Mastl/PP2A regulate Cdk1 in ooycte maturation

Resumption of oocyte meiotic maturation is driven by activation of cyclin-dependent kinase 1 (Cdk1), which phosphorylates target proteins that are important for nuclear envelope breakdown, chromosome condensation, and remodelling of the actin and microtubule cytoskeleton. As a consequence, a bipolar spindle is formed and condensed chromosomes become aligned at the metaphase plate. The spindle assembly checkpoint (SAC) prevents the activation of the anaphase-promoting complex/ cyclosome (APC/C Cdc20) during meiosis I progression until all kinetochores come under tension [for review see: 1]. Upon the satisfaction of SAC, APC/C becomes active, and degrades cyclin B and securin. Degradation of cyclin B lowers Cdk1 activity and securin degradation activates separase, which cleaves cohesion holding sister chromatids together [2]. After cytokinesis, one set of chromosomes is retained in the oocyte and the other is segregated into the first polar body (PB). Although Cdk1/cyclin B complexes have long been considered sufficient for driving mitosis and meiosis, recent studies in various systems have shown that the simultaneous suppression of the antagonizing protein phosphatase 2A (PP2A), which is mediated by the Greatwall (Gwl) kinase (called Mastl [microtubule-associated serine/threonine kinase-like] in mammals), is also required for mitotic entry or progression [3-5]. Although protein phosphatases have previously been implicated in the regulation of oocyte maturation, the mechanisms regulating their functions have not been studied. To uncover the role of Mastl in the meiotic cell division of mouse oocytes, we generated a novel Mastl conditional knockout mouse line and studied Mastl-null oocytes [6]. We found that meiotic resumption and progression to metaphase I in Mastl-null oocytes was indistinguishable from the control oocytes; however, extrusion of the first PBs was delayed in the mutant oocytes. Securin degradation in Mastl-null oocytes was also delayed, suggesting that Mastl is required for the timely activation of APC/C that is needed for the completion of meiosis I. However, the delay in anaphase I onset and the first PB extrusion was not caused due to an unsatisfied SAC, which was indicated by a complete dissociation of Mad2 (an essential spindle checkpoint protein) from kinetochores of Mastl-null oocytes at metaphase I [6]. Meiosis in oocytes represents a specialized cell division whereby a sharp increase in Cdk1 activity after completion of meiosis I prevents them from entering S phase and oocytes transit directly to meiosis II. Moreover, the paired sister chromatids remain condensed during the meiosis I−meiosis II transition and form typical bipolar metaphase spindles and they remain …