title: Cyclin dependent kinase 5 is required for the normal development of oligodendrocytes and myelin formation.
abstract: The development of oligodendrocytes, the myelinating cells of the vertebrate CNS, is regulated by a cohort of growth factors and transcription factors. Less is known about the signaling pathways that integrate extracellular signals with intracellular transcriptional regulators to control oligodendrocyte development. Cyclin dependent kinase 5 (Cdk5) and its co-activators play critical roles in the regulation of neuronal differentiation, cortical lamination, neuronal cell migration and axon outgrowth. Here we demonstrate a previously unrecognized function of Cdk5 in regulating oligodendrocyte maturation and myelination. During late embryonic development Cdk5 null animals displayed a reduction in the number of MBP+ cells in the spinal cord, but no difference in the number of OPCs. To determine whether the reduction of oligodendrocytes reflected a cell-intrinsic loss of Cdk5, it was selectively deleted from Olig1+ oligodendrocyte lineage cells. In Olig1(Cre/+); Cdk5(fl/fl) conditional mutants, reduced levels of expression of MBP and PLP mRNA were observed throughout the CNS and ultrastructural analyses demonstrated a significant reduction in the proportion of myelinated axons in the optic nerve and spinal cord. Pharmacological inhibition or RNAi knockdown of Cdk5 in vitro resulted in the reduction in oligodendrocyte maturation, but had no effect on OPC cell proliferation. Conversely, over-expression of Cdk5 promoted oligodendrocyte maturation and enhanced process outgrowth. Consistent with this data, Cdk5(-/-) oligodendrocytes developed significantly fewer primary processes and branches than control cells. Together, these findings suggest that Cdk5 function as a signaling integrator to regulate oligodendrocyte maturation and myelination.
authors.affiliation: Department of Neurology, Case Western Reserve University, School of Medicine, 10900 Euclid, Ave., Cleveland, OH 44106, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Fucheng
authors.initials: F
authors.lastname: Luo
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.forename: Richard
authors.initials: R
authors.lastname: Lu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D009900:Optic Nerve / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D034622:RNA Interference; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051360:Cyclin-Dependent Kinase 5; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; C499047:Mbp protein, mouse; C494786:Olig1 protein, mouse; C047516:Plp1 protein, mouse