title: The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination.
abstract: The regulation of oligodendrocyte development and myelin formation in the CNS is poorly defined. Multiple signals influence the rate and extent of CNS myelination, including the noncanonical cyclin-dependent kinase 5 (Cdk5) whose functions are regulated by its activators p35 and p39. Here we show that selective loss of either p35 or p39 perturbed specific aspects of oligodendrocyte development, whereas loss of both p35 and p39 completely inhibited the development of mature oligodendrocytes and myelination. In the absence of p35, oligodendrocyte differentiation was delayed, process outgrowth was truncated in vitro, and the patterning and extent of myelination were perturbed in the CNS of p35(-/-) mice. In the absence of p39, oligodendrocyte maturation was transiently affected both in vitro and in vivo. However, loss of both p35 and p39 in oligodendrocyte lineage cells completely inhibited oligodendrocyte progenitor cell differentiation and myelination both in vitro and after transplantation into shiverer slice cultures. Loss of p35 and p39 had a more profound effect on oligodendrocyte development than simply the loss of Cdk5 and could not be rescued by Cdk5 overexpression. These data suggest p35 and p39 have specific and overlapping roles in oligodendrocyte development, some of which may be independent of Cdk5 activation.
authors.affiliation: Departments of Neurosciences and.
authors.forename: Fucheng
authors.initials: F
authors.lastname: Luo
authors.affiliation: Departments of Neurosciences and.
authors.forename: Jessie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC 20037.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Burke
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC 20037 yxy33@case.edu rhm3@email.gwu.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.affiliation: Neurology, Center for Translational Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, and yxy33@case.edu rhm3@email.gwu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D020536:Enzyme Activators; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D058635:Lipid-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D009924:Organ Culture Techniques; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C492236:Cdk5r1 protein, mouse; C578513:Cdk5r2 protein, mouse; D003598:Cytoskeletal Proteins; D020536:Enzyme Activators; D058635:Lipid-Linked Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D019081:O Antigens; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3
keywords: Cdk5; maturation; myelination; oligodendrocyte; p35; p39