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J Exp Med. 2017 May 1;214(5):1431-1452. doi: 10.1084/jem.20161517. Epub 2017 Apr 13.

Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior.

Author information

1
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
2
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
3
Department of Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan.
4
Life Science Research Center, University of Toyama, Toyama 930-0194, Japan.
5
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Aichi 470-1192, Japan.
6
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
7
Division of Bioscience, Institute for Datability Science, Osaka University, Osaka 565-0871, Japan.
8
iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
9
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan.
10
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan yamashita@molneu.med.osaka-u.ac.jp kshirahi@iam.u-tokyo.ac.jp.
11
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan yamashita@molneu.med.osaka-u.ac.jp kshirahi@iam.u-tokyo.ac.jp.
12
Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.

Abstract

Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional Smc3-knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of Smc3+/- mice. Smc3+/- mice also exhibited more anxiety-related behavior, which is a symptom of CdLS. Further, a gene ontology analysis after RNA-sequencing suggested the enrichment of immune processes, particularly the response to interferons, in the Smc3+/- mice. Indeed, fewer synapses formed in their cortical neurons, and this phenotype was rescued by STAT1 knockdown. Thus, low levels of cohesin expression in the developing brain lead to changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype.

PMID:
28408410
PMCID:
PMC5413336
DOI:
10.1084/jem.20161517
[Indexed for MEDLINE]
Free PMC Article

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