title: Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.
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.
authors.affiliation: Department of Physiology, Development and Neuroscience and Gurdon Institute, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Bolton
authors.affiliation: Department of Physiology, Development and Neuroscience and Gurdon Institute, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Sarah J L
authors.initials: SJL
authors.lastname: Graham
authors.affiliation: Department of Human Genetics, University of Leuven, KU Leuven, Leuven 3000, Belgium.
authors.forename: Niels
authors.initials: N
authors.lastname: Van der Aa
authors.affiliation: Department of Human Genetics, University of Leuven, KU Leuven, Leuven 3000, Belgium.
authors.forename: Parveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Human Genetics, University of Leuven, KU Leuven, Leuven 3000, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Theunis
authors.affiliation: Department of Human Genetics, University of Leuven, KU Leuven, Leuven 3000, Belgium.
authors.forename: Elia
authors.initials: E
authors.lastname: Fernandez Gallardo
authors.affiliation: Department of Human Genetics, University of Leuven, KU Leuven, Leuven 3000, Belgium.|Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
authors.affiliation: Department of Physiology, Development and Neuroscience and Gurdon Institute, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zernicka-Goetz
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001755:Blastocyst / Q000166:cytology*; D002452:Cell Count; D019070:Cell Lineage / Q000235:genetics*; D020090:Chromosome Segregation / Q000187:drug effects; D033481:Chromosomes, Mammalian / Q000187:drug effects; D010064:Embryo Implantation; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008938:Mitosis / Q000187:drug effects; D008957:Models, Genetic; D009025:Morpholines / Q000494:pharmacology; D009030:Mosaicism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015053:Zygote / Q000166:cytology / Q000187:drug effects
chemical_list: D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011687:Purines; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine