Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space

in Reproduction

During meiotic maturation of mammalian oocytes, two successive divisions occur without an intermediate phase of DNA replication, so that haploid gametes are produced. Moreover, these two divisions are asymmetric, to ensure that most of the maternal stores are retained within the oocyte. This leads to the formation of daughter cells with different sizes: the large oocyte and the small polar bodies. All these events are dependent upon the dynamic changes in the organization of the oocyte cytoskeleton (microtubules and microfilaments) and are highly regulated in time and space. We review here the current knowledge of the interplay between the cytoskeleton and the cell cycle machinery in mouse oocytes, with an emphasis on the two major activities that control meiotic maturation in vertebrates, MPF (Maturation promoting factor) and CSF (Cytostatic factor).

Abstract

During meiotic maturation of mammalian oocytes, two successive divisions occur without an intermediate phase of DNA replication, so that haploid gametes are produced. Moreover, these two divisions are asymmetric, to ensure that most of the maternal stores are retained within the oocyte. This leads to the formation of daughter cells with different sizes: the large oocyte and the small polar bodies. All these events are dependent upon the dynamic changes in the organization of the oocyte cytoskeleton (microtubules and microfilaments) and are highly regulated in time and space. We review here the current knowledge of the interplay between the cytoskeleton and the cell cycle machinery in mouse oocytes, with an emphasis on the two major activities that control meiotic maturation in vertebrates, MPF (Maturation promoting factor) and CSF (Cytostatic factor).

Introduction

In most animal species, sexual reproduction requires the fusion of two haploid gametes: the spermatozoon and the oocyte. Meiosis, which ensures the formation of these highly specialized cells, is a long process. In mammalian oocytes, the short period called meiotic maturation, which concludes meiosis, is absolutely crucial for the production of a functional gamete. During this period, the oocyte undergoes two cellular divisions without an intermediate phase of DNA replication. These divisions consist of a sequence of cellular events that are controlled by the cytoskeleton of the oocyte and are highly regulated in time (Fig. 1). Microtubules form the spindle and segregate homologous chromosomes during the first meiotic division (MI, a reductional division) and sister chromatids during the second division (MII, an equational division). In addition, spindle microtubules and actin microfilaments control the asymmetry of these meiotic divisions. Both divisions produce a small cell called the polar body and a large cell, the oocyte, which keeps its size and the entire maternal stores accumulated during oogenesis.

During the past few years, the understanding of the principles at play during the meiotic divisions in oocytes has been improved, mostly due to in vivo studies in mouse oocytes and in vitro analyses achieved in cytoplasmic egg extracts. In the light of these recent results, we review here our current knowledge on the mechanisms that control the organization of the cytoskeleton in time and space during meiotic maturation of mammalian oocytes.

Spindle assembly in the oocyte relies on chromosomes

Chromosomes control bipolar spindle assembly

During mitosis, spindle assembly is directed to a large extent by the centrosomes, the main sites of microtubule polymerization (Ou & Rattner 2004). At the onset of mitosis, the single centrosome has been duplicated and the two centrosomes separate and migrate to opposite sides of the nucleus. As a consequence, as soon as the nuclear envelope breaks down, growing microtubules emanating from both centrosomes interact with the chromosomes and become rapidly organized into a bipolar spindle. Oocytes lack centrosomes and the microtubules are polymerized at discrete sites in the cytoplasm called MTOCs (Microtubule organizing centers). In the mouse oocyte, where multiple MTOCs are dispersed in the cytoplasm, chromosomes take the lead in spindle assembly. At the onset of MI, just after GVBD (Germinal vesicle breakdown), MTOCs are preferentially activated and/or recruited in the vicinity of the chromosomes and microtubules are preferentially stabilized in this area. Randomly oriented growing microtubules are then progressively organized into a bipolar array around the chromosomes (Fig. 2).

The respective roles of chromosomes, microtubules and associated factors in meiotic spindle assembly have been enlightened by the study of the microtubules in mouse oocyte fragments lacking chromosomes, called cytoplasts (Brunet et al. 1998). In cytoplasts, microtubules assemble stable bipolar spindles. This observation indicates that in mouse oocytes, microtubules have the potential to polymerize and organize in the absence of chromosomes into bipolar structures due to the activities of motor proteins and MAPs (Microtubule associated proteins). This property plays an essential role in spindle formation in the mouse oocyte. Often, several bipolar spindles form in mouse oocyte cytoplasts, demonstrating that chromosomes are necessary to restrain MTOCs activity and microtubule organization in their vicinity. This restriction is crucial to form a unique spindle in the large volume of the oocyte. Moreover, the size of the observed bipolar spindles can vary from one cytoplast to the next. This indicates that chromosomes are involved in the control of the size of the spindle, most probably through local activation of microtubule stabilizing factors. Recently, a central role of chromosomes in spindle assembly has been established in other experimental systems. This role is required for spindle assembly with or without centrosomes and is based on the activity of the small GTPase ‘Ran’ (Karsenti & Vernos 2001, Kalab et al. 2002, Zheng 2004). During M phase, Ran, bound to GTP (RanGTP) is concentrated in the vicinity of the chromosomes and locally activates various factors required for spindle formation (Hetzer et al. 2002, Caudron et al. 2005). This mechanism is most probably at play during the meiotic divisions of the mouse oocyte. Among the characterized effectors of RanGTP, TPX2 (Targeting protein for Xenopus kinesin-like protein 2) is responsible for a RanGTP dependant microtubule polymerization around the chromosomes (Wittmann et al. 2000, Gruss et al. 2001). TPX2 is expressed in the mouse oocyte and is associated to the spindle microtubules, as it is in other systems. TPX2 is likely involved in spindle formation in the mouse oocyte by supporting microtubule assembly in the vicinity of the chromosomes (J Dumont and M H Verlhac, personal communication). The other RanGTP effectors involved in spindle assembly by stabilizing microtubules or controlling microtubule organization have not been studied yet in mouse oocytes. DOC1R (Deleted oral cancer 1 related), initially identified in the mouse oocyte as a MAP kinase substrate, may be a novel RanGTP effector (Terret et al. 2003a). This protein interacts with importins (M E Terret and M H Verlhac, personal communication) as shown for other RanGTP effectors. It is localized on the spindle during the meiotic M phases. DOC1R depletion in the oocyte induces the formation of microtubule asters in the whole cytoplasm (Terret et al. 2003a). DOC1R may be required to restrain the RanGTP gradient in the vicinity of the chromosomes in the oocyte.

