title: Enhancement of Schwann cell myelin formation by K252a in the Trembler-J mouse dorsal root ganglion explant culture.
abstract: The Trembler-J (TrJ) mouse, containing a point mutation in the peripheral myelin protein 22 gene, is characterized by severe hypomyelination and is a representative model of Charcot-Marie-Tooth 1A disease/Dejerine-Sottas Syndrome. Previous studies have shown that protein kinase inhibitor K252a enhances wild-type Schwann cell myelination in culture. We used a dorsal root ganglion (DRG) explant culture system from the heterozygous TrJ/+ mouse to investigate if myelination could be enhanced by K252a. The TrJ/+ DRG explant cultures replicated some important features of the TrJ/+ mouse, showing reduced myelin protein accumulation, thinner myelin sheaths, and shortened myelin internodes. K252a increased myelin protein accumulation and myelin sheath thickness but did not substantially increase myelin internode length. Furthermore, the TrJ/+ DRG explant culture and sciatic nerves continued to respond to K252a during the stage when myelination is complete in the wild type. A general tyrosine kinase inhibitor, genistein, but not inhibitors of serine/threonine protein kinase inhibitors, had a similar effect to K252a. K252a is therefore able to partially overcome hypomyelination by enhancing mutant Schwann cell myelin formation in the TrJ/+ mouse.
authors.affiliation: Department of Neurobiology, School of Medicine Stanford University, 299 Campus Drive, Fairchild Building D225, Stanford, CA 94305, USA. nliu@cmgm.stanford.edu
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.forename: Eric M
authors.initials: EM
authors.lastname: Shooter
authors.forename: Ravi J
authors.initials: RJ
authors.lastname: Tolwani
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019833:Genistein / Q000494:pharmacology; D026121:Indole Alkaloids; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission; D009185:Myelin Proteins / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009185:Myelin Proteins; C049985:staurosporine aglycone; D019833:Genistein; D011505:Protein-Tyrosine Kinases