9Proper timing of meiotic reentry is so critical that the oocyte applies yet another
mechanism to keep the cell cycle under arrest. This mechanism limits CDK1 activ-
ity by curtailing cyclin B1 levels in the cytoplasm. Protein degradation during the
metaphase-anaphase transition is controlled by the anaphase-promoting complex
(APC), a multisubunit E3 ligase. APC ubiquitinates protein substrates that marks
them for destruction by the 26S proteasome (Peters 2006 ). For activity, APC requires
the binding of a cofactor protein, either CDC20 or FZR1. In GV-stage mouse
oocytes, it is FZR1 that activates APC: oocytes lacking FZR1 undergo premature
germinal vesicle breakdown (GVBD) due to the absence of APC-mediated cyclin
B1 degradation (Holt et al. 2011 ). FZR1 is positively regulated by the phosphatase
CDC14B and inhibited by the early mitotic inhibitor (Emi). It has been demon-
strated that overexpression of CDC14B in mouse oocytes causes a delay in meiotic
resumption (Schindler and Schultz 2009 ), whereas microinjection of excess Emi
accelerates the reinitiation of meiosis and arrests the oocyte at the first metaphase
(Marangos et al. 2007 ). Thus, oocytes achieve a delicate balance between high and
low cyclin B1 levels via APC regulation: they maintain the arrest at the first pro-
phase through APC-/FZR1-mediated cyclin B1 degradation; increasing cyclin B
synthesis will eventually outweigh destruction by APC, and this leads to elevated
CDK1 activity and the induction of GVBD (Holt et al. 2013 ).
Similar to the presence of multiple control pathways in somatic cell division, yet
another mechanism is involved in the regulation of the cell cycle during oocyte
maturation. In Xenopus oocytes progesterone, the physiological inducer of meiotic
divisions, triggers the translation of mRNAs stored in the oocyte. Within 2–3 h of
progesterone stimulation, the production of the Mos protein begins and accumulates
during maturation. Mos is the product of the proto-oncogene c-mos and functions as
a Ser/Thr kinase in a meiosis-specific manner (reviewed by Dupré et al. 2011 ). Mos
appeared early during evolution as an oocyte-expressed kinase and functioned
ancestrally in the control of female meiosis (Amiel et al. 2009 ). It can stimulate
mitogen-activated protein kinase (MAPK) by directly phosphorylating and activat-
ing MEK, an immediate upstream activator of MAPK. The downstream target of
MAPK is p90Rsk, and together the activity of the Mos/MEK/MAPK/p90Rsk cascade
is known as the cytostatic factor (CSF). At the onset of oocyte maturation in
Xenopus, Mos production begins before the increase in MPF activity. Based on this
observation, it has been suggested that Mos, along with its downstream effectors, is
an activator of MPF (Sagata et al. 1988 ). In the mouse and rat, Mos synthesis is also
stimulated in the maturing oocyte, but its accumulation takes place only after MPF
is activated (Verlhac et al. 1993 ; Tan et al. 2001 ). This implies that Mos is not
required for MPF activation. These seemingly conflicting observations can be rec-
onciled in the light of the findings that although Mos synthesis begins soon after
progesterone stimulation, the protein remains unstable and cannot stimulate MAPK
until MPF is activated. Once activated, MPF stabilizes Mos via phosphorylation at
conserved serine residues (Freeman et al. 1992 ), which prevents it from being rec-
ognized by its ubiquitin ligase. Thus, Mos gains activity only after MPF activation
in both cases: it needs to be stabilized by MPF despite an early appearance in
Xenopus oocytes, whereas it is produced only after MPF activation in the mouse
1 Egg Activation at Fertilization