Shugoshin-2 is essential for the completion of meiosis but not for mitotic cell division in mice

Abstract

Shugoshin-2 (SGOL2) is one of the two mammalian orthologs of the Shugoshin/Mei-S322 family of proteins that regulate sister chromatid cohesion by protecting the integrity of the multiprotein cohesin complexes. This protective system is essential for faithful chromosome segregation during mitosis and meiosis, which is the physical basis of Mendelian inheritance. Regardless of its evolutionary conservation from yeast to mammals, little is known about the in vivo relevance and specific role that SGOL2 plays in mammals. Here we show that disruption of the gene encoding mouse SGOL2 does not cause any alteration in sister chromatid cohesion in embryonic cultured fibroblasts and adult somatic tissues. Moreover, mutant mice develop normally and survive to adulthood without any apparent alteration. However, both male and female Sgol2-deficient mice are infertile. We demonstrate that SGOL2 is necessary for protecting centromeric cohesion during mammalian meiosis I. In vivo, the loss of SGOL2 promotes a premature release of the meiosis-specific REC8 cohesin complexes from anaphase I centromeres. This molecular alteration is manifested cytologically by the complete loss of centromere cohesion at metaphase II leading to single chromatids and physiologically with the formation of aneuploid gametes that give rise to infertility.[Keywords: Cohesion; chromosome segregation; Shugoshin-2; mouse; mitosis; meiosis] Supplemental material is available at http://www.genesdev.org.

Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice

“…Furthermore, recruitment of PP2A that regulates Rec8 cleavage also depends on SgoI in fission and budding yeast (38). Rec8 localization to centromeres in mouse oocytes depends on SgoII and deletion of SgoII leads to fertility defects in mice (23,39). Together with these findings, our data suggest that the Bub1 function affected in our heterozygous model is its role in protecting centromere cohesion through recruitment of shugoshin, PP2A, and Rec8 proteins and prevention of separase-mediated removal of cohesin (19,20).…”

Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice

“…Sgo2 protects centromeric cohesion from degradation in MI, 32,33 and there is evidence that loss of Sgo2 during the uniquely long meiotic arrest of mammalian oocytes may account for aneuploidy by promoting cohesion loss. 7,31 In keeping with this hypothesis, and so explaining the resistance of C57Bl6/J mice to maternal-aging related aneuploidy, we observed little Sgo2 loss in oocytes in this strain.…”

“…Its continued presence is therefore essential to maintain dyad integrity until MII. 32,33 Any premature Sgo2 loss in MI would make centromeric cohesin vulnerable to separase-mediated cleavage, so generating single chromatids, which have been observed in other aging mouse strains. 6,7,31 However, single chromatids were not found in the C57Bl6/J strain employed here, therefore we would predict no such Sgo2 drop if there was any causal relationship.…”

Cohesins and Cohesin-Regulators in Meiosis

“…In mice it has been described the localization of SGOL2 in male meiosis and it corresponds with a protection function of centromeric cohesion during first meiotic division (Gomez et al, 2007). An interesting model is the SGOL2-deficient mouse, where a precocious dissociation of the meiosis-specific REC8 cohesin complexes from anaphase I centromeres was observed (Llano et al, 2008), demonstrating the specific implication of SGOL2 in centromere protection during meiosis.…”