Singla, Shruti and Iwamoto-Stohl, Lisa K. and Zhu, Meng and Zernicka-Goetz, Magdalena (2020) Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism. Nature Communications, 11 . Art. No. 2958. ISSN 2041-1723. PMCID PMC7290028. doi:10.1038/s41467-020-16796-3. https://resolver.caltech.edu/CaltechAUTHORS:20200611-161658303
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Abstract
The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity. However, the prevalence of aneuploidy dramatically declines as pregnancy progresses, with the steepest drop occurring as the embryo completes implantation. Despite the fact that the plasticity of the embryo in dealing with aneuploidy is fundamental to normal development, the mechanisms responsible for eliminating aneuploid cells are unclear. Here, using a mouse model of chromosome mosaicism, we show that aneuploid cells are preferentially eliminated from the embryonic lineage in a p53-dependent process involving both autophagy and apoptosis before, during and after implantation. Moreover, we show that diploid cells in mosaic embryos undertake compensatory proliferation during the implantation stages to confer embryonic viability. Together, our results indicate a close link between aneuploidy, autophagy, and apoptosis to refine the embryonic cell population and ensure only chromosomally fit cells proceed through development of the fetus.
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| Additional Information: | © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 11 July 2019. Accepted 11 May 2020. Published 11 June 2020. We are grateful to D. Glover, and M. Shahbazi for valuable comments on the paper; A. Weberling and C. Kyprianou for the post-implantation embryo recovery; A. Cox for the graphical representations; F. Antonica for help in the development of peri-implantation in vitro model. S.S. was supported by a Wellcome Trust PhD fellowship. This work was supported by Wellcome Trust (098287/Z/12/Z), ERC (669198), Rosetrees Trust (M877) and Open Philanthropy grants to M.Z.G. Author Contributions: S.S. designed and conducted the experiments, analysed and interpreted the data with the help of L.K.I.-S. and M.Z. in some of the experiments. M.Z.-G. conceived and supervised the project and helped to interpret the data. Data availability: The authors claim that all relevant data of the findings in this work are provided within the paper and Supplementary Information files. Raw data are provided in the Source Data File. Reporting summary: Further information on research design is available in the Nature Research Reporting Summary linked to this article. The authors declare no competing interests. Peer review information: Nature Communications thanks Christophe Royer, Stefano Santaguida and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. | ||||||||||
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| PubMed Central ID: | PMC7290028 | ||||||||||
| DOI: | 10.1038/s41467-020-16796-3 | ||||||||||
| Record Number: | CaltechAUTHORS:20200611-161658303 | ||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20200611-161658303 | ||||||||||
| Official Citation: | Singla, S., Iwamoto-Stohl, L.K., Zhu, M. et al. Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism. Nat Commun 11, 2958 (2020). https://doi.org/10.1038/s41467-020-16796-3 | ||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||
| ID Code: | 103860 | ||||||||||
| Collection: | CaltechAUTHORS | ||||||||||
| Deposited By: | George Porter | ||||||||||
| Deposited On: | 12 Jun 2020 14:51 | ||||||||||
| Last Modified: | 16 Nov 2021 18:25 |
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