RT Journal Article
SR Electronic
T1 Genotypic Complexity in Initial Cleavage Divisions of Mammalian Embryos is Contributed by Defective BUB1B/BUBR1 Signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.24.220475
DO 10.1101/2020.07.24.220475
A1 Kelsey E. Brooks
A1 Brittany L. Daughtry
A1 Brett Davis
A1 Melissa Y. Yan
A1 Suzanne S. Fei
A1 Lucia Carbone
A1 Shawn L. Chavez
YR 2020
UL http://biorxiv.org/content/early/2020/07/24/2020.07.24.220475.abstract
AB Embryonic aneuploidy is highly complex, often leading to developmental arrest, implantation failure, and/or spontaneous miscarriage in both natural and assisted reproduction. Despite our knowledge of mitotic missegregation in somatic cells, the molecular pathways regulating chromosome fidelity during the error-prone cleavage-stage of mammalian preimplantation development remain largely undefined. Using bovine embryos and live-cell fluorescent imaging, we observed frequent micro-/multi-nucleation of missegregated chromosomes in initial divisions that persisted, re-fused with the primary nucleus, or formed a chromatin bridge with neighboring cells. A correlation between a lack of syngamy, multipolar cytokinesis, and uniparental genome segregation was also revealed and single-cell DNA-seq showed complex genotypes propagated by subsequent divisions. Depletion of the checkpoint protein, BUB1B/BUBR1, resulted in atypical cytokinesis, micro-/multi-nuclei formation, chaotic aneuploidy, and developmental arrest. This demonstrates that embryonic micronuclei sustain multiple fates, provides an explanation for blastomeres with uniparental origins, and substantiates defective BUB1B/BUBR1 signaling as a major contributor to mitotic aneuploidy.Competing Interest StatementThe authors have declared no competing interest.