Chromatin controls metaphase plate formation

Once bipolar spindle assembly is achieved, chromosomes align on the spindle equator and form the metaphase plate. During mitosis, this alignment is monitored by the kinetochores, structures associated with the centromeres of both sister chromatids. Kinetochores capture, stabilize microtubules and form robust ‘kinetochore fiber’ (or K-fiber). When K-fibers connect both kinetochores of one chromosome to the opposite spindle poles, the chromosome is transported to the equator of the spindle (Biggins & Walczak 2003). In mouse oocytes, during the first meiotic M phase, bivalent chromosomes alignment on the metaphase plate involves alternative mechanisms. In contrast to the situation described in mitosis, the kinetochores associated with bivalents are not competent for anchoring and/or stabilizing microtubules during most of the first meiotic M phase. However, in the absence of K-fibers, bivalent chromosomes are nevertheless transported towards the equator of the spindle and maintained in this area for a few hours (Brunet et al. 1999). It has been shown that spindle microtubules exert pushing forces on the chromosome arms. These forces, also called ‘polar wind’, are mediated by microtubules motors associated with chromatin (Brunet & Vernos 2001). Two chromatin-associated motors Kif 4 and Kif 22, the respective homologs of the Xenopus kinesin-like proteins Xklp1 and Xkid, are likely required for bivalent congression in the oocyte. Xklp1 can anchor the microtubules to the chromosome arms by ‘freezing’ the dynamic properties of the microtubules contacting the arms (Vernos et al. 1995, Bringmann et al. 2004). Xkid is necessary for chromosome arms congression (Antonio et al. 2000, Funabiki & Murray 2000). Although in somatic cells the polar wind is not essential (Levesque & Compton 2001), it governs chromosome congression in the oocyte.

After this long prometaphase, the activation of the kinetochores triggers the formation of K-fibers leading to the accurate alignment of the chromosomes on the metaphase plate (Brunet et al. 1999). The mechanism leading to the late activation of the kinetochores in mouse oocytes remains elusive. Kinetochores may be submitted to a very slow and original maturation. Molecular components of the kinetochore including members of the SAC (Spindle assembly checkpoint) machinery (see below) or motors like the kinesin CENP-E are present on kinetochores just after GVBD. This suggests that kinetochore maturation is not regulated by the recruitment of kinetochore components but more likely by post-translational modifications of some of these factors. MI duration is determined by the kinetics of MPF (Maturation promoting factor) activity (see below). A high level of MPF activity, only reached late in MI, could induce post-translational modifications of kinetochore components leading to the setting up of K-fibers. In fact, K-fiber formation remains one of the ‘black boxes’ of Mitosis. Only a few proteins involved in this process have been characterized (Biggins & Walczak 2003) and their role and regulation during MI remain to be studied in oocytes.

The asymmetry of the oocyte divisions depends on chromosomes

Spindle motility depends on interactions between actin and the chromosomes

Both meiotic divisions of the mouse oocyte are asymmetric. They produce a small cell called the polar body and the oocyte, which conserves its original size. Such asymmetry is ensured by the positioning of the spindle in the periphery of the large oocyte. The MI spindle generally forms in the center of the oocyte and migrates toward its periphery (Longo & Chen 1985, Maro & Verlhac 2002). The first polar body is extruded in the axis of the migration. The MII spindle forms in the periphery of the oocyte and is maintained under the plasma membrane during the metaphase arrest. Fertilization or experimental activation triggers spindle rotation and the extrusion of a second polar body (Maro & Verlhac 2002, Maro et al. 1984). Our knowledge on the mechanisms of asymmetric divisions stems from investigations on mitotic cells (Betschinger & Knoblich 2004) where spindle positioning depends on interactions between the cell cortex and ‘astral’ microtubules that connect the spindle poles to the cell cortex (Cowan & Hyman 2004). Oocyte lack centrosomes and the spindles lack in turn astral microtubules: alternative mechanisms must be at play to position the spindle within the oocyte. In mouse oocytes, spindle migration and anchoring require actin microfilaments but not microtubules (Longo & Chen 1985, Maro et al. 1986, Van Blerkom & Bell 1986, Verlhac et al. 2000a, Leader et al. 2002, Maro & Verlhac 2002), in contrast to what was described in oocytes from other species (Weber et al. 2004, Yang et al. 2005). In mouse oocytes, these processes rely on original interactions between the microfilaments and the chromosomes themselves (Maro et al. 1986, Van Blerkom & Bell 1986, Verlhac et al. 2000a, Maro & Verlhac 2002), but the molecular basis of such interactions are so far unknown. First, actin microfilaments organization and dynamics in the oocyte remains to be characterized. Are actin-associated motors (myosins) required? A possible role of myosin II in polar body formation has been proposed (Simerly et al. 1998) but the mechanisms involved remain to be elucidated. What are the components linking chromosomes to the actin network? PARD6A, a member of the PAR family (PARtitioning defective; Ahringer 2003) may be involved in this process. During MI, PARD6A is concentrated on the spindle half that leads the migration. Upon microtubule depolymerization it concentrates on the surface of the chromosomes oriented toward the cortex (Vinot et al. 2004). It may be part of a multi-protein complex coupling chromosomes, microtubules and actin microfilaments and support spindle motility and anchoring.

Chromosomes control the cortical reorganization of the mouse oocyte

In mouse oocytes, the eccentric position of the spindle is associated with a local reorganization of the oocyte cortex (Fig. 1). This cortical domain appears during spindle migration and is maintained over the spindle during MII. Reorganization is marked by a local loss of microvilli (Johnson et al. 1975), an accumulation of actin microfilaments under the plasma membrane (Maro et al. 1984, Longo & Chen 1985) and the exclusion of cortical granules (Deng et al. 2005). The function of this process is unclear. It may serve to generate a restriction domain for the assembly of the contractile actin ring and cytokinesis in order to minimize the size of the polar body. The cortical reorganization depends on the actin network, on the chromosomes but not on microtubules (Maro et al. 1986, Van Blerkom & Bell 1986, Verlhac et al. 2000a, Maro & Verlhac 2002). In addition, it does not require physical interactions between the chromosomes and the cortex (Maro & Verlhac 2002). Thus, the chromosomes themselves trigger this reorganization by an ‘at distance’ effect. The molecular mechanisms at play are so far unexplored.

In conclusion, the asymmetry of the mouse oocyte divisions depends an original role of the chromosomes on the organization of the actin network. Direct interactions between chromosomes and actin govern spindle positioning. In addition, chromosomes mediate cortical actin reorganization by an ‘at distance’ effect. The similarity with the role of chromosomes in microtubule organization in the oocyte is striking. As far as microtubules are concerned, chromatin associated motors mediate physical interactions between the chromosomes and the spindle microtubules. In addition, chromosomes control in their vicinity the activation of factors required for spindle assembly (Karsenti & Vernos 2001, Kalab et al. 2002, Zheng 2004). On the basis of these similarities, we propose that in mouse and more generally in mammalian oocytes, chromosomes act as a ‘territory landmark’ to organize both microtubules and actin microfilaments within the large cytoplasm. This spatial control is essential to achieve the two asymmetric meiotic divisions that lead to the formation of a functional gamete.

Cyclin B coordinates meiotic maturation

During the cell cycle, M-phase is controlled through the activation and inactivation of the MPF (Masui & Markert 1971), composed of a kinase, p34cdk1 and its regulatory sub-unit, cyclin B (Lohka et al. 1988, Doree & Hunt 2002). The modulation of cyclin concentration by synthesis and degradation is of central importance for the control of MPF activity (Murray & Kirschner 1989). The mitotic cyclins are synthesized throughout the cell cycle and destroyed during a short period at the metaphase–anaphase transition (Evans et al. 1983) by the 6 ubiquitin pathway (Glotzer et al. 1991, Hershko et al. 1991). In the oocyte, all the cellular events taking place during meiotic maturation and leading to the two asymmetric cell divisions have to be ordered in a timely manner. The control of the timing of meiotic maturation most likely depends on cyclin B. Changes in cyclin B levels, through changes in MPF activity, regulate not only the timing of the cell cycle phases during meiosis but also the orderly events leading to the formation of functional meiotic spindles and asymmetric divisions.

