Among type 2A protein phosphatases, PP2A is the most famous and is widely researched. For a long time, accumulating evidence revealed its cellular and molecular importance. Studies also suggest that PP2A is involved in multiple steps of meiosis. In mouse oocytes, up-regulation of PP2A activity results in the meiotic arrest phenotype (Su et al., 2012). In Oikopleura dioica, PP2A is also necessary for meiotic arrest and precaution of parthenogenesis by restraining the abnormal Ca²⁺ burst (Matsuo et al., 2020). These results indicate that the function of PP2A is highly conserved in different organisms.

PP2A is essential for chromosome segregation during meiosis (Kerr et al., 2016). Several in vitro experiments have indicated that PP2A can associate with shugoshins and hold back the phosphorylation of Rec8 at the centromeres, a member of the cohesin complex, and finally stop split of Rec8 and keep the cohesion of chromatids in meiosis I (Kitajima et al., 2006; Lee et al., 2008; Rattani et al., 2013). In addition, Sororin and Shugoshin-PP2A collaborates in the regulation of centromeric cohesion during meiosis (Gomez et al., 2016). In Drosophila meiosis, the Shugoshin MEI-S332 and PP2A reciprocally promote localization of the other to centromeres and together they thus function to ensure accurate segregation (Pinto and Orr-Weaver, 2017). Also, a new study indicated that SCF (Skp1–Cul1–F box) -Fbxo42 down-regulates the protein level of the PP2A-B56 during synaptonemal complex assembly and maintenance (Barbosa et al., 2021). In mice spermatocytes, Previato de Almeida et al. found that Sgo2 is essential to protect centromere pairing by recruiting PP2A, while Sgo1 regulates non-exchange segregation by recruiting PP2A to centromeres (Previato de Almeida et al., 2019). In meiosis II, sister chromatids disjoin upon cleavage of centromeric Rec8. One assumption is that PP2A is separated from Rec8 by bipolar spindle forces in metaphase II. A recent experiment suggested that PP2A is removed from centromeres by the ubiquitin-ligase APC/C^Cdc20, which can decrease the activity of Sgo1 and kinase Mps1 (Arguello-Miranda et al., 2017; Jonak et al., 2017).

Exact kinetochores-microtubule (KT-MT) is essential for correct chromosome segregation. In mitosis, correct KT-MT attachments are stabilized by inner sister KT stretching and the phosphorylation level of the KT. However, because of inherent property of the MI chromosomes, there is a difference between meiosis I and mitosis. This may explain the high incidence of KT-MT attachment errors in oocytes. In meiosis, PP2A-B56, which is regulated by the BubR1, is essential to determine the stability of KT-MT attachments independently of bivalent stretching (Yoshida et al., 2015). Overall, PP2A is targeted by Shugoshin and BubR1 to protect centromeric cohesion and stabilize KT-MT attachments in yeast and mouse meiosis. In C. elegans meiosis, the function of PP2A remains unclear. A recent study found that PP2A is necessary for female meiotic progression, such as spindle assembly and chromosome segregation. The mechanism is that BUB-1 targets PP2A-B′56 via a conserved LxxIxE motif and this regulation is necessary for correct meiotic progression (Bel Borja et al., 2020).

In addition, treatment with okadaic acid (OA) or calyculin-A (CL-A), which inhibits PP2A, caused an absence of microtubule polymerization and spindles. These studies have also showed that PP2A participated in microtubule organization and spindle formation (Lu et al., 2002). Protein phosphatase 2A regulatory subunit B55α (PP2A-B55α) is encoded by Ppp2r2a. Liang et al. found that PP2A-B55α was an important regulator of oocyte asymmetric division, chromosome congression, DNA damage response and spindle dynamics by RNA interference (Liang et al., 2017). In Xenopus oocytes, protein phosphatase 2A regulatory subunit B′56 (PP2A-B′56) and calcineurin (CaN) jointly contributes to APC/C^Cdc20 activation by inhibiting phosphorylation of XErp1 (Heim et al., 2018). Two studies suggested that PP2A might be controlled by two distinct mechanisms in mouse oocytes. One is a post-translational modification by which MASTL (microtubule associated serine/threonine kinase-like), inhibit PP2A activity to promote anaphase (Adhikari et al., 2014). The other is CRL4-mediated degradation of the PP2A scaffold subunit, which reduces PP2A activity to facilitate non-reversible meiotic progression (Yu et al., 2015). These two regulation mechanisms of PP2A activity in conjunction with other meiotic regulators ensure precise meiotic progression in oocytes.

