Role of glial cell line-derived neurotrophic factor in intestinal inflammatory diseases
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Ciliary neurotrophic factor
Line (geometry)
Neurturin
Proto-Oncogene Proteins c-ret
Ectodomain
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Ciliary neurotrophic factor
Neurotrophin-3
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The c-ret protooncogene, RET, encodes a receptor tyrosine kinase. RET is activated by members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands, which include GDNF, neurturin, artemin, and persephin. The ligands bind RET through GDNF family receptor alpha, termed GFRalpha1-4. Despite the importance of RET signaling in the development of the enteric nervous system and the kidney, the differential signaling mechanisms between RET ligands are poorly established. It has been suggested that signal specificity is achieved through binding of the ligand to its preferred GFRalpha. To compare the signaling profiles of GDNF and neurturin, we have identified a cell line, NG108-15, which endogenously expresses RET and GFRalpha1 but not GFRalpha2-4. Immunoblot data showed that GDNF caused a transient activation, whereas neurturin caused a sustained activation, of both p44/p42 MAP kinases and PLCgamma. Under serum starvation, NG108-15 cells differentiate and form neurites. Neurturin but not GDNF stimulated neurite outgrowth, which could be blocked by the selective PLC inhibitor U73122. On the other hand, GDNF but not neurturin promoted cell survival, and this could be blocked by the p44/p42 MAP kinase inhibitor PD98059. Our findings not only show the differential signaling of GDNF and neurturin but also suggest that this can be achieved through binding to the same GFRalpha subtype, leading to distinct biological responses.
Neurturin
Proto-Oncogene Proteins c-ret
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We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the nerve lesion. Here, we analyzed whether this neuroprotective effect is long-lasting and studied the impact of the pronounced RGC rescue on axonal regeneration. To this aim, we co-injected a GDNF- and a CNTF-overexpressing neural stem cell line into the vitreous cavity of adult mice one day after an optic nerve crush and determined the number of surviving RGCs 4, 6 and 8 months after the lesion. Remarkably, we found no significant decrease in the number of surviving RGCs between the successive analysis time points, indicating that the combined administration of GDNF and CNTF conferred lifelong protection to injured RGCs. While the simultaneous administration of GDNF and CNTF stimulated pronounced intraretinal axon growth when compared to retinas treated with either factor alone, numbers of regenerating axons in the distal optic nerve stumps were similar in animals co-treated with both factors and animals treated with CNTF only.
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AbstractNeurotrophic factors play an essential role in the growth, survival, and differentiation of neurons in the nervous system. Several well-characterized neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, glial-cell-line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), insulin-like growth factor-1 (IGF-I), are currently in clinical trials and have potential for the treatment of neurological diseases.KeywordsRecombinant ProteinAmyotrophic Lateral SclerosisNeurotrophic FactorColumn VolumeEmbryonic Dorsal Root GanglionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Ciliary neurotrophic factor
Neurotrophin-3
Neurturin
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Ciliary neurotrophic factor
Trk receptor
Axoplasmic transport
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Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has been shown to be a highly potent neurotrophic factor that enhances survival of various neuronal cell types including motoneurons. To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells. Effects of GDNF treatment on pmn/pmn mice were compared with previous results obtained with ciliary neurotrophic factor (CNTF) [Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Eur J Neurosci 7:1313-1322]. In contrast to CNTF, GDNF did not increase the lifespan of pmn/pmn mice. However, GDNF significantly reduced the loss of facial motoneurons by 50%, a value similar to what was observed when CNTF was administered to the pmn/pmn mice. Surprisingly, myelinated axon counts revealed that GDNF had no effect on nerve degeneration. Therefore, despite its potential in rescuing motoneuron cell bodies, the inability of GDNF to prevent nerve degeneration in pmn/pmn mice suggests that its usefulness in the treatment of motor neuron diseases may be restricted to cotreatment with other factors that act on the nerve process.
Ciliary neurotrophic factor
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Abstract To understand the characteristics of tsAM5D cells immortalized with the temperature‐sensitive simian virus 40 large T‐antigen, we first examined the responsiveness of the cells to ligands of the glial cell line‐derived neurotrophic factor (GDNF) family. tsAM5D cells proliferated at the permissive temperature of 33°C in response to either GDNF or neurturin, but not persephin or artemin. At the nonpermissive temperature of 39°C, GDNF or neurturin caused tsAM5D cells to differentiate into neuron‐like cells; however, the differentiated cells died in a time‐dependent manner. Interestingly, ciliary neurotrophic factor (CNTF) did not affect the GDNF‐mediated cell proliferation at 33°C but promoted the survival and differentiation of GDNF‐treated cells at 39°C. In the presence of GDNF plus CNTF, the morphological change induced by the temperature shift was associated with up‐regulated expression of various neuronal marker genes, indicating that the cells had undergone neuronal differentiation. In addition, tsAM5D cells caused to differentiate by GDNF plus CNTF at 39°C became dependent solely on nerve growth factor (NGF) for their survival and neurite outgrowth. Moreover, upon treatment with GDNF plus CNTF, the dopaminergic phenotype was suppressed by the temperature shift. Thus, we demonstrated that tsAM5D cells had the capacity to differentiate terminally into neuron‐like cells in response to GDNF plus CNTF when the oncogene was inactivated by the temperature shift. This cell line provides a useful model system for studying the role of a variety of signaling molecules for GDNF/CNTF‐induced neuronal differentiation. © 2008 Wiley‐Liss, Inc.
Ciliary neurotrophic factor
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Proto-Oncogene Proteins c-ret
Neurturin
Ciliary neurotrophic factor
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