Cyclin B metabolism controls the timing of meiotic maturation

MPF is activated at GVBD (Fig. 3) and increases until it reaches a plateau at the end of the first meiotic M-phase (Choi et al. 1991, Verlhac et al. 1994). A transient decline in MPF activity takes place during the transition between meiosis I and meiosis II. MPF is reactivated rapidly to enter meiosis II and is maintained at a high level during the metaphase II arrest.

The immature oocyte contains only a small amount of cyclin B, just enough to induce entry into the first meiotic M-phase (Hampl & Eppig 1995, Winston 1997, Hashimoto & Kishimoto 1988, Ledan et al. 2001). It enters the germinal vesicle just prior to GVBD (Marangos & Carroll 2004). After GVBD, the level of synthesis of cyclin B increases progressively, reaching its maximum at the end of the first meiotic M phase, and the newly synthesized protein becomes associated immediately with the p34cdk1 kinase to form an active complex (Hampl & Eppig 1995, Winston 1997, Ledan et al. 2001). Cyclin B degradation is required for polar body extrusion (Ledan et al. 2001, Herbert et al. 2003, Terret et al. 2003b). Thus, MPF activity is regulated by a translation-dependent mechanism that determines the level of cyclin synthesis.

The role of cyclin B1 synthesis in the control of the duration of meiotic maturation was demonstrated using two strains of mice, CBA/Kw and KE, which differ greatly in the timing of meiotic maturation (Polanski et al. 1998). KE oocytes take approximately 3–4 hours longer than CBA/Kw oocytes to extrude the first polar body. The rate of cyclin B1 synthesis during prometaphase I is higher in CBA/Kw than in KE oocytes although the overall level of protein synthesis and the amount of cyclin B1 messenger RNA are identical in both strains, suggesting that cyclin B1 translation is controlled differently in these two strains (Polanski et al. 1998). Among the different mechanisms that control the expression of maternal mRNAs, polyadenylation has been implicated in cyclin B1 translation in Xenopus and mouse oocytes (Barkoff et al. 2000, de Moor & Richter 1999, Ledan et al. 2001, Tay et al. 2000). Finally, increasing cyclin B1 synthesis in KE oocytes speeds up first polar body extrusion (Ledan et al. 2001, Polanski et al. 1998).

The formation of the first meiotic spindle is regulated by cyclin B levels

During MI, the formation of a functional spindle is a very slow process. These kinetics correlate with the progressive increase in MPF activity (Polanski et al. 1998, Fig. 3). The MPF activity required for GVBD (sufficient for entry into M-phase) only allows the formation of a single aster of microtubules around the condensed chromosomes (Fig. 4). A first threshold in MPF activity is then required to organize the microtubules into a bipolar structure. In contrast, the further migration of the chromosomes toward the vicinity of the spindle equator does not depend on changes in MPF level. A second threshold in MPF activity is required at the end of MI for the activation of the kinetochores (Polanski et al. 1998, Brunet et al. 1999), it allows the capture and stabilization of microtubules by the kinetochores and the further assembly of robust K-fibers. The setting up of the whole set of K-fibers is rapidly followed by anaphase onset. These data indicate that MPF activity controls the formation of a functional spindle in the oocyte. MPF may also indirectly control the position of the spindle. Like kinetochore activation, spindle migration is only initiated once MPF activity has reached a high level. Thus, MPF may control the activity of proteins associated to the microfilaments (Satterwhite et al. 1992) and in turn induce spindle migration: the mechanisms and the molecules involved remain to be investigated.

Coupling time and space

In mitosis, a quality control mechanism called the spindle assembly checkpoint ensures accurate chromosome segregation by delaying anaphase onset until all the chromosomes are correctly attached to the spindle through their kinetochores. The spindle checkpoint prevents anaphase by inhibiting the anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase whose activity is required for cyclin B and securin degradation. The APC/C is therefore required for anaphase onset and exit from mitosis (Taylor et al. 2004). This checkpoint depends on the activity of Bub (Budding uninhibited by benzimidazole) and Mad (Mitotic arrest-deficient) kinetochore proteins (Hoyt et al. 1991, Li & Murray 1991). Until recently it was generally accepted that mammalian female meiotic divisions are error prone because they lack a functional spindle checkpoint (in humans, an estimated 20% of concepti have an abnormal chromosomal content as a consequence of errors occurring during female meiosis I). It has been now clearly established that the activity of the APC/C is required for meiotic progression and that the spindle assembly checkpoint is active in mouse oocytes (Brunet et al. 2003) through the checkpoint components Bub1 (Tsurumi et al. 2004) and Mad2 (Wassmann et al. 2003, Tsurumi et al. 2004, Homer et al. 2005).

As expected, inactivation the spindle assembly checkpoint in mouse oocytes accelerates progression through MI. However, only a 2–3 hours shortening of the first meiotic M-phase takes place (Tsurumi et al. 2004, Homer et al. 2005), suggesting that the APC/C is inactive during most of the first meiotic M-phase. Thus, activation of the APC/C would only occur when MPF activity has reached the second threshold level, also required for activation of the kinetochores (Polanski et al. 1998, Brunet et al. 1999). The spindle assembly checkpoint does not control the timing of the first meiotic M-phase but rather delays the meta-phase–anaphase transition until the spindle microtubules are attached to the kinetochores and the chromosomes are properly aligned on the metaphase plate (Fig. 4).

Since the metaphase–anaphase transition takes place when the spindle has reached the oocyte cortex (Verlhac et al. 2000a), one may wonder whether a checkpoint exists to monitor the position of the spindle. Such a checkpoint exists in budding yeasts: the mitotic exit network (MEN) verifies the correct positioning of one spindle pole in the newly formed bud (D’Amours & Amon 2004). This is unlikely to be the case in mouse oocytes: in mos−/− oocytes while the spindle does not migrate, the metaphase–ana-phase transition still happens at the right time (Verlhac et al. 1996, Verlhac et al. 2000a) leading to the formation of large polar bodies. Large polar bodies were also observed when meiotic maturation is accelerated by inactivation of the spindle assembly checkpoint (Homer et al. 2005).

Thus cyclin B levels, through the regulation of MPF activity, seems to synchronize the different events leading to the formation of the polar body (Fig. 4): setting up of the K-fibers (required for the final alignment of the chromosomes on the metaphase plate), activating the APC/C (required for chromosome separation and exit from the first meiotic M-phase) and spindle migration (required for asymmetric division). The time required for the formation of kinetochore fibers and the subsequent alignment of the pairs of homologous chromosome will allow spindle migration before the inactivation of the spindle assembly checkpoint leading to the metaphase–anaphase transition.

The peculiar case of the metaphase II spindle

In contrast to the first meiotic division, the entry into the second one is similar to mitosis: MPF activity increases rapidly and the spindle forms quickly. Moreover, the meiosis II chromosomes are identical to mitotic chromosomes, composed of sister chromatids with active kinetochores. However, the oocyte arrests at metaphase for many hours until fertilization, with the chromosomes perfectly aligned on the metaphase plate and high MPF activity. This meta-phase arrest is maintained through an activity called the Cytostatic factor (CSF; Masui & Markert 1971).

