title: Origins of oligodendrocytes in the cerebellum, whose development is controlled by the transcription factor, Sox9.
abstract: Development of oligodendrocytes, myelin-forming glia in the central nervous system (CNS), proceeds on a protracted schedule. Specification of oligodendrocyte progenitor cells (OPCs) begins early in development, whereas their terminal differentiation occurs at late embryonic and postnatal periods. However, for oligodendrocytes in the cerebellum, the developmental origins and the molecular machinery to control these distinct steps remain unclear. By in vivo fate mapping and immunohistochemical analyses, we obtained evidence that the majority of oligodendrocytes in the cerebellum originate from the Olig2-expressing neuroepithelial domain in the ventral rhombomere 1 (r1), while about 6% of cerebellar oligodendrocytes are produced in the cerebellar ventricular zone. Furthermore, to elucidate the molecular determinants that regulate their development, we analyzed mice in which the transcription factor Sox9 was specifically ablated from the cerebellum, ventral r1 and caudal midbrain by means of the Cre/loxP recombination system. This resulted in a delay in the birth of OPCs and subsequent developmental aberrations in these cells in the Sox9-deficient mice. In addition, we observed altered proliferation of OPCs, resulting in a decrease in oligodendrocyte numbers that accompanied an attenuation of the differentiation and an increased rate of apoptosis. Results from in vitro assays using oligodendrocyte-enriched cultures further supported our observations from in vivo experiments. These data suggest that Sox9 participates in the development of oligodendrocytes in the cerebellum, by regulating the timing of their generation, proliferation, differentiation and survival.
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Ryoya
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan. Electronic address: khori@ncnp.go.jp.
authors.forename: Kei
authors.initials: K
authors.lastname: Hori
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Owa
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan; Department of Electrical Engineering and Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyashita
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Dewa
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Masuyama
authors.affiliation: Department of Ultrastructural Research, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Yoneko
authors.initials: Y
authors.lastname: Hayase
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Yukiko U
authors.initials: YU
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Ultrastructural Research, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ichinohe
authors.affiliation: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Orthopaedics, Gifu University, Gifu 501-1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan. Electronic address: hoshino@ncnp.go.jp.
authors.forename: Mikio
authors.initials: M
authors.lastname: Hoshino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology; D000073637:Oligodendrocyte Precursor Cells / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000502:physiology*; D055758:SOX9 Transcription Factor / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse
keywords: Cerebellum; Oligodendrocyte development; Sox9