Disease relevance of GDNF

• Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient [1].
• GDNF may have utility in the treatment of Parkinson's disease, which is marked by progressive degeneration of midbrain dopaminergic neurons [2].
• We searched for germline mutations in GDNF in 16 cases of familial phaeochromocytoma (groups A, B and C) and looked for evidence of somatic change in GDNF in 28 sporadic phaeochromocytomas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas [3].
• GDNF (1-100 ng/ml) induced morphological differentiation in 34 of 38 primary neuroblastomas and an accompanying increase in c-Fos induction [4].
• The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion [5].
• The mature GDNF polypeptide was down-regulated in postmortem middle temporal gyrus (MTG) of Alzheimer’s disease (AD), measured by Western blot  [6].

Psychiatry related information on GDNF

• Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease [7].
• Rapid eye movement sleep was not affected by the lower doses of GDNF but was inhibited in rabbits after the high dose [8].
• However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals [9].
• We suggest that GDNF/ES combined treatment in cochlear implant recipients will improve auditory perception [10].
• Despite the increase in CGRP in GDNF-treated rats, there was no increase in thermal or mechanical pain sensitivity, while NGF-treated animals showed significant decreases in pain thresholds [11].

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

• Here, we show that the addition of glial cell line-derived neurotrophic factor (GDNF) induced G2/M cell cycle delay in human SK-N-MC neuroectodermal tumor cells that express RET tyrosine kinase, accompanying actin reorganization [19].
• Because GDNF and neurturin can rescue dopamine neurons in the animal models of Parkinson disease, as well as motoneurons in vivo, hopes have been raised that GDNF family ligands may be new drugs for the treatment of neurodegenerative diseases [20].
• Using reverse transcriptase-polymerase chain reaction, GDNF mRNA was detected in human gliomas and in rat C6 cells [21].
• Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [22].
• RESULTS: Expression of some of the integrin subunits in pancreatic cancer cells was enhanced by GDNF [23].

Biological context of GDNF

• No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p [1].
• BACKGROUND & AIMS: Glial cell line-derived neurotrophic factor (GDNF) signals through the product of the ret proto-oncogene, which is known to be mutated in Hirschsprung's disease and other conditions with gut dysmotility [24].
• Taken together, these data support the idea that sensitivity to GDNF is the mandatory condition, even for constitutively activated Ret mutants, to rescue neuroectodermic cells from apoptosis [25].
• GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hirschsprung disease and the R93W was not identified in 376 control alleles studied by others [3].
• In contrast, Cys(609) or Cys(620) mutations, which impair the terminal Ret glycosylation required for its insertion at the plasma membrane, abrogate GDNF-induced cell rescue [25].

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

• GDNF levels determined by immunoassay were higher in muscle than mucosal gut layers, and there was no difference between affected and unaffected segments of Hirschsprung's disease [24].
• We report that human T cells, B cells, and monocytes produce NTN but not GDNF, as seen by RT-PCR and immunocytochemistry [47].
• Using Xenopus nerve-muscle co-cultures, we show that GDNF and its family member neurturin (NRTN) facilitate the development of the neuromuscular junction (NMJ) [29].
• Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials [48].
• These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain [48].

References