The presence of CSF was demonstrated in vertebrate oocytes by transferring cytoplasm from a metaphase II arrested oocyte into cleaving frog (Masui & Markert 1971) and mouse (Masui & Markert 1971, Kubiak et al. 1993) embryos, leading to a cell cycle arrest in mitosis. CSF activity requires the activation of the Mos–MAP kinase pathway (Sagata et al. 1989, Haccard et al. 1993, Colledge et al. 1994, Hashimoto et al. 1994, Verlhac et al. 1996). The signaling pathway emerging from the Xenopus work performed mainly in oocyte extracts looks like a linear track, from Mos synthesis to the APC/C inhibitor Mad2 (Tunquist & Maller 2003). The Mos pathway in mouse oocytes (Fig. 5), emerging from in vivo studies performed using Mos−/− oocytes, is more complex (Verlhac et al. 1996, Verlhac et al. 2000b, Lefebvre et al. 2002, Terret et al. 2003a, Dumont et al. 2005). Although it was thought that the only requirement to induce a proper meta-phase arrest was to maintain a high MPF activity, recent work demonstrated that the organization of the spindle has to be maintained by specific mechanisms (Fig. 5).

Keeping a metaphase spindle

Metaphase is a transient state of mitosis. In CSF arrested oocytes, it can last for many hours or even days. While spindle microtubules turn over rapidly, as in mitosis, the meiotic spindle remains as a stable structure during the arrest (de Pennart et al. 1988, Gorbsky et al. 1990), with chromosomes perfectly aligned on the equator of the spindle (Brunet et al. 1999). Specific mechanisms and components are required to maintain such a stable structure (Lefebvre et al. 2002, Terret et al. 2003a). MISS (MAP kinase-interacting and spindle-stabilizing protein) and DOC1R are two MAP kinase substrates associated with the spindle in metaphase II arrested oocytes (Lefebvre et al. 2002, Terret et al. 2003a). DOC1R accumulates during meiotic maturation while MISS is only present during MII. DOC1R depletion leads to the formation of elongated spindles enriched in astral microtubules with numerous asters of microtubules in the cytoplasm during MII. Oocytes depleted for MISS show disorganized MII spindles often lacking one pole, or have long microtubules emanating from both poles and cytoplasmic asters. In both cases, the MII spindle forms normally but become later disorganized indicating a role for both proteins in the maintenance of the spindle structure during the arrest. MISS and DOC1R are regulated by multiple phosphorylations, through the activity of MAP kinase and other kinases, likely MPF. Thus, cooperation between MPF and the MAP kinase pathway (leading to CSF activity) is at play to maintain the spindle structure when the metaphase state is highly prolonged.

Keeping MPF high

Again, cyclin metabolism plays a key role during the metaphase II arrest (Fig. 5). It is supported throughout the continuous balanced synthesis and degradation of cyclin (Kubiak et al. 1993). The equilibrium between these two processes is dependent upon CSF that slows down degradation (Kubiak et al. 1993) and the continuous synthesis of cyclin B that is maintained at the highest level (Winston 1997). After first polar body extrusion cyclin degradation stops (Ledan et al. 2001) and the APC/C is only reactivated upon entry into the second meiotic M-phase by the high level of MPF. Cyclin degradation can only take place in the meiosis II oocyte once spindle formation has been completed and the chromosomes aligned on the metaphase plate, thus removing the inhibitory effect of the spindle assembly checkpoint. During the CSF arrest, the SAC is inactive, but it can be reactivated when spindle organization is perturbed, leading to a complete inhibition of the cyclin degradation pathway (Kubiak et al. 1993, Winston et al. 1995, Winston 1997). It was proposed in Xenopus that the CSF arrest was mediated through the activity of p90rsk (Bhatt & Ferrell 1999, Gross et al. 1999) and the spindle assembly checkpoint proteins Bub 1 and Mad 2 (Tunquist et al. 2002, Tunquist et al. 2003), downstream of the Mos–MAP kinase pathway. However, in mouse oocytes, it was demonstrated that neither p90rsk (a characterized MAP kinase substrate in mouse oocytes; Kalab et al. 1996), nor Bub1 or Mad2 are required for the metaphase II arrest (Tsurumi et al. 2004, Dumont et al. 2005). Thus, the APC/C inhibitor responsible for the maintenance of a high level of MPF activity during the metaphase II arrest remains to be identified. The most likely candidate is Emi2/Xerp1 (Liu & Maller 2005, Rauh et al. 2005, Schmidt et al. 2005, Tung et al. 2005), although it does not seem to be regulated by the Mos–MAP kinase pathway in Xenopus egg extracts (Schmidt et al. 2005). Emi2/Xerp1 is a target of CamKII, a kinase that is transiently activated by Ca++ at fertilization and mediates CSF inactivation (Lorca et al. 1993, Winston and Maro 1995).

Thus, the oocyte during the metaphase II arrest is in a very dynamic state, with highly dynamic spindle microtubules keeping all the chromosomes perfectly aligned on the metaphase plate (Brunet et al. 1999), with a stable level of MPF dependent upon the constant synthesis of cyclin B counterbalanced by regulated degradation (Kubiak et al. 1993). These equilibriums are regulated by downstream targets of the Mos–MAP kinase pathway, some of them remaining to be identified.

Conclusion

The production of functional female gametes is essential for the propagation of all mammalian species. It is dependent to a large extent on the dynamic organization of the oocyte cytoskeleton during the two successive meiotic divisions. Defects in the cytoskeleton organization during these divisions can first lead to chromosome segregation errors with dramatic consequences. In humans, it is estimated that 15–20% of oocytes display chromosome abnormalities linked to segregation errors (Pellestor et al. 2005). Moreover, at least 5% of all pregnancies are aneuploid as a result of such errors in oocytes, that strongly correlate with increased maternal age (Hassold & Hunt 2001). The recent demonstration of the existence of a functional spindle checkpoint in mammalian oocytes is essential. It implies that in addition to spindle checkpoint deficiencies (intensively studied in mitotic systems), other uncharacterized mechanisms contribute to the high frequency of missegregations in the mammalian oocyte. The elucidation of the chromosome-dependant mechanisms controlling microtubule and actin networks organization in the oocyte may be of a great importance to identify the cellular and molecular basis of aneuploidy.

In addition, the formation of a mature oocyte also relies on microtubule and actin microfilament-dependent processes. Anomalies in any of these processes can prevent the production of competent oocytes and lead to fertility problems. A striking example is the female sterility of formin 2 knockout mice, formin 2 encodes an actin-polymerizing protein involved in spindle migration in the oocyte (Leader et al. 2002). Similarly, cytoskeleton-dependent asymmetry of the meiotic division maintains the maternal stores accumulated during oogenesis in the oocyte (Matzuk et al. 2002). Loss of asymmetry in the meiotic division, and more generally disorganization of the oocyte cytoskeleton are characteristics of ageing or low-quality gametes (Webb et al. 1986, Diaz & Esponda 2004).

Understanding all the dynamic processes involved in the formation of a mammalian oocyte competent for fertilization is a major goal for reproductive biologists. Some of the principles at play during the meiotic divisions of the mammalian oocytes are just starting to be understood, but the mechanisms remains to be elucidated at the cellular and molecular levels. The mouse oocyte, which allows the combination of molecular cell biology with genetics, appears more and more as the system to investigate these questions.

