Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes

Abstract

The chromosome segregation process in human oocytes is highly error-prone, generating meiosis II (MII) oocytes with unbalanced chromatids that contribute to aneuploidy in offspring. This raises questions regarding the mechanism for transmission of chromatids and how chromatids evade the error correction mechanisms in MII oocytes. Here, we analyse the behaviour of chromatids in mouse MII oocytes. We find that chromatids align at the spindle equator at the metaphase stage of MII and that their presence does not obstruct entry into the anaphase stage. The alignment process is mediated by merotelic (bi-directional) microtubule-kinetochore attachments, revealing a multi-domain organization of the kinetochore of mammalian meiotic chromosomes. Our results suggest that biorientation of chromatids stabilize microtubule attachments at the kinetochores in a tension-dependent manner. Our results also suggest that merotelic attachments contribute to chromosome mis-segregation in wild-type MII oocytes. Thus, merotely is an important promoter of aneuploidy in mammalian oocytes.

Segregating Chromosomes in the Mammalian Oocyte

“…The identities of the microtubule depolymerising activities at the poles and kinetochores that drive microtubule shortening are unclear, though members of the kinesin-13 family of microtubule depolymerases [77] have been implicated in these activities in other systems. Lagging chromosomes are detected in a relatively high proportion of untreated (wild-type) oocytes, suggesting that biorientation of sister chromatid pairs during metaphase-II spindle assembly may be inherently error-prone [68,78]. Anaphase-II also comprises a spindle elongation which, similar to anaphase-I, is relatively minor [62], presumably to enable the formation of a small second polar body and retain the majority of the cytoplasm in the egg.…”

Age-Related Loss of Cohesion: Causes and Effects

“…Researchers indicate that the mitotic spindle checkpoint cannot detect this attachment orientation, which can induce chromosome lag during anaphase [ 103 , 105 ]. Consistent with mitotic anaphase, merotelic attachment persists during meiotic anaphase II and could cause chromosome lag and tailing [ 106 , 107 ]. Tension established through merotelic attachment of chromatids can maintain spindle checkpoint inactivation, which promotes chromatid transmission and the formation of aneuploid cells [ 103 , 107 ].…”

Chromosomal instability and aneuploidy: a conundrum in cancer evolution

“…Unlike other forms of attachment, merotelic attachments create kinetochore tension allowing them to bypass the mitotic checkpoint (8). Studies using oocytes demonstrate that merotelic attachments silence Mad2-signalling which contributes to the inactivation of the mitotic checkpoint and to chromosome missegregation in wild-type MII oocytes (22). When this improper attachment continues into anaphase, it can lead to the presence of lagging chromatids, which followed by cytokinesis, can give rise to aneuploid cells (7).…”