title: Bre1a, a histone H2B ubiquitin ligase, regulates the cell cycle and differentiation of neural precursor cells.
abstract: Cell cycle regulation is crucial for the maintenance of stem cell populations in adult mammalian tissues. During development, the cell cycle length in neural stem cells increases, which could be associated with their capabilities for self-renewal. However, the molecular mechanisms that regulate differentiation and cell cycle progression in embryonic neural stem cells remain largely unknown. Here, we investigated the function of Bre1a, a histone H2B ubiquitylation factor, which is expressed in most but not all of neural precursor cells (NPCs) in the developing mouse brain. We found that the knockdown of Bre1a in NPCs lengthened their cell cycle through the upregulation of p57(kip2) and the downregulation of Cdk2. In addition, the knockdown of Bre1a increased the expression of Hes5, an effector gene of Notch signaling, through the action of Fezf1 and Fezf2 genes and suppressed the differentiation of NPCs. Our data suggest that Bre1a could be a bifunctional gene that regulates both the differentiation status and cell cycle length of NPCs. We propose a novel model that the Bre1a-negative cells in the ventricular zone of early embryonic brains remain undifferentiated and are selected as self-renewing neural stem cells, which increase their cell cycle time during development.
authors.affiliation: Division of Neurobiology and Bioinformatics, and Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8787, Japan, Department of Physiological Sciences, School of Life Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan, Department of Integrative Physiology, Shiga University of Medical Science, Otsu 520-2192, Japan, Institute of Molecular and Cellular Biosciences, and Department of Neurobiology, The University of Tokyo, Tokyo 113-0032, Japan, Division of Embryology, National Institute for Basic Biology, Okazaki 444-8787, Japan, and Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ishino
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masae
authors.initials: M
authors.lastname: Naruse
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomita
authors.forename: Makoto
authors.initials: M
authors.lastname: Sanbo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fuchigami
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujiki
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Toyooka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujimori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitoshi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D017930:Genes, Reporter; D018816:Genes, cdc / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics; D019579:Neocortex / Q000166:cytology / Q000254:growth & development; D058953:Neural Stem Cells / Q000502:physiology*; D010957:Plasmids; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D008156:Luciferases; C571257:RNF20 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: H2B ubiquitylation; brain development; differentiation; epigenetics; neural stem cells; proliferation