Age-Related Decrease of Meiotic Cohesins in Human Oocytes

Abstract

Aneuploidy in fetal chromosomes is one of the causes of pregnancy loss and of congenital birth defects. It is known that the frequency of oocyte aneuploidy increases with the human maternal age. Recent data have highlighted the contribution of cohesin complexes in the correct segregation of meiotic chromosomes. In mammalian oocytes, cohesion is established during the fetal stages and meiosis-specific cohesin subunits are not replenished after birth, raising the possibility that the long meiotic arrest of oocytes facilitates a deterioration of cohesion that leads to age-related increases in aneuploidy. We here examined the cohesin levels in dictyate oocytes from different age groups of humans and mice by immunofluorescence analyses of ovarian sections. The meiosis-specific cohesin subunits, REC8 and SMC1B, were found to be decreased in women aged 40 and over compared with those aged around 20 years (P<0.01). Age-related decreases in meiotic cohesins were also evident in mice. Interestingly, SMC1A, the mitotic counterpart of SMC1B, was substantially detectable in human oocytes, but little expressed in mice. Further, the amount of mitotic cohesins of mice slightly increased with age. These results suggest that, mitotic and meiotic cohesins may operate in a coordinated way to maintain cohesions over a sustained period in humans and that age-related decreases in meiotic cohesin subunits impair sister chromatid cohesion leading to increased segregation errors.

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

“…During the long prophase arrest that precedes meiosis I in female mammals, cohesin levels decline gradually and in aged oocytes this reduction in cohesin causes destabilization of chiasmata and separation of sister centromeres, which can result in chromosome missegregation during meiosis I (Lister et al, 2010;TachibanaKonwalski et al, 2010;Tsutsumi et al, 2014). This current study determined that SMC5/6 protein levels decrease in oocytes isolated showing even metaphase I to anaphase I chromosome segregation (MI to AI even), chromosome stretching (MI to AI stretch); and in anaphase I (n=40 for control and n=53 for Smc5 cKO) showing no lagging chromosomes (AI no lagging) and lagging chromosomes (AI lagging).…”

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

“…Oxidative stress is likely to impact several pathways within the cell and damage of meiotic spindle components, kinetochores, or the spindle assembly checkpoint (SAC) could lead to meiotic segregation errors in older oocytes (62-65). However, because there is evidence that cohesion deteriorates with age (8,(11)(12)(13)(14)(15)(16)(17)(18), and because NDJ is more pronounced when SOD is knocked down in mtrm +/− oocytes, we were specifically interested in examining the effect of oxidative stress on the integrity of meiotic cohesion.If SOD KD leads to premature loss of cohesion, then oocytes with a reduced level of functional cohesin may be more susceptible to the effect of SOD KD on NDJ. To test this possibility, we used females heterozygous for a deletion of the smc1 gene (smc1Δ/+) in which the protein level of the cohesin subunit SMC1 is lowered (11), but still adequate to support accurate meiotic chromosome segregation (11) (Fig.…”

The effect of DHEA on apoptosis and cohesin levels in oocytes in aged mice

“…The rate of a trisomy increases greatly from nearly 2% for women in their 20s to 35% for women in their 40s (13). A recent study has suggested that the deterioration of cohesins might be responsible for age-related aneuploidy (22). In mice, this phenomenon is thought to be related to the strain.…”

“…Since the density of the cohesin subunit STAG3 changes little in the ovarian aging process (22), the current study only detected the levels of three cohesin subunits: REC8, SMC1β, and SMC3. Ovarian slides were blocked and then incubated with primary and secondary antibodies as described (37).…”

“…In senescence-accelerated mice (SAM), immunostaining of REC8 between the chromosome arms and centromeres in aged oocytes was either absent or disrupted (21). In oocytes of women in their 40s, levels of the cohesin complex subunits REC8 and SMC1β decreased substantially in comparison to levels in women age 20 (22). In the process of maternal aging, ovarian function changes markedly in line with the loss of cohesin complexes in oocytes.…”