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Elife. 2016 Jan 8;5:e09584. doi: 10.7554/eLife.09584.

The REST remodeling complex protects genomic integrity during embryonic neurogenesis.

Author information

1
Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, United States.
2
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States.
3
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
4
Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
5
Technische Universität München, Munich, Germany.
6
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
7
Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität, Munich, Germany.

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.

KEYWORDS:

REST complex; developmental biology; genomic instability; knockout animals; mouse; neurogenesis; repression; stem cells; transcription factors

Comment in

PMID:
26745185
PMCID:
PMC4728133
DOI:
10.7554/eLife.09584
[Indexed for MEDLINE]
Free PMC Article

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