SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction

Abstract

Mitotic chromosome segregation is facilitated by the cohesin complex, which maintains physical connections between sister chromatids until anaphase. Meiotic cell division is considerably more complex, as cohesion must be released sequentially to facilitate orderly segregation of chromosomes at both meiosis I and meiosis II. This necessitates meiosis-specific cohesin components; recent studies in rodents suggest that these influence chromosome behavior during both cell division and meiotic prophase. To elucidate the role of the meiosis-specific cohesin SMC1beta (encoded by Smc1l2) in oogenesis, we carried out meiotic studies of female SMC1beta-deficient mice. Our results provide the first direct evidence that SMC1beta acts as a chiasma binder in mammals, stabilizing sites of exchange until anaphase. Additionally, our observations support the hypothesis that deficient cohesion is an underlying cause of human age-related aneuploidy.

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…This suggests that defects in cohesin instigates a slippage of the chiasmata towards the ends of chromosome during long meiosis I in older female mice. 80 These findings may support the hypothesis that the degradation of the cohesin complex contributes to reduced number of chiasmata that will lead to an agedependent increase of non-disjunction events in meiosis I. Although the mode of turnover for the cohesin complex has remained elusive to date, it is very possible that this will be revealed in the near future.…”

The association between the oocyte pool and aneuploidy: a comparative study of the reproductive potential of young and aged mice

“…A leading hypothesis for explaining agerelated aneuploidy is the deterioration of chromosome cohesion with increasing maternal age. In human eggs, the maternal-ageassociated deterioration of chromosome cohesion is indicated by increased inter-kinetochore distances between sister chromatids [40], and the precocious loss of chromosome cohesion contributes to a high risk of meiotic errors [20,41]. Protein complexes known as Cohesins maintain chromatid adhesion, facilitate the segregation of homologous chromosomes and maintain sister chromosomes pairing at the centromere until their separation at meiosis II during fertilization [41,42].…”

“…In human eggs, the maternal-ageassociated deterioration of chromosome cohesion is indicated by increased inter-kinetochore distances between sister chromatids [40], and the precocious loss of chromosome cohesion contributes to a high risk of meiotic errors [20,41]. Protein complexes known as Cohesins maintain chromatid adhesion, facilitate the segregation of homologous chromosomes and maintain sister chromosomes pairing at the centromere until their separation at meiosis II during fertilization [41,42]. It has been speculated that the deterioration of this protein complex over time might be relevant to the age-related rise in aneuploidy [42], and several recent publications support this idea.…”

Screening of genes involved in chromosome segregation during meiosis I: in vitro gene transfer to mouse fetal oocytes

“…This gene is important for maintaining the chiasma until adulthood, although its expression is clearly detectable only during the fetal stages and is barely evident in later stages in the female. 31 As the loading of SMC1B onto chromosomes begins at the leptotene stage during prophase I to establish meiotic cohesion, this protein needs to remain functional during a long meiotic arrest period in which it is not replenished. 19,32 The high expression of Smc1b transcripts in NF mice implies that robust cohesion might be established by this stage.…”