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First published online October 22, 2008
doi: 10.1242/10.1242/jcs.036855
Commentary |
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
* Author for correspondence (e-mail: Kornb001{at}mc.duke.edu)
Accepted 11 September 2008
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Summary |
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 Top Summary IntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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Key words: Anaphase-promoting complex, CSF, Cdc2–cyclin-B, Emi2, Mos
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Introduction |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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). Following fertilization, the early embryonic divisions ensue, with oscillations in Cdc2–cyclin-B activity driving each division. These characteristic waves of Cdc2–cyclin-B kinase activity result primarily from the repeated synthesis and degradation of cyclin-B protein with each division (Fig. 1).
In 1971, Masui and Markert injected egg extracts into a two-cell-stage embryo and found that the injected blastomere arrested at the next mitosis (Masui and Markert, 1971). Careful examination of these M-phase-arrested cells revealed that they contained a metaphase spindle of similar morphology to that seen in a metaphase-II-arrested egg, prompting them to postulate the existence of an activity present in eggs that is responsible for inducing meiosis-II arrest. This activity was named cytostatic factor (CSF). Although the existence of CSF was initially proposed in 1971, its precise molecular identity remained unclear for more than three decades. During the intervening years, much effort has been devoted to understanding the nature of CSF. The recent identification and characterization of Emi2 (also known as FBX43, and as XErp1 in Xenopus), a meiotic inhibitor of the anaphase-promoting complex/cyclosome (APC/C), has provided considerable insight into CSF and its regulation. Nonetheless, there remain many interesting and crucial questions concerning the molecular nature and regulation of CSF activity. We review here the history, current state of knowledge and unresolved questions that surround the mechanisms underlying CSF-mediated arrest of vertebrate eggs in MII.
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CSF in the pre-Emi2 era |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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) proposed that this activity should meet several criteria, as described most recently in several excellent, extensive reviews on the topic by James Maller and colleagues (Liu et al., 2007; Tunquist and Maller, 2003). First, the activity should emerge during oocyte maturation and peak at metaphase II. Second, it should induce M-phase arrest upon injection into embryonic blastomeres. Finally, this activity should be inactivated by the enhanced levels of cytoplasmic Ca2+ that are induced by fertilization or egg activation. Almost two decades after CSF was initially proposed, Sagata et al. identified Mos as a kinase that is synthesized during Xenopus laevis oocyte maturation (Sagata et al., 1988). Exogenous introduction of Mos into one blastomere of a two-cell-stage embryo promoted a CSF-like arrest (Sagata et al., 1989). Importantly, both Mos protein and mRNA were rapidly degraded after fertilization (Lorca et al., 1991). Because Mos nicely satisfied the criteria proposed by Masui and Markert for CSF, Mos was proposed as the factor responsible for CSF arrest in vertebrate eggs. However, the detailed molecular mechanism linking Mos expression to metaphase-II arrest was, at that time, entirely undefined.
The biochemical characterization of Mos revealed that it could act as a mitogen-activated protein kinase (MAPK) kinase kinase (Posada et al., 1993). Furthermore, constitutively active MAPK was found to cause M-phase arrest in the dividing blastomere. In that the ability of Mos to confer CSF arrest was abrogated if MAPK kinase activity had been inactivated by either neutralizing antibody, MAPK phosphatase or pharmacological MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, it was concluded that the MAPK-stimulatory activity of Mos accounted for its ability to promote MII arrest (Abrieu et al., 1996; Cross and Smythe, 1998; Gotoh and Nishida, 1995; Haccard et al., 1993; Kosako et al., 1994a; Kosako et al., 1994b). In 1999, this pathway was extended with the discovery of ribosomal S6 kinase (Rsk; also known as KS6A3), which acts downstream of MAPK (Bhatt and Ferrell, 1999; Gross et al., 1999). Similar to MAPK, constitutively active Rsk that was injected into one blastomere of a two-cell-stage embryo caused M-phase arrest, and Rsk depletion from egg extracts prevented the in vitro development of CSF activity (Bhatt and Ferrell, 1999; Gross et al., 1999). Thus, the Mos-MEK-MAPK-Rsk pathway was generally accepted to be responsible for the metaphase-II arrest in eggs (Fig. 2A). How Rsk, as the terminal kinase in this cascade, was able to communicate with the cell-cycle machinery that controls cyclin-B stability and M-phase arrest would remain unclear for almost a decade.
