Inherent Instability of Correct Kinetochore-Microtubule Attachments during Meiosis I in Oocytes

Abstract

A model for mitosis suggests that correct kinetochore-microtubule (KT-MT) attachments are stabilized by spatial separation of the attachment sites from Aurora B kinase through sister KT stretching. However, the spatiotemporal regulation of attachment stability during meiosis I (MI) in oocytes remains unclear. Here, we found that in mouse oocytes, Aurora B and C (B/C) are located in close proximity to KT-MT attachment sites after bivalent stretching due to an intrinsic property of the MI chromosomes. The Aurora B/C activity destabilizes correct attachments while allowing a considerable amount of incorrect attachments to form. KT-MT attachments are eventually stabilized through KT dephosphorylation by PP2A-B56 phosphatase, which is progressively recruited to KTs depending on the BubR1 phosphorylation resulting from the timer Cdk1 and independent of bivalent stretching. Thus, oocytes lack a mechanism for coordinating bivalent stretching and KT phosphoregulation during MI, which may explain the high frequency of KT-MT attachment errors.

PP2A regulates kinetochore-microtubule attachment during meiosis I in oocyte

“…33,34 In both mitosis and meiosis, the phosphorylation level of the KMN network is negatively correlated with the stability of KT-MT attachments 14,26,34 ( Fig. 4A-C).…”

“…After fully stretching bivalents, stable KT-MT attachments increases. 5,14 The loss of PP2Acs caused severe chromosome misalignment in the spindle, which indicated the absence of stable and balanced forces on bivalents. To monitor the biorientation and stretching of bivalents in oocytes during meiosis I, we analyzed the inter-KT distances at 2, 4, 6, and 8 h after GVBD.…”

“…The correct KT-MT attachment is formed and stabilized on fully stretched bivalents. 5,[13][14][15] At the end of meiosis I, cohesins along the chromosome arms are cleaved by separase whereas centromeric cohesin is not cleaved, then all bivalents are segregated synchronously. 16 Interestingly, during mouse oocyte maturation, the activity of PP2A oscillates: it increases in prometaphase I and prometaphase II.…”

“…Previous studies have shown that PP2A can be recruited to KTs to facilitate correct KT-MT attachments formation both in mitosis and meiosis. 14,[26][27][28] However, how PP2A regulate KT-MT attachments in oocyte meiosis I remains elusive.…”

Error-prone meiotic division and subfertility in mice with oocyte-conditional knockdown of pericentrin

“…The basis of inefficient SAC function in oocytes is not fully understood, although it has been proposed that the SAC is potentially silenced during MI by the tension applied between the kinetochores of paired homologous chromosomes and that SAC activity has a low threshold for silencing in oocytes (Kitajima et al, 2011; Kolano Kouznetsova et al, 2007;Lane et al, 2012). However, it is also plausible that loss of Pcnt may promote disruptions that limit the capacity of oocytes to correct inappropriate chromosome-MT attachments (Kitajima et al, 2011;Yoshida et al, 2015). For example, spindle MT regrowth was delayed and/or diminished in Tg oocytes following cold treatment, which could potentially influence the frequency and/or stability of kinetochore-MT interactions.…”