8
arrives when a surge of luteinizing hormone (LH), produced by the pituitary gland,
binds to its receptor on the follicular cells surrounding the oocyte. In teleosts, LH
triggers the production of the maturation-inducing hormone (MIH) in the granulosa
cells (Patiño and Sullivan 2002 ). In amphibians, the synthesis of another steroid
hormone, progesterone, is stimulated (Elinson 1997 ), whereas in mammals LH
induces the removal of a follicular inhibitor (Dupré et al. 2011 ). Although the sig-
nals are different between animal groups, they all activate signaling pathways in the
oocyte that act on the same target: they stimulate a burst in the activity of CDK1. As
mentioned above, CDK1 gains activity when it forms a complex with cyclin B1,
thereby generating MPF. During the prophase I arrest, MPF activity is low, proba-
bly because of limited availability of CDK1 and cyclin B1. Low levels of both
subunits are the major determining factors for the maintenance of the first meiotic
arrest in large mammals where protein translation is essential for the resumption of
meiosis I (Mattioli et al. 1991 ; Tatemoto and Horiuchi 1995 ).
Once the oocyte reaches its final size, an additional mechanism helps to maintain
the meiotic arrest. Cyclic adenosine monophosphate (cAMP), whose level in the
ooplasm is tightly controlled by the granulosa cells, becomes a key regulator of
CDK1 activity (Bornslaeger et al. 1986 ). High concentrations of cAMP are needed
for the meiotic arrest; this has been demonstrated in mice, where removing the
immature oocyte from the follicle leads to an abrupt reduction in ooplasmic cAMP
levels and also to meiotic resumption (Conti et al. 1998 ). The cumulus cells control
ooplasmic cAMP levels by transferring cyclic guanosine monophosphate (cGMP)
to the oocyte through cytoplasmic projections across the zona pellucida. cGMP
blocks phosphodiesterase 3A, an enzyme that can hydrolyze (and destroy) cAMP
(Masciarelli et al. 2004 ). By inhibiting its hydrolysis, cGMP maintains high cAMP
levels in the ooplasm. The connection between the CDK1 and cAMP pathways is
provided by a serine/threonine kinase, protein kinase A (PKA). In somatic cells,
cAMP can bind PKA, which in turn phosphorylates (and activates) WEE1B and
MYT1 kinases. PKA can also phosphorylate the phosphatase CDC25, which as a
result becomes inhibited (Kirschner et al. 2009 ). WEE1B and MYT1 are known to
block CDK1, while CDC25 is responsible for CDK1 activation (Morgan 1995 ).
Thus, cAMP-dependent activation of PKA results in CDK1 inhibition through two
separate pathways: activation of the CDK1 inhibitors WEE1B and MYT1 and inhi-
bition of the CDK1 activator CDC25. During the meiotic arrest, high levels of
cAMP stimulate PKA. Active PKA promotes WEE1B activity and at the same time
inhibits the action of CDC25; high WEE1B activity combined with CDC25 inhibi-
tion leads to phosphorylated (i.e., inactive) CDK1 and the maintenance of meiotic
arrest. In response to the ovulatory LH surge, the amount of cGMP transferred from
the cumulus cells drops, partly because of reduced production and partly because of
the closure of gap junctions between the cumulus cells and the oocyte. The subse-
quent increase in phosphodiesterase activity causes a dramatic drop in cAMP levels
that results in inactive PKA. In the absence of functional PKA, WEE1B activity
drops and CDC25 activity increases. This causes the dephosphorylation and activa-
tion of CDK1 that favors meiotic resumption.
Z. Machaty et al.