APC/C-Cdh1 coordinates neurogenesis and cortical size during development

Maria Delgado-Esteban, Irene García-Higuera, Carolina Maestre, Sergio Moreno and Angeles Almeida ()
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Maria Delgado-Esteban: Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Fundación IECSCYL
Irene García-Higuera: Instituto de Biología Funcional y Genómica (IBFG), CSIC/Universidad de Salamanca, IBSAL
Carolina Maestre: Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Fundación IECSCYL
Sergio Moreno: Instituto de Biología Funcional y Genómica (IBFG), CSIC/Universidad de Salamanca, IBSAL
Angeles Almeida: Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Fundación IECSCYL

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1—which regulates mitosis exit and G1-phase length in dividing cells—regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.

Date: 2013
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DOI: 10.1038/ncomms3879

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