Figure 1

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Figure 1

The cellular events of meiotic maturation in mouse oocytes. At GVBD (first row), microtubules (in green) polymerize radially around the mass of chromosomes and organize progressively into a bipolar spindle. At the end of MI (second row), the bipolar spindle migrates toward the oocyte cortex. Spindle migration induces the local reorganization of the cortex of the oocyte (red and pink area). The first polar body is extruded in the axis of spindle migration. During MII arrest (third row), the metaphase spindle is anchored under the plasma membrane. The cortex reorganization is maintained in the vicinity of the spindle. Fertilization or experimental activation of the oocyte triggers a 90° spindle rotation and the extrusion of the second polar body.

Citation: Reproduction 130, 6; 10.1530/rep.1.00364

Figure 2

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Figure 2

Chromosomes monitor MI spindle assembly in mouse oocyte. Chromosomes (in blue) locally restrain the assembly and organization of microtubules. MTOCs (in dark green) are locally activated and RanGTP (blue gradient) triggers the polymerization of microtubules around the chromosomes (in light green). The microtubules progressively organize into a bipolar structure around the chromosomes. The kinetochores associated with the bivalents are inactive during most of the MI (light blue discs). As a consequence, bivalents migration toward the spindle equator is achieved by direct interactions between chromosome arms and spindle microtubules. At the end of MI, kinetochores are activated (yellow discs) and become able to anchor microtubules and form kinetochore fibers (in dark green): the complete formation of K-fiber correlates with a brief meta-phase transition and triggers anaphase onset.

Citation: Reproduction 130, 6; 10.1530/rep.1.00364

Figure 3

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Figure 3

MPF and MAPK activities during meiotic maturation in mouse oocytes. MPF activity appears as a red line and MAPK as a green line. The different steps of meiotic maturation are schematized as in Figure 1.

Citation: Reproduction 130, 6; 10.1530/rep.1.00364

Figure 4

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Figure 4

Cyclin B synthesis controls the timing of meiotic maturation through the level of MPF activity.

Citation: Reproduction 130, 6; 10.1530/rep.1.00364

Figure 5

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Figure 5

The metaphase II arrest in mouse oocytes. The components and interactions shown in grey remain to be discovered.

Citation: Reproduction 130, 6; 10.1530/rep.1.00364

Received 23 August 2005
 First decision 10 October 2005
 Revised manuscript received 14 October 2005
 Accepted 17 October 2005

SB was supported by the Ligue Nationale contre le Cancer and the Association pour la Recherche contre le Cancer (GL/VP 4082). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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  • Brunet SSanta Maria AGuillaud PDujardin DKubiak JZ & Maro B1999 Kinetochore fibers are not involved in the formation of the first meiotic spindle in mouse oocytes but control the exit from the first meiotic metaphase. Journal of Cell Biology1461–12.

  • Caudron MBunt GBastiaens P & Karsenti E2005 Spatial coordination of spindle assembly by chromosome-mediated signaling gradients. Science3091373–1376.

  • Choi TAoki FMori MYamashita MNagahama Y & Kohmoto K1991 Activation of p34cdc2 protein kinase activity in meiotic and mitotic cell cycles in mouse oocytes and embryos. Development113789–795.

  • Colledge WHCarlton MBLUdy GB & Evans MJ1994 Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs. Nature37065–68.

  • Cowan CR & Hyman AA2004 Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. Annual Reviews in Cell and Developmental Biology20427–453.

  • D’Amours D & Amon A2004 At the interface between signaling and executing anaphase–Cdc14 and the FEAR network. Genes and Development182581–2595.

  • de Moor CH & Richter JD1999 Cytoplasmic polydenylation elements mediate masking and unmasking of cyclin B1 mRNA. EMBO Journal182294–2303.

  • de Pennart HHouliston E & Maro B1988 Post-translational modifications of tubulin and the dynamics of microtubules in mouse oocytes and zygotes. Biology of the Cell64375–378.

  • Deng MWilliams CJ & Schultz RM2005 Role of MAP kinase and myosin light chain kinase in chromosome-induced development of mouse egg polarity. Developmental Biology278358–366.

  • Diaz H & Esponda P2004 Ageing-induced changes in the cortical granules of mouse eggs. Zygote1295–103.

  • Doree M & Hunt T2002 From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? Journal of Cell Science1152461–2464.

  • Dumont JUmbhauer MRassinier PHanauer A & Verlhac MH2005 p90Rsk is not involved in cytostatic factor arrest in mouse oocytes. Journal of Cell Biology169227–231.

  • Evans TRosenthal ETYoungblom JDistel D & Hunt T1983 Cyclin: A protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell33389–396.

  • Funabiki H & Murray AW2000 The Xenopus chromokinesin Xkid is essential for metaphase chromosome alignment and must be degraded to allow anaphase chromosome movement. Cell102411–424.

  • Glotzer MMurray AW & Kirschner MW1991 Cyclin is degraded by the ubiquitin pathway. Nature349132–138.

  • Gorbsky GJSimerly CSchatten G & Borisy GG1990 Microtubules in the metaphase-arrested mouse oocyte turn over rapidly. PNAS876049–6053.

  • Gross SDSchwab MSLewellyn AL & Maller JL1999 Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk. Science2861365–1367.

  • Gruss OJCarazo-Salas RESchatz CAGuarguaglini GKast JWilm MLe Bot NVernos IKarsenti E & Mattaj IW2001 Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity. Cell10483–93.

  • Haccard OSarcevic BLewellyn AHartley RRoy LIzumi TErikson E & Maller JL1993 Induction of metaphase arrest in cleaving xenopus embryos by MAP kinase. Science2621262–1265.

  • Hampl A & Eppig JJ1995 Translational regulation of the gradual increase in histone H1 kinase activity in maturing mouse oocytes. Molecular Reproduction and Development409–15.

  • Hashimoto N & Kishimoto T1988 Regulation of meiotic metaphase by a cytoplasmic maturation-promoting factor during mouse oocyte maturation. Developmental Biology126242–252.

  • Hashimoto NWatanabe NFuruta YTamemoto HSagata NYokoyama MOkazaki KNagayoshi MTakeda NIkawatll Y & Aizawai S1994 Parthenogenetic activation of oocytes in c-mos-deficient mice. Nature37068–71.

  • Hassold T & Hunt P2001 To err (meiotically) is human: the genesis of human aneuploidy. Nature Reviews Genetics2280–291.

  • Herbert MLevasseur MHomer HYallop KMurdoch A & McDougall A2003 Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nature Cell Biology51023–1025.

  • Hershko AGanoth DPehrson JPalazzo RE & Cohen LH1991 Methylated ubiquitin inhibits cyclin degradation in clam embryo extracts. Journal of Biological Chemistry26616376–16379.

  • Hetzer MGruss OJ & Mattaj IW2002 The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nature Cell Biology4E177–E184.

  • Homer HAMcDougall ALevasseur MYallop KMurdoch AP & Herbert M2005 Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes and Development19202–207.

  • Hoyt MATotis L & Roberts BT1991S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell66507–517.

  • Johnson MHEager DMuggleton-Harris AL & Graves HM1975 Mosaicism in the organisation of concanavalin A receptors on surface membrane of mouse eggs. Nature257321–322.

  • Kalab PWeis K & Heald R2002 Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science2952452–2456.