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; Schwab et al., 2001; Tunquist et al., 2003). However, when the same spindle-checkpoint proteins were depleted from eggs, APC/C inhibition was not affected, nor did the ablation affect Ca2+-induced CSF release (Abrieu et al., 2001; Sharp-Baker and Chen, 2001; Tunquist et al., 2003; Tunquist et al., 2002).
These results strongly suggested the presence of an additional CSF-specific APC/C inhibitor that is distinct from the spindle-checkpoint proteins (Fig. 2B). In retrospect, this is not surprising because CSF-arrested eggs contain an intact metaphase plate that would not be expected to trigger spindle-checkpoint activation (Masui and Markert, 1971). Moreover, the fact that Mos can induce an M-phase arrest in interphase egg extracts in the absence of any genomic DNA strongly indicates that spindle-checkpoint proteins are not required for CSF arrest. Nonetheless, it has been reported that some spindle-checkpoint proteins are activated during maturation and some of them could potentially be targets of the Mos pathway (Schwab et al., 2001). Thus, spindle-checkpoint proteins might play an as-yet unidentified role during metaphase-II arrest.
The relationship between Mos and the APC/C
The recognition that the Mos-MEK-MAPK-Rsk pathway was responsible for CSF arrest and that this arrest relied on APC/C inhibition begged the question of whether these two pathways worked independently or cooperatively. In seeking to address this issue, Gross et al. injected radiolabeled cyclin B1 into Xenopus eggs and monitored cyclin-B degradation by the APC/C in the presence or absence of the MEK inhibitor U0126. This treatment reduced the half-life of cyclin B, indicating that Mos might be working through APC/C inhibition (Gross et al., 2000). When endogenous cyclin B was examined in the presence of U0126 in mouse eggs, this treatment caused cyclin-B degradation and pathenogenetic activation (Phillips et al., 2002). However, the same inhibitor did not cause CSF release in Xenopus eggs (Reimann and Jackson, 2002; Tunquist et al., 2002). This failure might have resulted from insufficient inhibition of the Mos pathway. Indeed, more recently it was found that treating Xenopus eggs with U0126 at higher doses for longer time periods could promote endogenous cyclin-B degradation (Wu et al., 2007a). These observations are consistent with a report showing that immunological neutralization of Mos function caused spontaneous CSF release in Xenopus eggs (Yamamoto et al., 2005). Collectively, these findings established the APC/C as a mediator of Mos-induced CSF arrest (Fig. 2C).
Upon fertilization, CaMKII activity is elevated and consequent APC/C activation typically results in cyclin-B degradation within 
10 minutes. By contrast, Mos protein can persist for at least 30 minutes following egg activation or fertilization (Lorca et al., 1991). It is possible that Mos activity is at least partially inhibited (although not degraded) following fertilization. However, another interesting possibility is that Mos works through an intermediary to inactivate the APC/C and it is the inactivation of the intermediary, rather than of Mos itself, that induces APC/C activation and cyclin-B degradation following fertilization. In 2002, Emi1 (also known as FBX5) was proposed as the CSF-specific APC/C inhibitor (Reimann and Jackson, 2002). Not only can recombinant Emi1 induce mitotic arrest, but depletion of Emi1 from CSF-arrested egg extracts led to APC/C activation and cyclin-B degradation.
Despite these interesting findings, the physiological relevance of Emi1 to CSF activity was soon called into question. First, Emi1 is not stable under CSF arrest and endogenous Emi1 concentrations in eggs appear to be below the concentration that is necessary to induce CSF arrest. Second, Emi1 does not require active MAPK to induce mitotic arrest. Moreover, Emi1-induced arrest is distinct from CSF in its ability to promote stabilization of both cyclin A and cyclin B, whereas CSF arrest promotes the stabilization of only cyclin B. Finally, Emi1-induced arrest is not sensitive to Ca2+ (Geley et al., 2001; Ohsumi et al., 2004; Tung et al., 2005). Thus, despite its undisputed ability to act as an APC/C inhibitor, Emi1 was unlikely to be relevant to CSF arrest, leaving the identification of the CSF-specific APC/C inhibitor open (Fig. 2C).
