Abdelmoti, L.G., Galperin, E., Bradley, L.H., Cass, W.A., Gash, D.M., Gerhardt, G.A. Peptides. (2014) [Pubmed]
  15. Retrograde control of neural circuit formation. Deppmann, C.D., Ginty, D.D. Cell (2006) [Pubmed]
  16. Extracellular crosstalk: when GDNF meets N-CAM. Zhou, F.Q., Zhong, J., Snider, W.D. Cell (2003) [Pubmed]
  17. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Paratcha, G., Ledda, F., Ibáñez, C.F. Cell (2003) [Pubmed]
  18. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Salomon, R., Attié, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S., Goulet, O., Ricour, C., Nihoul-Fékété, C., Munnich, A., Lyonnet, S. Nat. Genet. (1996) [Pubmed]
  19. Activation of c-Jun amino-terminal kinase by GDNF induces G2/M cell cycle delay linked with actin reorganization. Fukuda, T., Asai, N., Enomoto, A., Takahashi, M. Genes Cells (2005) [Pubmed]
  20. GDNF - a stranger in the TGF-beta superfamily? Saarma, M. Eur. J. Biochem. (2000) [Pubmed]
  21. Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Wiesenhofer, B., Stockhammer, G., Kostron, H., Maier, H., Hinterhuber, H., Humpel, C. Acta Neuropathol. (2000) [Pubmed]
  22. Functional recovery in parkinsonian monkeys treated with GDNF. Gash, D.M., Zhang, Z., Ovadia, A., Cass, W.A., Yi, A., Simmerman, L., Russell, D., Martin, D., Lapchak, P.A., Collins, F., Hoffer, B.J., Gerhardt, G.A. Nature (1996) [Pubmed]
  23. Alteration of integrin expression by glial cell line-derived neurotrophic factor (GDNF) in human pancreatic cancer cells. Funahashi, H., Takeyama, H., Sawai, H., Furuta, A., Sato, M., Okada, Y., Hayakawa, T., Tanaka, M., Manabe, T. Pancreas (2003) [Pubmed]
  24. Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease. Bär, K.J., Facer, P., Williams, N.S., Tam, P.K., Anand, P. Gastroenterology (1997) [Pubmed]
  25. The sensitivity of activated Cys Ret mutants to glial cell line-derived neurotrophic factor is mandatory to rescue neuroectodermic cells from apoptosis. Mograbi, B., Bocciardi, R., Bourget, I., Juhel, T., Farahi-Far, D., Romeo, G., Ceccherini, I., Rossi, B. Mol. Cell. Biol. (2001) [Pubmed]
  26. Persephin, a novel neurotrophic factor related to GDNF and neurturin. Milbrandt, J., de Sauvage, F.J., Fahrner, T.J., Baloh, R.H., Leitner, M.L., Tansey, M.G., Lampe, P.A., Heuckeroth, R.O., Kotzbauer, P.T., Simburger, K.S., Golden, J.P., Davies, J.A., Vejsada, R., Kato, A.C., Hynes, M., Sherman, D., Nishimura, M., Wang, L.C., Vandlen, R., Moffat, B., Klein, R.D., Poulsen, K., Gray, C., Garces, A., Johnson, E.M. Neuron (1998) [Pubmed]
  27. Sculpting organ innervation. Hempstead, B.L. J. Clin. Invest. (2004) [Pubmed]
  28. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Chan, C.L., Facer, P., Davis, J.B., Smith, G.D., Egerton, J., Bountra, C., Williams, N.S., Anand, P. Lancet (2003) [Pubmed]
  29. Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin. Wang, C.Y., Yang, F., He, X.P., Je, H.S., Zhou, J.Z., Eckermann, K., Kawamura, D., Feng, L., Shen, L., Lu, B. J. Biol. Chem. (2002) [Pubmed]
  30. A homozygous missense mutation in the tyrosine E kinase domain of the RET proto-oncogene in an infant with total intestinal aganglionosis. Shimotake, T., Go, S., Inoue, K., Tomiyama, H., Iwai, N. Am. J. Gastroenterol. (2001) [Pubmed]
  31. Glial cell line-derived neurotrophic factor reverses ethanol-mediated increases in tyrosine hydroxylase immunoreactivity via altering the activity of heat shock protein 90. He, D.Y., Ron, D. J. Biol. Chem. (2008) [Pubmed]
