title: The REST remodeling complex protects genomic integrity during embryonic neurogenesis.
abstract: The timely transition from neural progenitor to post-mitotic neuron requires down-regulation and loss of the neuronal transcriptional repressor, REST. Here, we have used mice containing a gene trap in the Rest gene, eliminating transcription from all coding exons, to remove REST prematurely from neural progenitors. We find that catastrophic DNA damage occurs during S-phase of the cell cycle, with long-term consequences including abnormal chromosome separation, apoptosis, and smaller brains. Persistent effects are evident by latent appearance of proneural glioblastoma in adult mice deleted additionally for the tumor suppressor p53 protein (p53). A previous line of mice deleted for REST in progenitors by conventional gene targeting does not exhibit these phenotypes, likely due to a remaining C-terminal peptide that still binds chromatin and recruits co-repressors. Our results suggest that REST-mediated chromatin remodeling is required in neural progenitors for proper S-phase dynamics, as part of its well-established role in repressing neuronal genes until terminal differentiation.
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, United States.
authors.forename: Tamilla
authors.initials: T
authors.lastname: Nechiporuk
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, United States.
authors.forename: James
authors.initials: J
authors.lastname: McGann
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, United States.
authors.forename: Karin
authors.initials: K
authors.lastname: Mullendorff
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.|Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Technische Universität München, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D002453:Cell Cycle; D002454:Cell Differentiation; D055785:Gene Knockdown Techniques; D051379:Mice; D055495:Neurogenesis; D009474:Neurons / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: REST complex; developmental biology; genomic instability; knockout animals; mouse; neurogenesis; repression; stem cells; transcription factors