  • Kalab PKubiak JZVerlhac M-HColledge WH & Maro B1996 Activation of p90rsk during meiotic maturation and first mitosis in mouse oocytes and eggs: MAP kinase-independent and dependent activation. Development1221957–1964.

  • Karsenti E & Vernos I2001 The mitotic spindle: a self-made machine. Science294543–547.

  • Kubiak JZWeber Mde Pennart HWinston NJ & Maro B1993 The metaphase II arrest in mouse oocytes is controlled through microtubule-dependent destruction of cyclin B in the presence of CSF. EMBO Journal123773–3778.

  • Leader BLim HCarabatsos MJHarrington AEcsedy JPellman DMaas R & Leder P2002 Formin-2 polyploidy hypofertility and positioning of the meiotic spindle in mouse oocytes. Nature Cell Biology4921–928.

  • Ledan EPolanski ZTerret M-E & Maro B2001 Meiotic maturation of the mouse oocyte requires an equilibrium between cyclin B synthesis and degradation. Developmental Biology232400–413.

  • Lefebvre CTerret MEDjiane ARassinier PMaro B & Verlhac MH2002 Meiotic spindle stability depends on MAPK-interacting and spindle-stabilizing protein (MISS) a new MAPK substrate. Journal of Cell Biology157603–613.

  • Levesque AA & Compton DA2001 The chromokinesin Kid is necessary for chromosome arm orientation and oscillation but not congression on mitotic spindles. Journal of Cell Biology1541135–1146.

  • Li R & Murray AW1991 Feedback control of mitosis in budding yeast. Cell66519–531 [Erratum. 1994 Cell79 388].

  • Liu J & Maller JL2005 Calcium Elevation at Fertilization Coordinates Phosphorylation of XErp1/Emi2 by Plx1 and CaMK II to Release Metaphase Arrest by Cytostatic Factor. Current Biology151458–1468.

  • Lohka MJHayes MK & Maller JL1988 Purification of maturation promoting factor an intracellular regulator of early mitotic events. PNAS853009–3013.

  • Longo FJ & Chen DY1985 Development of cortical polarity in mouse eggs: Involvement of the meiotic apparatus. Developmental Biology107382–394.

  • Lorca TCruzalequi FHFesquet DCavadore J-CMéry JMeans A & Dorée M1993 Calmodulin-dependent protein kinase II mediates Ca2+- dependent inactivation of MPF and CSF activities upon the fertillization of Xenopus eggs. Nature366270–273.

  • Marangos P & Carroll J2004 The dynamics of cyclin B1 distribution during meiosis I in mouse oocytes. Reproduction128153–162.

  • Maro B & Verlhac MH2002 Polar body formation: new rules for asymmetric divisions. Nature Cell Biology4E281–E283.

  • Maro BJohnson MHPickering SJ & Flach G1984 Changes in actin distribution duringfertilization of the mouse egg. Journal of Embryology and Experimental Morphology81211–237.

  • Maro BJohnson MHWebb M & Flach G1986 Mechanism of polar body formation in the mouse oocyte: an interaction between the chromosomes the cytoskeleton and the plasma membrane. Journal of Embryology and Experimental Morphology9211–32.

  • Masui Y & Markert CL1971 Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. Journal of Experimental Zoology117129–146.

  • Matzuk MMBurns KHViveiros MM & Eppig JJ2002 Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science2962178–2180.

  • Murray AW & Kirschner MW1989 Cyclin synthesis drives the early embryonic cell cycle. Nature339275–280.

  • Ou Y & Rattner JB2004 The centrosome in higher organisms: structure composition and duplication. International Reviews in Cytology238119–182.

  • Pellestor FAnahory T & Hamamah S2005 Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes. Cytogenetics and Genome Research111206–212.

  • Polanski ZLedan EBrunet SLouvet SKubiak JZVerlhac M-H & Maro B1998 Cyclin synthesis controls the progression of meiotic maturation in mouse oocytes. Development1254989–4997.

  • Rauh NRSchmidt ABormann JNigg EA & Mayer TU2005 Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature4371048–1052.

  • Sagata NWatanabe NVan de Woude GF & Ikawa Y1989 The c-mos proto-oncogene product is a cytostatic factor responsible for meiotic arrest in vertebrate eggs. Nature342512–518.

  • Satterwhite LLLohka MJWilson KLScherson TYCisek LJCorden JL & Pollard TD1992 Phosphorylation of myosin-II regulatory light chain by cyclin-p34cdc2: a mechanism for the timing of cytokinesis. Journal of Cell Biology118595–605.

  • Schmidt ADuncan PIRauh NRSauer GFry AMNigg EA & Mayer TU2005 Xenopus polo-like kinase Plx1 regulates XErp1 a novel inhibitor of APC/C activity. Genes and Development19502–513.

  • Simerly CNowak Gde Lanerolle P & Schatten G1998 Differential expression and functions of cortical myosin IIA and IIB isotypes during meiotic maturation fertilization and mitosis in mouse oocytes and embryos. Molecular Biology of the Cell92509–2525.

  • Tay JHodgman R & Richter JD2000 The control of cyclin B1 mRNA translation during mouse oocyte maturation. Developmental Biology2211–9.

  • Taylor SSScott MI & Holland AJ2004 The spindle checkpoint: a quality control mechanism which ensures accurate chromosome segregation. Chromosome Research12599–616.

  • Terret MELefebvre CDjiane ARassinier PMoreau JMaro B & Verlhac MH2003a DOC1R: a MAP kinase substrate that control microtubule organization of metaphase II mouse oocytes. Development1305169–5177.

  • Terret MEWassmann KWaizenegger IMaro BPeters JM & Verlhac MH2003b The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity. Current Biology131797–1802.

  • Tsurumi CHoffmann SGeley SGraeser R & Polanski Z2004 The spindle assembly checkpoint is not essential for CSF arrest of mouse oocytes. Journal of Cell Biology1671037–1050.

  • Tung JJHansen DVBan KHLoktev AVSummers MKAdler JR 3rd & Jackson PK2005 A role for the anaphase-promoting complex inhibitor Emi2/XErp1 a homolog of early mitotic inhibitor 1 in cytostatic factor arrest of Xenopus eggs. PNAS1024318–4323.

  • Tunquist BJ & Maller JL2003 Under arrest: cytostatic factor (CSF)-mediated metaphase arrest in vertebrate eggs. Genes and Development17683–710.

  • Tunquist BJSchwab MSChen LG & Maller JL2002 The spindle checkpoint kinase bub1 and cyclin e/cdk2 both contribute to the establishment of meiotic metaphase arrest by cytostatic factor. Current Biology121027–1033.

  • Tunquist BJEyers PAChen LGLewellyn AL & Maller JL2003 Spindle checkpoint proteins Mad1 and Mad2 are required for cytostatic factor-mediated metaphase arrest. Journal of Cell Biology1631231–1242.

  • Van Blerkom J & Bell H1986 Regulation of development in the fully grown mouse oocyte: chromosome-mediated temporal and spatial differentiation of cytoplasm and plasma membrane. Journal of Embryology and Experimental Morphology93213–238.

  • Verlhac M-HKubiak JZClarke HJ & Maro B1994 Microtubule and chromatin behavior follow MAP kinase activity but not MPF activity during meiosis in mouse oocytes. Development1201017–1025.

