title: Cyclin-dependent kinase 5 mediates adult OPC maturation and myelin repair through modulation of Akt and GsK-3β signaling.
abstract: Failure of remyelination in diseases, such as multiple sclerosis (MS), leads to permanent axonal damage and irreversible functional loss. The mechanisms controlling remyelination are currently poorly understood. Recent studies implicate the cyclin-dependent kinase 5 (Cdk5) in regulating oligodendrocyte (OL) development and myelination in CNS. In this study, we show that Cdk5 is also an important regulator of remyelination. Pharmacological inhibition of Cdk5 inhibits repair of lysolecithin lesions. This inhibition is a consequence of Cdk5 disruption in neural cells because remyelination in slice cultures is blocked by Cdk5 inhibitors, whereas specific deletion of Cdk5 in OLs inhibits myelin repair. In CNP-Cre;Cdk5(fl/fl) conditional knock-out mouse (Cdk5 cKO), myelin repair was delayed significantly in response to focal demyelinating lesions compared with wild-type animals. The lack of myelin repair was reflected in decreased expression of MBP and proteolipid protein and a reduction in the total number of myelinated axons in the lesion. The number of CC1(+) cells in the lesion sites was significantly reduced in Cdk5 cKO compared with wild-type animals although the total number of oligodendrocyte lineage cells (Olig2(+) cells) was increased, suggesting that Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination. The failure of remyelination in Cdk5 cKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3β signaling pathways. Together, these data suggest that Cdk5 is critical in regulating the transition of adult oligodendrocyte precursor cells to mature OLs that is essential for myelin repair in adult CNS.
authors: Departments of Neurosciences and.
authors: FuCheng
authors: F
authors: Luo
authors: Departments of Neurosciences and.
authors: Kathryn
authors: K
authors: Burke
authors: Departments of Neurosciences and.
authors: Christopher
authors: C
authors: Kantor
authors: Departments of Neurosciences and Neurology and Center for Translational Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106 rhm3@case.edu yxy33@case.edu.
authors: Robert H
authors: RH
authors: Miller
authors: Neurology and Center for Translational Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106 rhm3@case.edu yxy33@case.edu.
authors: Yan
authors: Y
authors: Yang
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000172:deficiency / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002531:Cerebellum; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology* / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D008070:Lipopolysaccharides; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse
keywords: cyclin-dependent kinase 5; demyelination; myelination; oligodendrocyte; remyelination