Overlapping and non-overlapping functions of condensins I and II in neural stem cell divisions

PLoS Genet. 2014 Dec 4;10(12):e1004847. doi: 10.1371/journal.pgen.1004847. eCollection 2014 Dec.

Abstract

During development of the cerebral cortex, neural stem cells (NSCs) divide symmetrically to proliferate and asymmetrically to generate neurons. Although faithful segregation of mitotic chromosomes is critical for NSC divisions, its fundamental mechanism remains unclear. A class of evolutionarily conserved protein complexes, known as condensins, is thought to be central to chromosome assembly and segregation among eukaryotes. Here we report the first comprehensive genetic study of mammalian condensins, demonstrating that two different types of condensin complexes (condensins I and II) are both essential for NSC divisions and survival in mice. Simultaneous depletion of both condensins leads to severe defects in chromosome assembly and segregation, which in turn cause DNA damage and trigger p53-induced apoptosis. Individual depletions of condensins I and II lead to slower loss of NSCs compared to simultaneous depletion, but they display distinct mitotic defects: chromosome missegregation was observed more prominently in NSCs depleted of condensin II, whereas mitotic delays were detectable only in condensin I-depleted NSCs. Remarkably, NSCs depleted of condensin II display hyperclustering of pericentric heterochromatin and nucleoli, indicating that condensin II, but not condensin I, plays a critical role in establishing interphase nuclear architecture. Intriguingly, these defects are taken over to postmitotic neurons. Our results demonstrate that condensins I and II have overlapping and non-overlapping functions in NSCs, and also provide evolutionary insight into intricate balancing acts of the two condensin complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / physiology*
  • Animals
  • Apoptosis / genetics
  • Cell Division / genetics*
  • Cells, Cultured
  • Chromatin Assembly and Disassembly / genetics
  • Chromosome Segregation / genetics
  • DNA Damage / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Embryo, Mammalian
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis / genetics
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Pregnancy

Substances

  • DNA-Binding Proteins
  • Multiprotein Complexes
  • condensin complexes
  • Adenosine Triphosphatases

Grant support

This work was supported by Grant-in-Aid for Scientific Research B (to KN; grant number 24770194) and Grant-in-Aid for Specially Promoted Research (to TH; grant number 20002010) and Grant-in-Aid for Scientific Research A (to TH; grant number 25251023) from JSPS (http://www.jsps.go.jp/english/index.html). KN was a RIKEN Special Postdoctoral Researcher (http://www.riken.jp/en/careers/programs/spdr/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.