To ensure equal chromosome segregation and the stability of the genome during cell division,
Separase is strictly regulated primarily by
Securin binding and inhibitory phosphorylation. By generating a mouse model that contained a mutation to the inhibitory phosphosite of
Separase, we demonstrated that mice of both sexes are infertile. We showed that
Separase deregulation leads to chromosome mis-segregation,
genome instability, and eventually apoptosis of primordial germ cells (PGCs) during embryonic oogenesis. Although the PGCs of mutant male mice were completely depleted, a population of PGCs from mutant females survived
Separase deregulation. The surviving PGCs completed oogenesis but produced deficient initial follicles. These results indicate a sexual dimorphism effect on PGCs from
Separase deregulation, which may be correlated with a gender-specific discrepancy of
Securin. Our results reveal that
Separase phospho-regulation is critical for
genome stability in oogenesis. Furthermore, we provided the first evidence of a pre-zygotic mitotic chromosome segregation error resulting from
Separase deregulation, whose sex-specific differences may be a reason for the sexual dimorphism of
aneuploidy in gametogenesis.