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cyclin- B mRNA by deadenylation, and studies in cycling Xenopus egg extract iden-
tified maskin as an important regulator in this process (Groisman et al. 2002 ).
To allow cyclin-B to accumulate during M-phase, the APC/C must be kept in an
inhibited state. It is known that, in Xenopus, inhibitory mechanisms such as the SAC and
the inhibitory protein Emi1 are not present till MBT (Ohsumi et al. 2004 ; Gerhart et al.
1984 ) raising the question of how APC/C regulation is achieved in such a scenario.
Studies in Xenopus embryos revealed that the function of XErp1/Emi2 as an APC/C
inhibitor is critical for early embryonic divisions (Tischer et al. 2012 ). Depletion of
XErp1 results in slower division cycles and untimely destruction of cyclin-B, ultimately
resulting in death at MBT (Tischer et al. 2012 ; Vinod et al. 2013 ). Since XErp1 protein
levels remain constant until MBT, its activity must be regulated in a posttranslational
manner (Tischer et al. 2012 ; Inoue et al. 2007 ). As aforementioned (see Sect. 3.5.2),
during the metaphase II arrest, the activity of XErp1 is controlled such that increasing
concentrations of cyclin-B result in XErp1 phosphorylation and inactivation which leads
to APC/C-mediated destruction of cyclin-B until a lower threshold of cyclin-B is
reached, which allows the reactivation of XErp1 and, hence, APC/C re-inhibition. The
basic concept of Cdk1/cyclin- B- mediated XErp1 inactivation also applies to the fast
embryonic cycles with the following modifications. First, since c-Mos is absent during
the fast embryonic divisions, the recruitment of XErp1 to PP2A-B ́56 which antago-
nises Cdk1/cyclin-B phosphorylations is not mediated by p90RSK—the downstream
component of the MAPK pathway—but by PKA. Second, to ensure oscillating APC/C
activity, the system must work as a switch rather than as a thermostat. Based on studies
performed in extracts of Xenopus embryos, the following model was proposed: During
S-phase when Cdk1/cyclin-B activity is low, XErp1 can bind to and inhibit the APC/C
resulting in the accumulation of cyclin-B. As cyclin-B levels rise, Cdk1 activity increases
and the embryo enters M-phase. At this level of Cdk1/cyclin-B activity, PP2A-B ́56
recruited to XErp1 is capable of antagonising the inhibitory phosphorylations of Cdk1/
cyclin-B. Once the activity of Cdk1/cyclin-B reaches an upper threshold, it prevails over
PP2A-B ́56 resulting in the dissociation of XErp1 from the APC/C and hence anaphase
onset. While this model nicely explains entry into M-phase and the transition into ana-
phase, it remains elusive how XErp1 is kept inactive during exit from M-phase despite
the fact that Cdk1 activity decreases due to cyclin-B destruction. Such a mechanism has
to exist to ensure efficient cyclin-B destruction and avoid futile cycles of XErp1 inactiva-
tion and reactivation.
In mice, ZGA occurs at the two-cell stage and is followed by cleavage cycles, which
are asynchronous (Gamow and Prescott 1970 ), giving rise to the blastocyst composed of
the ICM and the trophoblast. The ICM contains pluripotent stem cells (ES cells) that
will form the embryo proper, whereas the trophoblast will form part of the pla-
centa (Ciemerych and Sicinski 2005 ). The cell cycle programme of the pluripotent ES
cells of the ICM and trophoblast cells is clearly distinct. Trophoblast cells undergo mul-
tiple rounds of endoreduplication to amplify their genomes to up to 500-fold (Barlow
and Sherman 1972 ; Varmuza et al. 1988 ), whereas the stem cells arising from the ICM
maintain their diploid state by undergoing rapid mitotic division cycles with short G1
and G2 phases (Fujii-Yamamoto et al. 2005 ). The striking difference in the cell cycle
programme of pluripotent ICM cells and trophoblast cells might be attributed to a dif-
ferentially regulated activity of the APC/C. Initial studies suggested that cell cycles in
A. Heim et al.