Decreased Cohesin in the Brain Leads to Defective Synapse Development and Anxiety-Related Behavior

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / etiology*
  • Anxiety / physiopathology
  • Brain / metabolism
  • Brain / physiopathology*
  • Brain Chemistry / physiology
  • Cell Cycle Proteins / deficiency*
  • Cell Cycle Proteins / physiology
  • Chondroitin Sulfate Proteoglycans / physiology
  • Chromosomal Proteins, Non-Histone / deficiency*
  • Chromosomal Proteins, Non-Histone / physiology
  • Female
  • Gene Expression Regulation / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Synapses / physiology*

Substances

  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • Cspg6 protein, mouse
  • cohesins