  • Verlhac M-HKubiak JZWeber MGéraud GColledge WHEvans MJ & Maro B1996 Mos is required for MAP kinase activation and is involved in microtubule organisation during mouse meiosis. Development122815–822.

  • Verlhac M-HLefebvre CGuillaud PRassinier P & Maro B2000a Asymmetric division in mouse oocytes: with or without Mos. Current Biology101303–1306.

  • Verlhac M-HLefebvre CKubiak JZUmbhauer MRassinier PColledge W & Maro B2000b Mos activates MAP kinase in mouse oocytes through two opposite pathways. EMBO Journal196065–6074.

  • Vernos IRaats JHirano THeasman JKarsenti E & Wylie C1995 Xklp1 a chromosomal Xenopus kinesin-like protein essential for spindle organization and chromosome positioning. Cell81117–127.

  • Vinot SLe TMaro B & Louvet-Vallée S2004 Two PAR6 proteins become asymmetricallylocalized during establishment of polarity in mouse oocytes. Current Biology14520–525.

  • Wassmann KNiault T & Maro B2003 Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Current Biology131596–1608.

  • Webb MHowlett SK & Maro B1986 Parthenogenesis and cyto-skeletal organization in ageing mouse eggs. Journal of Embryology and Experimental Morphology95131–145.

  • Weber KLSokac AMBerg JSCheney RE & Bement WM2004 A microtubule-binding myosin required for nuclear anchoring and spindle assembly. Nature431325–329.

  • Winston NJ1997 Stability of cyclin B protein during meiotic maturation and the first meiotic cell cycle division in mouse oocyte. Biology of the Cell89211–219.

  • Winston NJ & Maro B1995 Calmodulin-dependent protein kinase II is activated transiently in ethanol-stimulated mouse oocytes. Developmental Biology170350–352.

  • Winston NJMcGuinness OJohnson MH & Maro B1995 The exit of mouse oocytes from meiotic M-phase requires an intact spindle during intracellular calcium release. Journal of Cell Science108143–151.

  • Wittmann TWilm MKarsenti E & Vernos I2000 TPX2 A novel xenopus MAP involved in spindle pole organization. Journal of Cell Biology1491405–1418.

  • Yang HYMains PE & McNally FJ2005 Kinesin-1 mediates translocation of the meiotic spindle to the oocyte cortex through KCA-1 a novel cargo adapter. Journal of Cell Biology169447–457.

  • Zheng Y2004 G protein control of microtubule assembly. Annual Reviews of Cell and Developmental Biology20867–894.

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An official journal of

Society for Reproduction and Fertility

Sections

Figures

  • View in gallery

    The cellular events of meiotic maturation in mouse oocytes. At GVBD (first row), microtubules (in green) polymerize radially around the mass of chromosomes and organize progressively into a bipolar spindle. At the end of MI (second row), the bipolar spindle migrates toward the oocyte cortex. Spindle migration induces the local reorganization of the cortex of the oocyte (red and pink area). The first polar body is extruded in the axis of spindle migration. During MII arrest (third row), the metaphase spindle is anchored under the plasma membrane. The cortex reorganization is maintained in the vicinity of the spindle. Fertilization or experimental activation of the oocyte triggers a 90° spindle rotation and the extrusion of the second polar body.

  • View in gallery

    Chromosomes monitor MI spindle assembly in mouse oocyte. Chromosomes (in blue) locally restrain the assembly and organization of microtubules. MTOCs (in dark green) are locally activated and RanGTP (blue gradient) triggers the polymerization of microtubules around the chromosomes (in light green). The microtubules progressively organize into a bipolar structure around the chromosomes. The kinetochores associated with the bivalents are inactive during most of the MI (light blue discs). As a consequence, bivalents migration toward the spindle equator is achieved by direct interactions between chromosome arms and spindle microtubules. At the end of MI, kinetochores are activated (yellow discs) and become able to anchor microtubules and form kinetochore fibers (in dark green): the complete formation of K-fiber correlates with a brief meta-phase transition and triggers anaphase onset.

  • View in gallery

    MPF and MAPK activities during meiotic maturation in mouse oocytes. MPF activity appears as a red line and MAPK as a green line. The different steps of meiotic maturation are schematized as in Figure 1.

  • View in gallery

    Cyclin B synthesis controls the timing of meiotic maturation through the level of MPF activity.

  • View in gallery

    The metaphase II arrest in mouse oocytes. The components and interactions shown in grey remain to be discovered.

References

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D’Amours D & Amon A2004 At the interface between signaling and executing anaphase–Cdc14 and the FEAR network. Genes and Development182581–2595.

de Moor CH & Richter JD1999 Cytoplasmic polydenylation elements mediate masking and unmasking of cyclin B1 mRNA. EMBO Journal182294–2303.

de Pennart HHouliston E & Maro B1988 Post-translational modifications of tubulin and the dynamics of microtubules in mouse oocytes and zygotes. Biology of the Cell64375–378.

Deng MWilliams CJ & Schultz RM2005 Role of MAP kinase and myosin light chain kinase in chromosome-induced development of mouse egg polarity. Developmental Biology278358–366.

Diaz H & Esponda P2004 Ageing-induced changes in the cortical granules of mouse eggs. Zygote1295–103.

Doree M & Hunt T2002 From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? Journal of Cell Science1152461–2464.

Dumont JUmbhauer MRassinier PHanauer A & Verlhac MH2005 p90Rsk is not involved in cytostatic factor arrest in mouse oocytes. Journal of Cell Biology169227–231.

Evans TRosenthal ETYoungblom JDistel D & Hunt T1983 Cyclin: A protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell33389–396.

Funabiki H & Murray AW2000 The Xenopus chromokinesin Xkid is essential for metaphase chromosome alignment and must be degraded to allow anaphase chromosome movement. Cell102411–424.

Glotzer MMurray AW & Kirschner MW1991 Cyclin is degraded by the ubiquitin pathway. Nature349132–138.

Gorbsky GJSimerly CSchatten G & Borisy GG1990 Microtubules in the metaphase-arrested mouse oocyte turn over rapidly. PNAS876049–6053.

Gross SDSchwab MSLewellyn AL & Maller JL1999 Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk. Science2861365–1367.

Gruss OJCarazo-Salas RESchatz CAGuarguaglini GKast JWilm MLe Bot NVernos IKarsenti E & Mattaj IW2001 Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity. Cell10483–93.

Haccard OSarcevic BLewellyn AHartley RRoy LIzumi TErikson E & Maller JL1993 Induction of metaphase arrest in cleaving xenopus embryos by MAP kinase. Science2621262–1265.

Hampl A & Eppig JJ1995 Translational regulation of the gradual increase in histone H1 kinase activity in maturing mouse oocytes. Molecular Reproduction and Development409–15.

Hashimoto N & Kishimoto T1988 Regulation of meiotic metaphase by a cytoplasmic maturation-promoting factor during mouse oocyte maturation. Developmental Biology126242–252.

Hashimoto NWatanabe NFuruta YTamemoto HSagata NYokoyama MOkazaki KNagayoshi MTakeda NIkawatll Y & Aizawai S1994 Parthenogenetic activation of oocytes in c-mos-deficient mice. Nature37068–71.

Hassold T & Hunt P2001 To err (meiotically) is human: the genesis of human aneuploidy. Nature Reviews Genetics2280–291.

Herbert MLevasseur MHomer HYallop KMurdoch A & McDougall A2003 Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nature Cell Biology51023–1025.

