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. 2014 May 7;9(5):e96710.
doi: 10.1371/journal.pone.0096710. eCollection 2014.

Age-related decrease of meiotic cohesins in human oocytes

Makiko Tsutsumi  1 , Reiko Fujiwara  1 , Haruki Nishizawa  2 , Mayuko Ito  3 , Hiroshi Kogo  4 , Hidehito Inagaki  1 , Tamae Ohye  1 , Takema Kato  1 , Takuma Fujii  2 , Hiroki Kurahashi  1
Affiliations

Age-related decrease of meiotic cohesins in human oocytes

Makiko Tsutsumi et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Immunofluorescent staining of human oocytes in ovarian sections from 19- and 49-year-old women.
(A, B) REC8 or SMC1B (green) proteins co-immunostained with RAD21. (C, D) SMC3 or SMC1A (green) signals counterstained with DAPI. C-KIT (red) was used as a marker of oocytes. Asterisks indicate autofluorescence in the cytoplasmic region of the oocytes. Bar, 10 µm.
Figure 2
Figure 2. Quantitative results for meiosis-specific cohesins in human oocytes.
(A, B) Relative signal intensity of REC8 or SMC1B. Intensities were determined as described in Figure S2. Specimens were obtained from two 40 year old female subjects (40a and 40b). Horizontal bars indicate the mean cohesin levels for each subject. (C) Regression analyses of the mean cohesin signal intensities shown in (A) and (B) (mean ± SD). The regression lines are indicated by solid lines. The coefficients of determination are indicated in parentheses. (D, E) Comparisons of the signal intensity means between grouped samples. Women were grouped as younger (≤29-year-old) or older (≥40-year-old). (D) The cohesin signal intensity means shown in (A–C) were compared between groups (mean ± SD). (E) The cohesin signal intensity means in single oocytes were compared between groups (mean ± SD). *P<0.05, **P<0.01, Student's t-test.
Figure 3
Figure 3. Quantitative results for the mitotic cohesin levels in human oocytes.
(A–C) Relative signal intensities for SMC3, RAD21 or SMC1A. (D) Regression analyses of the cohesin signal intensity means shown in (A–C) (mean ± SD). Lines are the regression lines. The coefficients of determination are in parentheses. (E, F) Comparisons of the signal intensity means between grouped samples. Women were grouped as indicated in Figure 2. (E) The cohesin signal intensity means shown in (A–D) were compared between groups (mean ± SD). (F) The cohesin signal intensity means in single oocytes were compared between groups (mean ± SD). *P<0.05, Student's t-test.
Figure 4
Figure 4. Immunofluorescent staining of mouse oocytes in ovarian sections from 2- and 10-month-old female mice.
(A) Slides were co-immunostained with REC8 (green) and SMC3 (red). (B) Slides were co-immunostained with SMC1B (green) and RAD21 (red). (C) SMC1A (green) signals with DAPI nuclear counterstaining. Asterisks indicate autofluorescence. Bar, 10 µm.
Figure 5
Figure 5. Quantitative results for meiosis-specific cohesin levels in 2- and 10-month-old mouse oocytes.
(A, B) Relative signal intensity of REC8 or SMC1B. Intensities were determined as indicated in Figure S2. Three mice were used at each age. Horizontal bars are the mean cohesin levels within each female. (C) Cohesin signal intensity means in each female (mean ± SD). (D) Cohesin signal intensity means in each oocyte (mean ± SD). *P<0.05, **P<0.01, Student's t-test.
Figure 6
Figure 6. Quantitative results for mitotic cohesin levels in mouse oocytes.
(A–C) Signal intensities for SMC3, RAD21 or SMC1A determined as described in Figure S2. (D) Cohesin signal intensity means in each female (mean ± SD). (E) Cohesin signal intensity means in each oocyte (mean ± SD). **P<0.01, Student's t-test.
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Grants and funding

This work was supported by grants from JSPS KAKENHI (22790334 and 25860255 to MT and 21028020 and 23013019 to HK, URL: http://www.jsps.go.jp/j-grantsinaid/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.