The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors

Nat Commun. 2013;4:2880. doi: 10.1038/ncomms3880.

Abstract

The E3-ubiquitin ligase APC/C-Cdh1 is essential for endoreduplication but its relevance in the mammalian mitotic cell cycle is still unclear. Here we show that genetic ablation of Cdh1 in the developing nervous system results in hypoplastic brain and hydrocephalus. These defects correlate with enhanced levels of Cdh1 substrates and increased entry into the S phase in neural progenitors. However, cell division is prevented in the absence of Cdh1 due to hyperactivation of cyclin-dependent kinases, replicative stress, induction of p53, G2 arrest and apoptotic death of these progenitor cells. Concomitant ablation of p53 rescues apoptosis but not replicative stress, resulting in the presence of damaged neurons throughout the adult brain. These data indicate that the inactivation of Cdh1 in vivo results in replicative stress, cell cycle arrest and cell death, supporting recent therapeutic proposals aimed to inhibit the APC/C in tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / genetics
  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Animals
  • Apoptosis*
  • Brain / cytology
  • Brain / embryology
  • Brain / enzymology
  • Brain / metabolism*
  • Cdh1 Proteins / genetics
  • Cdh1 Proteins / metabolism*
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Division
  • DNA Replication*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Stem Cells / cytology
  • Neural Stem Cells / enzymology
  • Neural Stem Cells / metabolism*
  • Neurogenesis
  • Neurons / cytology
  • Neurons / enzymology
  • Neurons / metabolism*
  • Organ Size
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Fzr1 protein, mouse
  • Tumor Suppressor Protein p53
  • Anaphase-Promoting Complex-Cyclosome