Cell fragmentation in mouse preimplantation embryos induced by ectopic activation of the polar body extrusion pathway

Abstract

Cell fragmentation is commonly observed in human preimplantation embryos and is associated with poor prognosis during assisted reproductive technology (ART) procedures. However, the mechanisms leading to cell fragmentation remain largely unknown. Here, light sheet microscopy imaging of mouse embryos reveals that inefficient chromosome separation due to spindle defects, caused by dysfunctional molecular motors Myo1c or dynein, leads to fragmentation during mitosis. Extended exposure of the cell cortex to chromosomes locally triggers actomyosin contractility and pinches off cell fragments. This process is reminiscent of meiosis, during which small GTPase‐mediated signals from chromosomes coordinate polar body extrusion (PBE) by actomyosin contraction. By interfering with the signals driving PBE, we find that this meiotic signaling pathway remains active during cleavage stages and is both required and sufficient to trigger fragmentation. Together, we find that fragmentation happens in mitosis after ectopic activation of actomyosin contractility by signals emanating from DNA, similar to those observed during meiosis. Our study uncovers the mechanisms underlying fragmentation in preimplantation embryos and, more generally, offers insight into the regulation of mitosis during the maternal‐zygotic transition. image Cell fragmentation is a poorly understood process and a major defect commonly observed in human embryos. Here, a study in mouse preimplantation embryos reveals that ectopic activation of a meiotic pathway during mitosis triggers cell fragmentation via induction of a local actomyosin contraction. Inhibition of the motor proteins Myo1c or dynein leads to cell fragmentation in mouse embryos. Ectopic contractions of the embryonic actomyosin cortex pinch off cell fragments. In contrast to other mitotic cells where chromosomes induce polar relaxation, the proximity of DNA to the cortex promotes contraction in mouse blastomeres. Ectopic contractions are triggered during mitosis by the continuous post‐meiotic activation of the polar body extrusion pathway components Cdc42 and Ect2.