p38 mitogen-activated protein kinase is required for central nervous system myelination.
The p38 MAPKs are a family of kinases that regulate a number of cellular functions including cell migration, proliferation, and differentiation. Here, we report that p38 regulates oligodendrocyte differentiation. Inhibition of p38 with PD169316 and SB203580 prevented accumulation of protein and mRNA of cell-stage specific markers characteristic of differentiated oligodendrocytes, including myelin basic protein, myelin-associated glycoprotein, and the glycosphingolipids, galactosylceramide and sulfatide. In addition, the cell cycle regulator p27(kip1) and the transcription factor Sox10 were also significantly reduced. Most significantly, p38 inhibitors completely and irreversibly blocked myelination of dorsal root ganglion neurons by oligodendrocytes and prevented the axolemmal organization of the axo-glial adhesion molecule Caspr. Our results suggest a role(s) for this kinase in key regulatory steps in the maturation of OLGs and initiation of myelination.
Fragoso
Gabriela
G
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Haines
Jeffery D
JD
Roberston
Janice
J
Pedraza
Liliana
L
Mushynski
Walter E
WE
Almazan
Guillermina
G
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000502:physiology*; D002855:Chromatography, Thin Layer; D018920:Coculture Techniques; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology / Q000648:ultrastructure; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000302:isolation & purification; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology / Q000648:ultrastructure; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology / Q000648:ultrastructure; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D003470:Culture Media; D004791:Enzyme Inhibitors; D008055:Lipids; D034741:RNA, Small Interfering; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases