Augmin deficiency in neural stem cells causes p53-dependent apoptosis and aborts brain development
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Spain
- Division of Biological Science, Graduate School of Science, Nagoya University, Japan
Abstract
Microtubules that assemble the mitotic spindle are generated by centrosomal nucleation, chromatin-mediated nucleation, and nucleation from the surface of other microtubules mediated by the augmin complex. Impairment of centrosomal nucleation in apical progenitors of the developing mouse brain induces p53-dependent apoptosis and causes non-lethal microcephaly. Whether disruption of non-centrosomal nucleation has similar effects is unclear. Here we show, using mouse embryos, that conditional knockout of the augmin subunit Haus6 in apical progenitors led to spindle defects and mitotic delay. This triggered massive apoptosis and abortion of brain development. Co-deletion of Trp53 rescued cell death, but surviving progenitors failed to organize a pseudostratified epithelium, and brain development still failed. This could be explained by exacerbated mitotic errors and resulting chromosomal defects including increased DNA damage. Thus, in contrast to centrosomes, augmin is crucial for apical progenitor mitosis, and, even in the absence of p53, for progression of brain development.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Marina Villamor-Payà
Funding
Ministerio de Economía, Industria y Competitividad, Gobierno de España (BFU2015-69275-P)
- Jens Lüders
Ministerio de Ciencia, Innovación y Universidades (PGC2018-099562-B-I00)
- Jens Lüders
Agència de Gestió d'Ajuts Universitaris i de Recerca (2017 SGR 1089)
- Jens Lüders
Ministerio de Ciencia, Innovación y Universidades (SVP-2014-068770)
- Ricardo Viais
Japan Society for the Promotion of Science (15H06270)
- Sadanori Watanabe
Ministerio de Ciencia, Innovación y Universidades (PRE2019-089526)
- Marcos Fariña-Mosquera
Ministerio de Ciencia, Innovación y Universidades (RED2018-102723-T)
- Jens Lüders
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the mouse strains were maintained on a mixed 129/SvEv-C57BL/6 background in strict accordance with the European Community (2010/63/UE) guidelines in the Specific-Pathogen Free (SPF) animal facilities of the Barcelona Science Park (PCB). All protocols were approved by the Animal Care and Use Committee of the PCB/University of Barcelona (IACUC; CEEA-PCB) and by the Departament de Territori I Sostenibilitat of the Generalitat de Catalunya in accordance with applicable legislation (Real Decreto 53/2013). All efforts were made to minimize use and suffering.
Copyright
© 2021, Viais et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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