Cyclin B2 is required for progression through meiosis in mouse oocytes

Abstract

Cyclins associate with cyclin-dependent serine/threonine kinase 1 (CDK1) to generate the M phase-promoting factor (MPF) activity essential for progression through mitosis and meiosis. Although cyclin B1 (CCNB1) is required for embryo development, previous studies concluded that CCNB2 is dispensable for cell cycle progression. Given previous findings of high Ccnb2 mRNA translation rates in prophasearrested oocytes, we re-evaluated the role of this cyclin during meiosis. Ccnb2 −/− oocytes underwent delayed germinal vesicle breakdown and showed defects during the metaphase-to-anaphase transition. This defective maturation was associated with compromised Ccnb1 and Moloney sarcoma oncogene (Mos) mRNA translation, delayed spindle assembly and increased errors in chromosome segregation. Given these defects, a significant percentage of oocytes failed to complete meiosis I because the spindle assembly checkpoint remained active and anaphase-promoting complex/cyclosome function was inhibited. In vivo, CCNB2 depletion caused ovulation of immature oocytes, premature ovarian failure, and compromised female fecundity. These findings demonstrate that CCNB2 is required to assemble sufficient pre-MPF for timely meiosis re-entry and progression. Although endogenous cyclins cannot compensate, overexpression of CCNB1/ 2 rescues the meiotic phenotypes, indicating similar molecular properties but divergent modes of regulation of these cyclins.

Cycling through mammalian meiosis: B-type cyclins in oocytes

“…The authors suggest that the metaphase I arrest observed in a significant proportion of Ccnb2-/oocytes is due to SAC activation because inhibition of the essential SAC kinase Mps1 can rescue polar body extrusion. Ccnb2-/oocytes that fail to extrude a polar body show kinetochore recruitment of the SAC component Mad2 indicating prolonged SAC activation, even though under normal conditions the SAC is activated only very transiently in meiosis I (Daldello et al 2019). A small caveat of this assay is the fact that without a functional SAC, oocytes undergo metaphase-to-anaphase transition precociously and with much lower Cdk1 activity (Touati et al 2015;Rattani et al 2014).…”

“…Below we introduce progression through the meiotic divisions (meiotic maturation) from a cell cycle point of view, before describing the roles of the three existing mammalian B-type cyclins B1, B2 and B3 (Nieduszynski, Murray, and Carrington 2002;Chapman and Wolgemuth 1992;Pines and Hunter 1989), all three of which have now been studied by knock-out approaches in mouse oocytes J. Li et al 2018;Daldello et al 2019;Y. Li et al 2019;Brandeis et al 1998).…”

“…Unlike cyclin B2 in Ccnb1-/oocytes, no upregulation of cyclin B1 to compensate for loss of cyclin B2 was observed. Quite the opposite, translation of mRNA coding for cyclin B1 was affected in the absence of cyclin B2 in a proportion of oocytes, indicating that this cyclin has a specific role in translational control of cyclin B1 and other, oocyte-specific mRNAs such as coding for Mos (Daldello et al 2019). How cyclin B2 brings about translational control of meiotic transcripts is currently unknown, but may involve phosphorylation of CPEB1, which occurs in a Cdk1-dependent manner (Han et al 2017).…”

“…Because of missing cyclin B2 protein in GV oocytes and failure to accumulate sufficiently high levels of cyclin B1, overall MPF activity is lower in Ccnb2-/oocytes, resulting in defects in spindle formation, delayed and inefficient APC/C activation, delay in anaphase I onset and reduced number of oocytes that succeed to extrude a polar body and exit meiosis I. These defects were rescued by overexpression of cyclin B1 (Daldello et al 2019). The authors suggest that the metaphase I arrest observed in a significant proportion of Ccnb2-/oocytes is due to SAC activation because inhibition of the essential SAC kinase Mps1 can rescue polar body extrusion.…”

“…Overall, the data obtained from complete loss of either cyclin indicates that cyclin B1 and B2 harbour specific roles during meiotic maturation mainly because of their expression profiles brought about in part by a specific role of cyclin B2 for translational control of cyclin B1. They can substitute for each other when expressed at the required times during meiotic maturation (Daldello et al 2019;J. Li et al 2018), indicating that they can phosphorylate the same substrates throughout meiosis I and II.…”