title: Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis.
abstract: 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.
authors.affiliation: Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xu
authors.forename: Meizhi
authors.initials: M
authors.lastname: Wang
authors.forename: Xinxing
authors.initials: X
authors.lastname: Gao
authors.forename: Bian
authors.initials: B
authors.lastname: Hu
authors.forename: Yinan
authors.initials: Y
authors.lastname: Du
authors.forename: Jiankui
authors.initials: J
authors.lastname: Zhou
authors.forename: Xuemei
authors.initials: X
authors.lastname: Tian
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D020090:Chromosome Segregation; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005306:Fertilization; D042822:Genomic Instability / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis; D009866:Oogenesis; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology; D010060:Ovulation; D010063:Ovum / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D064249:Securin; D064247:Separase; D012727:Sex Characteristics
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D064249:Securin; D010450:Endopeptidases; D064247:Separase