Hershko AGanoth DPehrson JPalazzo RE & Cohen LH1991 Methylated ubiquitin inhibits cyclin degradation in clam embryo extracts. Journal of Biological Chemistry26616376–16379.

Hetzer MGruss OJ & Mattaj IW2002 The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nature Cell Biology4E177–E184.

Homer HAMcDougall ALevasseur MYallop KMurdoch AP & Herbert M2005 Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes and Development19202–207.

Hoyt MATotis L & Roberts BT1991S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell66507–517.

Johnson MHEager DMuggleton-Harris AL & Graves HM1975 Mosaicism in the organisation of concanavalin A receptors on surface membrane of mouse eggs. Nature257321–322.

Kalab PWeis K & Heald R2002 Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science2952452–2456.

Kalab PKubiak JZVerlhac M-HColledge WH & Maro B1996 Activation of p90rsk during meiotic maturation and first mitosis in mouse oocytes and eggs: MAP kinase-independent and dependent activation. Development1221957–1964.

Karsenti E & Vernos I2001 The mitotic spindle: a self-made machine. Science294543–547.

Kubiak JZWeber Mde Pennart HWinston NJ & Maro B1993 The metaphase II arrest in mouse oocytes is controlled through microtubule-dependent destruction of cyclin B in the presence of CSF. EMBO Journal123773–3778.

Leader BLim HCarabatsos MJHarrington AEcsedy JPellman DMaas R & Leder P2002 Formin-2 polyploidy hypofertility and positioning of the meiotic spindle in mouse oocytes. Nature Cell Biology4921–928.

Ledan EPolanski ZTerret M-E & Maro B2001 Meiotic maturation of the mouse oocyte requires an equilibrium between cyclin B synthesis and degradation. Developmental Biology232400–413.

Lefebvre CTerret MEDjiane ARassinier PMaro B & Verlhac MH2002 Meiotic spindle stability depends on MAPK-interacting and spindle-stabilizing protein (MISS) a new MAPK substrate. Journal of Cell Biology157603–613.

Levesque AA & Compton DA2001 The chromokinesin Kid is necessary for chromosome arm orientation and oscillation but not congression on mitotic spindles. Journal of Cell Biology1541135–1146.

Li R & Murray AW1991 Feedback control of mitosis in budding yeast. Cell66519–531 [Erratum. 1994 Cell79 388].

Liu J & Maller JL2005 Calcium Elevation at Fertilization Coordinates Phosphorylation of XErp1/Emi2 by Plx1 and CaMK II to Release Metaphase Arrest by Cytostatic Factor. Current Biology151458–1468.

Lohka MJHayes MK & Maller JL1988 Purification of maturation promoting factor an intracellular regulator of early mitotic events. PNAS853009–3013.

Longo FJ & Chen DY1985 Development of cortical polarity in mouse eggs: Involvement of the meiotic apparatus. Developmental Biology107382–394.

Lorca TCruzalequi FHFesquet DCavadore J-CMéry JMeans A & Dorée M1993 Calmodulin-dependent protein kinase II mediates Ca2+- dependent inactivation of MPF and CSF activities upon the fertillization of Xenopus eggs. Nature366270–273.

Marangos P & Carroll J2004 The dynamics of cyclin B1 distribution during meiosis I in mouse oocytes. Reproduction128153–162.

Maro B & Verlhac MH2002 Polar body formation: new rules for asymmetric divisions. Nature Cell Biology4E281–E283.

Maro BJohnson MHPickering SJ & Flach G1984 Changes in actin distribution duringfertilization of the mouse egg. Journal of Embryology and Experimental Morphology81211–237.

Maro BJohnson MHWebb M & Flach G1986 Mechanism of polar body formation in the mouse oocyte: an interaction between the chromosomes the cytoskeleton and the plasma membrane. Journal of Embryology and Experimental Morphology9211–32.

Masui Y & Markert CL1971 Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. Journal of Experimental Zoology117129–146.

Matzuk MMBurns KHViveiros MM & Eppig JJ2002 Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science2962178–2180.

Murray AW & Kirschner MW1989 Cyclin synthesis drives the early embryonic cell cycle. Nature339275–280.

Ou Y & Rattner JB2004 The centrosome in higher organisms: structure composition and duplication. International Reviews in Cytology238119–182.

Pellestor FAnahory T & Hamamah S2005 Effect of maternal age on the frequency of cytogenetic abnormalities in human oocytes. Cytogenetics and Genome Research111206–212.

Polanski ZLedan EBrunet SLouvet SKubiak JZVerlhac M-H & Maro B1998 Cyclin synthesis controls the progression of meiotic maturation in mouse oocytes. Development1254989–4997.

Rauh NRSchmidt ABormann JNigg EA & Mayer TU2005 Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature4371048–1052.

Sagata NWatanabe NVan de Woude GF & Ikawa Y1989 The c-mos proto-oncogene product is a cytostatic factor responsible for meiotic arrest in vertebrate eggs. Nature342512–518.

Satterwhite LLLohka MJWilson KLScherson TYCisek LJCorden JL & Pollard TD1992 Phosphorylation of myosin-II regulatory light chain by cyclin-p34cdc2: a mechanism for the timing of cytokinesis. Journal of Cell Biology118595–605.

Schmidt ADuncan PIRauh NRSauer GFry AMNigg EA & Mayer TU2005 Xenopus polo-like kinase Plx1 regulates XErp1 a novel inhibitor of APC/C activity. Genes and Development19502–513.

Simerly CNowak Gde Lanerolle P & Schatten G1998 Differential expression and functions of cortical myosin IIA and IIB isotypes during meiotic maturation fertilization and mitosis in mouse oocytes and embryos. Molecular Biology of the Cell92509–2525.

Tay JHodgman R & Richter JD2000 The control of cyclin B1 mRNA translation during mouse oocyte maturation. Developmental Biology2211–9.

Taylor SSScott MI & Holland AJ2004 The spindle checkpoint: a quality control mechanism which ensures accurate chromosome segregation. Chromosome Research12599–616.

Terret MELefebvre CDjiane ARassinier PMoreau JMaro B & Verlhac MH2003a DOC1R: a MAP kinase substrate that control microtubule organization of metaphase II mouse oocytes. Development1305169–5177.

Terret MEWassmann KWaizenegger IMaro BPeters JM & Verlhac MH2003b The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity. Current Biology131797–1802.

Tsurumi CHoffmann SGeley SGraeser R & Polanski Z2004 The spindle assembly checkpoint is not essential for CSF arrest of mouse oocytes. Journal of Cell Biology1671037–1050.

Tung JJHansen DVBan KHLoktev AVSummers MKAdler JR 3rd & Jackson PK2005 A role for the anaphase-promoting complex inhibitor Emi2/XErp1 a homolog of early mitotic inhibitor 1 in cytostatic factor arrest of Xenopus eggs. PNAS1024318–4323.

Tunquist BJ & Maller JL2003 Under arrest: cytostatic factor (CSF)-mediated metaphase arrest in vertebrate eggs. Genes and Development17683–710.

Tunquist BJSchwab MSChen LG & Maller JL2002 The spindle checkpoint kinase bub1 and cyclin e/cdk2 both contribute to the establishment of meiotic metaphase arrest by cytostatic factor. Current Biology121027–1033.

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