title: p38α and p38β mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons.
abstract: Although the p38 mitogen-activated protein kinases are active in many neuronal populations in the peripheral and central nervous systems, little is known about the physiological functions of p38 in postmitotic neurons. We report that p38 activity determines in vitro and in vivo the switch from noradrenergic to cholinergic neurotransmission that occurs in sympathetic neurons on exposure to the neuropoietic cytokines CNTF and LIF. This transdifferentiation serves as a model for the plastic mechanisms that enable mature neurons to change some of their central functions without passing through the cell cycle. We demonstrate that in postmitotic neurons, p38 and STAT pathways are concurrently activated by neuropoietic cytokine treatment for at least 12 h overlapping with changes in neurotransmitter marker gene expression. Inhibition of p38 blocks the upregulation of the nuclear matrix protein Satb2 and of cholinergic markers by CNTF without affecting STAT3 phosphorylation. Conversely, overexpression of p38α or β in the absence of cytokines stimulates cholinergic marker expression. The neurotransmitter switch in vitro is impaired in neurons isolated from p38β(-/-) mice. Consistent with these in vitro results, a substantial loss of cells expressing cholinergic properties is observed in vivo in the stellate ganglion of mature mice deficient in the p38β isoform.
authors.affiliation: Institute for Neuroscience, Innsbruck Medical University, MZA, 6020 Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loy
authors.forename: Galina
authors.initials: G
authors.lastname: Apostolova
authors.forename: Roland
authors.initials: R
authors.lastname: Dorn
authors.forename: Victoria A
authors.initials: VA
authors.lastname: McGuire
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Georg
authors.initials: G
authors.lastname: Dechant
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D059329:Cholinergic Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000172:deficiency / Q000235:genetics*; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000235:genetics*; D018377:Neurotransmitter Agents / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013233:Stellate Ganglion / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development
chemical_list: D018377:Neurotransmitter Agents; D050791:STAT Transcription Factors; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D000109:Acetylcholine