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.
| Original language | English (US) |
|---|---|
| Article number | e09584 |
| Journal | eLife |
| Volume | 5 |
| Issue number | JANUARY2016 |
| DOIs | |
| State | Published - Jan 8 2016 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
- Medicine(all)
- Neuroscience(all)
Cite this
The REST remodeling complex protects genomic integrity during embryonic neurogenesis. / Nechiporuk, Tamilla; McGann, James; Mullendorff, Karin; Hsieh, Jenny; Wurst, Wolfgang; Floss, Thomas; Mandel, Gail.
In: eLife, Vol. 5, No. JANUARY2016, e09584, 08.01.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The REST remodeling complex protects genomic integrity during embryonic neurogenesis
AU - Nechiporuk, Tamilla
AU - McGann, James
AU - Mullendorff, Karin
AU - Hsieh, Jenny
AU - Wurst, Wolfgang
AU - Floss, Thomas
AU - Mandel, Gail
PY - 2016/1/8
Y1 - 2016/1/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84956908265&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84956908265&partnerID=8YFLogxK
U2 - 10.7554/eLife.09584.001
DO - 10.7554/eLife.09584.001
M3 - Article
C2 - 26745185
AN - SCOPUS:84956908265
VL - 5
JO - eLife
JF - eLife
SN - 2050-084X
IS - JANUARY2016
M1 - e09584
ER -