期刊
NATURE COMMUNICATIONS
卷 4, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3879
关键词
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资金
- Instituto de Salud Carlos III [PS09/0366, PI12/0685, RD06/0026/1008, RD12/0014/0007]
- FEDER (European regional development fund)
- Ministerio de Economia y Competitividad [BFU2011-28274, CSD2007-00015]
- Junta de Castilla y Leon [CSI240A12-1]
- Fundacion Cientifica de la Asociacion Espanola contra el Cancer (AECC)
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.
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