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Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential

Bolton, Helen and Graham, Sarah J. L. and Van der Aa, Niels and Kumar, Parveen and Theunis, Koen and Fernandez Gallardo, Elia and Voet, Thierry and Zernicka-Goetz, Magdalena (2016) Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nature Communications, 7 . Art. No. 11165. ISSN 2041-1723. PMCID PMC4820631. https://resolver.caltech.edu/CaltechAUTHORS:20190405-170315061

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Abstract

Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/ncomms11165DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820631/PubMed CentralArticle
ORCID:
AuthorORCID
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Additional Information:© 2016 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Received 10 June 2015. Accepted 26 February 2016. Published 29 March 2016. We thank Simon Z.-G. for the motivation to develop this model, Samantha Morris for providing reagents, Aisha Elami for the FISH experiments, and Ivan Bedzhov and Monika Bialecka for postimplantation embryo recovery. We acknowledge the Wellcome Trust for supporting this work. H.B was supported by a Wellcome Trust clinical PhD fellowship. We acknowledge the Research Foundation Flanders (FWO) (FWO-G.A093.11 and FWO-G.0924.15 to T.V.; the travel grant V.4.140.10.N.00 to T.V.; N.V.d.A., E.F.G. and K.T. are Ph.D. students supported by FWO 1.1.H.28.12, FWO G.0924.15 and FWO 1126016N, respectively) and KU Leuven SymBioSys (PFV/10/016 to T.V.; P.K. is a PhD. student supported with PFV/10/016). Author Contributions: H.B. designed and performed the majority of experiments with help from S.J.L.G. N.V.d.A., P.K., K.T. and E.F.G. performed and analysed the single-cell genome sequencing. T.V. supervised the single-cell genome sequencing. M.Z.-G. conceived the project, designed experiments and supervised the study. S.J.L.G., H.B. and M.Z.-G. wrote the manuscript. Accession codes: Single-cell genome sequences have been deposited in the European Nucleotide Archive (ENA) database under accession code PRJEB12768 (ERP014275). The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
Wellcome TrustUNSPECIFIED
Fonds Wetenschappelijk Onderzoek (FWO)FWO-G.A093.11
Fonds Wetenschappelijk Onderzoek (FWO)FWO-G.0924.15
Fonds Wetenschappelijk Onderzoek (FWO)V.4.140.10.N.00
Fonds Wetenschappelijk Onderzoek (FWO)FWO 1.1.H.28.12
Fonds Wetenschappelijk Onderzoek (FWO)FWO G.0924.15
Fonds Wetenschappelijk Onderzoek (FWO)FWO 1126016N
Katholieke Universiteit LeuvenPFV/10/016
PubMed Central ID:PMC4820631
Record Number:CaltechAUTHORS:20190405-170315061
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190405-170315061
Official Citation:Bolton, H. et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat. Commun. 7:11165 doi: 10.1038/ncomms11165 (2016).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94537
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:09 Apr 2019 20:44
Last Modified:03 Oct 2019 21:04

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