Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2.
BACKGROUND
The growing trend for women to postpone childbearing has resulted in a dramatic increase in the incidence of trisomic pregnancies. Maternal age-related miscarriage and birth defects are predominantly a consequence of chromosome segregation errors during the first meiotic division (MI), which involves the segregation of replicated recombined homologous chromosomes. Despite the importance to human reproductive health, the events precipitating female age-related meiotic errors are poorly understood.


RESULTS
Here we use a long-lived wild-type mouse strain to show that the ability to segregate chromosomes synchronously during anaphase of MI declines dramatically during female aging. This is preceded by depletion of chromosome-associated cohesin in association with destabilization of chiasmata, the physical linkages between homologous chromosomes, and loss of the tight association between sister centromeres. Loss of cohesin is not due to an age-related decline in the ability of the spindle checkpoint to delay separase-mediated cleavage of cohesin until entry into anaphase I. However, we find that reduced cohesin is accompanied by depletion of Sgo2, which protects centromeric cohesin during MI.


CONCLUSIONS
The data indicate that cohesin declines gradually during the long prophase arrest that precedes MI in female mammals. In aged oocytes, cohesin levels fall below the level required to stabilize chiasmata and to hold sister centromeres tightly together, leading to chromosome missegregation during MI. Cohesin loss may be amplified by a concomitant decline in the levels of the centromeric cohesin protector Sgo2. These findings indicate that cohesin is a key molecular link between female aging and chromosome missegregation during MI.
Lister
Lisa Martine
LM
Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
Kouznetsova
Anna
A
Hyslop
Louise Ann
LA
Kalleas
Dimitrios
D
Pace
Sarah Louise
SL
Barel
Jaclyn Catharina
JC
Nathan
Abinaya
A
Floros
Vasileios
V
Adelfalk
Caroline
C
Watanabe
Yoshinori
Y
Jessberger
Rolf
R
Kirkwood
Thomas B
TB
Höög
Christer
C
Herbert
Mary
M
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000166:cytology*; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000097722:Cohesins; C510590:SGO2 protein, human