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Connecting Mos to the APC/C – filling the gap with Emi2 |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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). In so doing, they successfully identified a crucial missing component of CSF, the Emi2 protein. Given these findings and the differences between CSF activity and Emi1 function described above, Jackson and colleagues proposed that their Emi1 antibody might cross-react with a related protein that was actually responsible for CSF arrest (Tung et al., 2005), because immunodepletion using their antibody promoted activation of APC/C in CSF-arrested egg extracts. In characterizing their anti-Emi1 antibody, they also identified Emi2, which, as described below, met the criteria for a component of CSF much more satisfyingly [note that this work was also expertly reviewed by Thomas Mayer and colleagues (Schmidt et al., 2006)].
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; Liu and Maller, 2005; Rauh et al., 2005) (Fig. 3). These findings strongly suggested that Emi2 was the long-sought CSF-specific APC/C inhibitor that is responsible for mediating metaphase-II arrest. Upon egg activation, CaMKII and Plx1 coordinately promote Emi2 degradation, thereby relieving APC/C inhibition and promoting exit from MII.
Emi2 as an APC/C inhibitor
Spindle-checkpoint proteins can strongly interact with Cdc20, and this interaction enables them to inhibit the catalytic activity of the APC/C (Sudakin et al., 2001). Because mouse Emi2 appears to interact with Cdc20 as well, Shoji et al. proposed that Emi2, similar to the spindle-checkpoint proteins, works through Cdc20 to inhibit the APC/C (Shoji et al., 2006). However, in our laboratory, we found that Xenopus Emi2 can interact with the core APC/C directly through its C-terminus and that this interaction is key to its APC/C-inhibitory ability (Wu et al., 2007b), raising the possibility that simple binding of Emi2 in some way blocks APC/C activity. However, it does not appear that binding of Emi2 to the APC/C is the only determinant of APC/C-inhibitory activity. It has been reported that Emi2 contains a zinc-binding region (ZBR) and that mutating a single amino acid within this region will lead to the complete inactivation of Emi2 (Schmidt et al., 2005). We have found, however, that ZBR-mutant Emi2 retains its ability to interact with the APC/C, suggesting that this interaction is not sufficient for the APC/C-inhibitory activity of Emi2 (Wanli Tang, J.Q.W. and S.K., unpublished data; and see below).
A feedback loop controlling Emi2
Although Emi2 can bind directly to the APC/C, this interaction can be controlled by the phosphorylation status of Emi2: Cdc2-mediated phosphorylation of Emi2 at two residues in the C-terminal region of the protein, T545 and T551, weakens the interaction between Emi2 and the APC/C, thus allowing activation of the APC/C (Wu et al., 2007b). Because cyclin B is continually synthesized in MII-arrested eggs, this Cdc2-mediated Emi2 inactivation is used by the eggs to prevent a significant accumulation of cyclin B during the prolonged CSF arrest. Such cyclin-B accumulation might otherwise disrupt normal egg activation and the sharp transition into the first embryonic interphase. The Cdc2–cyclin-B-mediated phosphorylation of the T545 and T551 residues is antagonized by protein phosphatase 2A (PP2A) (Wu et al., 2007b). Thus, when cyclin-B levels rise sufficiently for Emi2-directed Cdc2 kinase activity to exceed Emi2-directed PP2A activity, Emi2 is phosphorylated.
The consequence of phosphorylation at Cdc2–cyclin-B sites within the Emi2 C-terminus is to dissociate Emi2 from the APC/C, whereas similar phosphorylation of a cluster of sites within the Emi2 N-terminus shortens the half-life of Emi2 (Wu et al., 2007a; Wu et al., 2007b). Together, these alterations in Emi2 alleviate APC/C inhibition, allowing some level of cyclin-B degradation to occur, although the egg remains arrested in MII. This degradation is, in turn, held in check because falling cyclin-B levels reduce Cdc2 kinase activity, allowing PP2A-mediated Emi2 dephosphorylation to predominate. This re-stabilizes Emi2 and allows its re-association with the APC/C, thereby preventing the complete degradation of cyclin B that would otherwise result in MII exit. By controlling Emi2 stability and activity, the balance between Cdc2 and PP2A allows homeostatic control of cyclin-B levels to both maintain the CSF arrest and allow rapid M-phase exit upon fertilization (Fig. 4).