By using genetically modified mouse models, we further studied the functions of PP2A in oocyte meiosis We employed the conditional knockout method by using growth differentiation factor 9 (Gdf9)-Cre mice to gain mutant mice with depletion of PPP2R1α in oocytes in order to research its function in female meiosis. The results indicated that oocyte-specific depletion of PPP2R1α resulted in female subfertility because of production of aneuploid oocytes came from wrong separation of sister chromatids, but did not affect folliculogenesis, ovulation and spindle formation during meiosis II (Hu et al., 2014). Interestingly, another report generated conditional knockout mice by crossing Ppp2ca^f/f and (or) Ppp2cb^f/f with Zp3-Cre mice to study PP2A in female meiosis. They found that single knockout PPP2ACα females or PPP2ACβ females were fertile, indicating the paralogs were functionally redundant. Only the deficiency of both PPP2ACα and PPP2ACβ in oocytes finally resulted in female infertility (Tang et al., 2016). In this study, they also found that the PP2A can regulate chromosome behavior and bipolar spindle formation in meiosis I. PP2A counteracts Aurora kinase B/C to ensure bivalent stretching and KT-MT attachment stability (Tang et al., 2016). In contrast, PP2A is also essential for spermatogenesis, especially meiosis (Pan et al., 2015). However, the study is descriptive only, with a lack on mechanistic insight. It will be fascinating to reveal the deeply regulatory mechanism of PP2A in male meiosis.

PP4 has been widely studied over the past decade. However, there is a relative lack of information about PP4 in meiosis. In C. elegans, PP4 is indispensable for spindle formation during male meiosis, but it is not essential for female meiosis (Sumiyoshi et al., 2002). Moreover, at least four critical events in prophase require PP4, such as synapsis-independent chromosome pairing, prevention of non-homologous chromosome synapsis, DSB initiation, and crossover formation. The failure of these series of events eventually results in the failure of chiasmata formation (Sato-Carlton et al., 2014). In yeast, PP4 seems to be highly active during the whole meiotic progression. PP4 has an important role in single-end invasions, synaptonemal complex assembly, spindle formation and centromere pairing (Falk et al., 2010). To clarify whether PP4 has conserved functions in meiosis in mammalian species, we generated its catalytic subunit gene Ppp4c conditional knockout (Ppp4c^f/f) mouse strain using CRISPR/Cas9 technology, and showed that loss of PPP4C did not affect male germ cell meiosis, acrosome formation, nuclear condensation and elongation, but caused the defect of cytoplasm removal, which in turn leads to the failure of spermiogenesis completion and male infertility (Han et al., 2020). Hence, the physiological roles and regulatory mechanism of PP4 in other organisms remain to be further studied.

Like other type 2A serine/threonine protein phosphatases, PP6 is also ubiquitously expressed in cells. However, PP6 has suffered less notice than its near relative PP2A and PP4, especially in meiosis. Until now, there only three papers about the functions of PP6 in meiosis. We showed that knockout of PP6 in oocytes from primary follicle stage resulted in female subfertility by disturbing MII spindle formation and MII exit after fertilization, indicating that PP6 can act as antagonizer to oocyte aneuploidy. But it is dispensable in oocyte meiotic maturation, follicle growth and ovulation (Hu et al., 2015). However, we showed that knockout of PP6 in oocytes from primordial follicle stage resulted in complete infertility of female mice. Deletion of PP6 caused meiotic prophase oocyte loss and abnormal folliculogenesis because of aberrant phosphorylation level of H2AX, which then led to lots of oocyte disappearance and eventually premature ovarian failure (POF). These results indicated that PP6 can also safeguard oocyte genomic integrity and regulate folliculogenesis during the long prophase I arrest (Hu et al., 2016). In male meiosis, our recent study by crossing Ppp6c^f/f mice with Stra8-Cre mice to obtain genetically mutant mice with specific malformation of the Ppp6c in male germ cells. We discovered that the mutant mice were male infertile and male germ cells were blocked at the pachytene stage during meiosis. Further study found that the loss of PP6 in male germ cells affected chromatin relaxation owing to abnormal MAPK pathway activity, thus stopping the recruitment of DSB repair factors to the appropriate sites on chromosomes (Lei et al., 2020).