  32. Is GAS1 a co-receptor for the GDNF family of ligands? Schueler-Furman, O., Glick, E., Segovia, J., Linial, M. Trends Pharmacol. Sci. (2006) [Pubmed]
  33. Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. Gattei, V., Celetti, A., Cerrato, A., Degan, M., De Iuliis, A., Rossi, F.M., Chiappetta, G., Consales, C., Improta, S., Zagonel, V., Aldinucci, D., Agosti, V., Santoro, M., Vecchio, G., Pinto, A., Grieco, M. Blood (1997) [Pubmed]
  34. Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. Vieira, P., Thomas-Crusells, J., Vieira, A. Cell. Mol. Neurobiol. (2003) [Pubmed]
  35. Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase. Murakami, H., Iwashita, T., Asai, N., Iwata, Y., Narumiya, S., Takahashi, M. Oncogene (1999) [Pubmed]
  36. Versatile reporter systems show that transactivation by human T-cell leukemia virus type 1 Tax occurs independently of chromatin remodeling factor BRG1. Zhang, L., Liu, M., Merling, R., Giam, C.Z. J. Virol. (2006) [Pubmed]
  37. Pain with no gain: Allodynia following neural stem cell transplantation in spinal cord injury. Macias, M.Y., Syring, M.B., Pizzi, M.A., Crowe, M.J., Alexanian, A.R., Kurpad, S.N. Exp. Neurol. (2006) [Pubmed]
  38. Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease. Eketjäll, S., Ibáñez, C.F. Hum. Mol. Genet. (2002) [Pubmed]
  39. Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease. Carlomagno, F., Melillo, R.M., Visconti, R., Salvatore, G., De Vita, G., Lupoli, G., Yu, Y., Jing, S., Vecchio, G., Fusco, A., Santoro, M. Endocrinology (1998) [Pubmed]
  40. Glial cell-derived neurotrophic factor (GDNF)-induced migration and signal transduction in corneal epithelial cells. You, L., Ebner, S., Kruse, F.E. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  41. Glial cell-derived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase-9 in human pancreatic cancer. Okada, Y., Eibl, G., Duffy, J.P., Reber, H.A., Hines, O.J. Surgery (2003) [Pubmed]
  42. A rapid assay for glial cell line-derived neurotrophic factor and neurturin based on transfection of cells with tyrosine hydroxylase promoter-luciferase construct. Tanaka, M., Xiao, H., Hirata, Y., Kiuchi, K. Brain Res. Brain Res. Protoc. (2003) [Pubmed]
  43. Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. Melillo, R.M., Santoro, M., Ong, S.H., Billaud, M., Fusco, A., Hadari, Y.R., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2001) [Pubmed]
  44. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Mufson, E.J., Kroin, J.S., Sendera, T.J., Sobreviela, T. Prog. Neurobiol. (1999) [Pubmed]
  45. Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET. Kjaer, S., Ibáñez, C.F. J. Biol. Chem. (2003) [Pubmed]
  46. Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. Lindahl, M., Poteryaev, D., Yu, L., Arumae, U., Timmusk, T., Bongarzone, I., Aiello, A., Pierotti, M.A., Airaksinen, M.S., Saarma, M. J. Biol. Chem. (2001) [Pubmed]
  47. Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells. Vargas-Leal, V., Bruno, R., Derfuss, T., Krumbholz, M., Hohlfeld, R., Meinl, E. J. Immunol. (2005) [Pubmed]
  48. Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Behrstock, S., Ebert, A., McHugh, J., Vosberg, S., Moore, J., Schneider, B., Capowski, E., Hei, D., Kordower, J., Aebischer, P., Svendsen, C.N. Gene Ther. (2006) [Pubmed]
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