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; Nishiyama et al., 2007a). Moreover, Rsk, a downstream kinase in the Mos pathway, was shown to phosphorylate Emi2 directly, and this phosphorylation promoted Emi2 stabilization and activation. Because Cdc2 could promote Emi2 degradation and inactivation, we speculated that Rsk-mediated Emi2 phosphorylation would antagonize the function of Cdc2–cyclin-B. Consistent with this, our laboratory found that Rsk-mediated Emi2 phosphorylation could recruit the protein phosphatase PP2A to Emi2 (Wu et al., 2007a). Emi2-bound PP2A promotes Emi2 dephosphorylation at T545 and T551, thus promoting the Emi2-APC/C interaction and allowing APC/C inhibition. Moreover, as alluded to above, we discovered four additional S/T-P phosphorylation sites on Emi2, the Cdc2-mediated phosphorylation of which would lead to Emi2 instability. The same PP2A that promotes Emi2 T545 and/or T551 dephosphorylation was also shown to enhance dephosphorylation of these four sites, thus stabilizing Emi2 during CSF arrest (Fig. 4).
Collectively, these findings suggest that Mos, through its downstream kinases, promotes CSF arrest through the regulation of Emi2 and that Emi2 is the CSF-specific APC/C inhibitor that links the Mos pathway to the APC/C. Although this is clearly the case in vertebrates, the target of the Mos pathway in other systems is yet to be identified. For example, in starfish, the Mos pathway was also reported to be responsible for a G1 arrest (Mori et al., 2006). However, the target of the Mos kinase cascade in this arrest is currently unknown.
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CSF – unresolved questions |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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; Enquist-Newman et al., 2008; Kimata et al., 2008; Miller et al., 2006).
Emi2 has a sequence that is related to the proposed Emi1 pseudosubstrate region, raising the possibility that Emi2 could also exert its effects via a pseudosubstrate mechanism. Similar to Emi2, Emi1 also contains a ZBR. A single amino-acid mutation in this domain, which is distant from the pseudosubstrate domain, has been reported to completely disrupt the ability of Emi2 to inhibit the APC/C (Schmidt et al., 2005), suggesting that Emi2 employs a mechanism that is entirely distinct from pseudosubstrate inhibition to prevent APC/C activation. Consistent with this notion, we have observed considerable Emi2-APC/C interactions in the ZBR mutant, suggesting that APC/C-binding alone is not sufficient for APC/C inhibition (Wanli Tang, J.Q.W. and S.K., unpublished data). It is interesting to note that another APC/C inhibitor that was previously identified in our laboratory, Xnf7, also contains a ZBR (Casaletto et al., 2005), raising the possibility that Xnf7 and Emi2 share a common mechanism for inhibiting the APC/C. For any models of inhibition that require stable binding of Emi2 to the APC/C, it seems problematic that the levels of Emi2 in the egg are sub-stoichiometric to the APC/C. This can only be overcome by invoking the inhibition of particular APC/C pools at distinct sub-cellular locales, or by inhibiting distinct pools of the APC/C by individual, distinct inhibitors (Nishiyama et al., 2007a; Yamano et al., 2004).
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Mos-dependent and -independent Emi2 dephosphorylation |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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). This might be due to a redundant pathway that is responsible for Emi2 phosphorylation and thus PP2A binding. In starfish, it was discovered that Myt1, a Rsk substrate in Xenopus, can be inactivated by Akt (Okumura et al., 2002). This suggests that Akt or a related kinase is responsible for Emi2 phosphorylation in the absence of Rsk. Substrate recognition by PP2A is typically mediated through a substrate-targeting subunit (B subunit). For Emi2 dephosphorylation, the identity of the relevant B subunit has not yet been established. Moreover, it is not clear whether Rsk-mediated phosphorylation of Emi2 directly promotes PP2A B-subunit binding, C-subunit binding or both. It is also possible that Mos (and, by extension, Rsk) directly affects PP2A subunits in addition to acting directly at the level of Emi2. In this regard, it would be of interest to determine whether Mos affects dephosphorylation of PP2A targets other than Emi2.
