BUB1B Depletion Induces Multipolar Divisions and Asymmetrical Genome Partitioning in Preimplantation Embryos

Cleavage-stage human embryos are highly aneuploid, often leading to in vitro fertilization (IVF) failure. While several causes of chromosome missegregation are known, none have been studied in detail during preimplantation development. Here, we determined that ~87% of bovine embryos up to the 12-cell stage contain at least one aneuploid blastomere due primarily to non-reciprocal mitotic errors. Frequent micro-/multi-nucleation of missegregated chromosomes was also observed and live-cell fluorescent imaging revealed micronuclei fate as well as a correlation between a lack of syngamy, multipolar divisions, and disproportionate allocation of DNA to daughter cells. Depletion of BUB1B/BUBR1, the largest component of the mitotic checkpoint complex that monitors bipolar attachment of spindle microtubules to kinetochores, resulted in abnormal cytokinesis and embryo arrest, producing blastomeres with chaotic aneuploidy and asymmetrical genome partitioning. These findings demonstrate that defective BUB1B signaling contributes to mitotic aneuploidy in early embryogenesis and identifies a potential target to improve IVF success.