The Anaphase-Promoting Complex activator Fizzy-Related-1 (FZR1) is essential for the mitotic divisions of early mammalian embryos but not for the completion of female meiosis (#48)
In early embryos of various species it is thought that CDC20 is the only essential co-activator of the important cell cycle regulator, the Anaphase-Promoting Complex (APC). In contrast Fzr1, the other major co-activator of APC, is thought to be non-essential. In agreement with this, normal preimplantation development is observed in Fzr1 knockout mouse embryos. However the role of Fzr1 during preimplantation embryo development cannot be accurately elucidated in these knockout mice due to presence of maternal stores. In this study, the use of an oocyte-specific Fzr1 knockout (Fzr1∆/∆) allowed for the examination of Fzr1 function during early mouse embryo development in the absence of any maternal stores. In such a knockout, Fzr1 is only lost in the oocyte and following initiation of follicle growth. We observed that maternal Fzr1 is not vital for meiotic completion, and in addition, when these females were mated with wild-type males, viable pups were born. However, a different outcome was achieved in the absence of both maternal and paternal Fzr1 in early embryos, which was bought about by parthenogenetically activating MII eggs isolated from Fzr1∆/∆ mice. Fzr1∆/∆ parthenotes displayed delayed and less synchronous cell cleavage divisions up until morulae. In addition, the loss of Fzr1 led to dramatic loss of genomic integrity, resulting in a large proportion of embryos arresting at the 2-cell stage after having undergone only one mitotic division. These embryos were found to contain numerous g-H2AX foci suggesting damaged DNA. In the 10% of embryos that developed to the 4-cell stage, cell division occurred so slowly that compaction was initiated prematurely. No Fzr1∆/∆ embryos were ever observed to develop into blastocysts. Therefore, in conclusion Fzr1 is a surprising essential gene in maintaining genome integrity during preimplantation mitotic division in the mammalian embryo.