In interphase extracts that have been prepared from Xenopus eggs (which lack Mos protein), a background Emi2-directed phosphatase activity has been observed (Wu et al., 2007b), suggesting the existence of a Mos-independent phosphatase activity that is directed towards Emi2. Moreover, the treatment of CSF-arrested Xenopus egg extracts with okadaic acid can induce a release from CSF arrest. We have found that, even at concentrations of okadaic acid that are known to completely inhibit PP2A, a rapid Emi2 gel-mobility downshift is seen as egg extracts entered interphase, suggesting the presence of a phosphatase that is distinct from PP2A and can promote Emi2 dephosphorylation. We would speculate that this phosphatase is PP1 because the gel-mobility downshift of Emi2 was prevented when higher concentrations of okadaic acid that were inhibitory to PP1 were used to induce CSF release (J.Q.W. and S.K., unpublished data). PP2B has been recently reported to be crucial for fertilization and CSF release (Mochida and Hunt, 2007; Nishiyama et al., 2007b); this Mos-independent phosphatase, however, is unlikely to be PP2B because the dephosphorylation of Emi2 was studied in the context of okadaic-acid-induced release from CSF arrest (in the absence of Ca2+) and PP2B is not an okadaic-acid-sensitive phosphatase.
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Extra-CSF roles of Emi2 – regulation of embryonic divisions and control of oocyte maturation |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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). Although levels of Emi2 in embryos are only at 20% of those found in eggs, this amount of Emi2 would be sufficient to induce metaphase arrest if Mos were also present (Liu et al., 2006); thus, the absence of Mos in embryos is crucial for allowing the early embryonic cell divisions to proceed (Fig. 1). The introduction of exogenous Mos into embryos or in vitro cell-cycle extracts most probably induces M-phase arrest by enhancing endogenous Emi2 activity, because Emi2 is stable during the short mitoses of embryogenesis and Mos does not modulate Emi2 translation.
It has been noted that MAPK is activated at mitosis in early embryos even in the absence of Mos. This raises the interesting question, why does this MAPK not cause Emi2 activation and thus mitotic arrest? Because there is a lag between Cdc2 activation and MAPK activation (Bhatt and Ferrell, 1999; Guadagno and Ferrell, 1998), it is possible that Cdc2 promotes Emi2 inactivation before Rsk would phosphorylate, and thus activate, Emi2. This temporally controlled regulation of Emi2 could, therefore, be crucial for embryonic divisions.
During oocyte maturation, Mos translation begins soon after progesterone stimulation and Mos protein persists throughout the entire maturation process (Fig. 1) (Sagata et al., 1988). So why do eggs arrest at MII but not MI? It has been reported that Emi2 translation starts immediately after entry into MI; however, no significant accumulation of Emi2 is observed until MII by immunoblotting (Liu et al., 2006; Madgwick et al., 2006; Ohe et al., 2007; Tung et al., 2007). Therefore, it was postulated that the slow translation of Emi2 in MI is responsible for the smooth transition from MI to MII. Surprisingly, we observed a significant amount of Emi2 accumulation in MI, providing that Emi2 degradation was inhibited by treatment with the proteasome inhibitor MG132 (Tang et al., 2008). In addition, 35S-labeled Emi2 injected into oocytes was quickly degraded in MI. Furthermore, expression of a non-degradable Emi2 at levels comparable with endogenous Emi2 in oocytes under circumstances in which endogenous Emi2 translation had been prevented resulted in MI arrest (Tang et al., 2008). These observations strongly suggest that a smooth MI-to-MII transition relies on Emi2 degradation in MI. These observations raised the question of why Emi2 is stable only in MII and not in MI, despite the presence of Mos-pathway activity in both phases. In this regard, we found that Cdc2 activity in MI is twice as high as that in MII, which promotes Emi2 instability in MI, thus ensuring a smooth MI-to-MII transition (Fig. 1) (Tang et al., 2008). Nonetheless, it still remains to be determined why Cdc2 exhibits higher activity in MI than in MII.
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Conclusions and perspectives |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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Acknowledgments |
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References |
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TopSummaryIntroductionCSF in the pre-Emi2...Connecting Mos to the...CSF - unresolved questionsMos-dependent and -independent...Extra-CSF roles of Emi2...Conclusions and perspectivesReferences |
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