Ras/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons.
Neurotrophin (NT)-3 is expressed in the neuronal target tissue of the developing rat cochlea and has been shown to promote the survival and neurite outgrowth of spiral ganglion (SG) neurons, suggesting a role for this protein during the innervation of the organ of Corti. In other neurons, NT-3 can mediate neuritogenesis and survival via a number of intracellular signal pathways. To date, the intracellular transduction pathways involved in the mediation of NT-3 effects have not been investigated in SG neurons. To determine whether the activities of NT-3 on SG neurons are dependent on the activation of mitogen-activated protein kinase kinases (MEK)/extracellular-signal-regulated kinases (ERK), Ras, and/or p38, SG explants from postnatal-day 4 rats were cultured with NT-3 and increasing concentrations of the MEK inhibitor U0126, the Ras farnesyl-transferase inhibitor (FTI)-277, and the p38 inhibitor SB203580. After fixation and immunocytochemical labeling, neurite growth was evaluated. A dose-dependent decrease of the effects of NT-3 on length and number of processes was observed in the U0126- and FTI-277-treated SG neurons. In contrast, SB203580 had no significant effect on NT-3-mediated stimulation of neurite growth, in terms of either number or length. The results suggest that NT-3 effects on SG neurons are mediated primarily by the Ras/MEK/ERK signaling pathway.
Aletsee
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Department of Surgery/Otolaryngology and Neurosciences, UCSD School of Medicine and VA Medical Center, La Jolla, CA 92093, USA.
Beros
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Mullen
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Palacios
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Pak
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Dazert
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Ryan
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D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D046508:Culture Techniques; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D020933:Neurotrophin 3 / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013136:Spiral Ganglion / Q000166:cytology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
D002070:Butadienes; D004791:Enzyme Inhibitors; C096856:FTI 277; D007093:Imidazoles; D020933:Neurotrophin 3; D009570:Nitriles; D011725:Pyridines; C113580:U 0126; D008715:Methionine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C093642:SB 203580; D004121:Dimethyl Sulfoxide