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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.M.E. was supported by the Spanish Ministry of Economy and Competitiveness (MINECO). This work was funded by grants from the Foundation Ramón Areces and MINECO SAF2012-38215 to M.M.). The Cell Division and Cancer Group of the CNIO are supported by the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, the OncoBIO Consolider-Ingenio 2010 Programme (MINECO, CSD2007-00017) and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).Peer Reviewe

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