Vertebrate Development Maternal to Zygotic Control (Advances in Experimental Medicine and Biology)

31

on the MPF machinery. It was demonstrated that Ca2+ mobilized from the endoplas-
mic reticulum binds calmodulin, a Ca2+-binding messenger protein located in the
cytoplasm. Ca2+-calmodulin then stimulates calmodulin-dependent protein kinase II
(CaMKII), an important transducer of Ca2+ signals (Lorca et al. 1993 ). In mamma-
lian oocytes, CaMKII activity increases at fertilization: the activity oscillates in
synchrony with the repetitive Ca2+ signal (Markoulaki et al. 2004 ). In turn, activated
CaMKII phosphorylates Emi. In Xenopus it was demonstrated that this creates a
docking site for polo-like kinase that further phosphorylates Emi, causing its
destruction through ubiquitination by the E3 ligase Skpl-Cullin-F-box protein (Liu
and Maller 2005 ). With the degradation of Emi the APC is relieved from inhibition.
Active APC stimulates the ubiquitination and destruction of cyclin B. In mouse
eggs, cyclin B1 undergoes proteolysis soon after the initiation of the sperm-induced
Ca2+ signal (Nixon et al. 2002 ). In the absence of its regulatory subunit, MPF loses
its activity, the cell cycle is resumed, and meiosis progresses to anaphase. The
importance of this cascade has been demonstrated in mouse oocytes, where Emi
levels drop after parthenogenetic activation (Madgwick et al. 2006 ), and constitu-
tively active CaMKII is able to stimulate embryo development to the blastocyst
stage (Knott et al. 2006 ). In the metaphase II-arrested Xenopus egg, MPF ensures
Mos stability through phosphorylation on its Ser3 residues; therefore, the inactiva-
tion of MPF at this point leads to the dephosphorylation of Mos and its destruction
through a yet unidentified ubiquitin ligase (Castro et al. 2001 ) (Fig. 1.4).

Release from

MII arrest

Pronucleus

formation

Inactive MPF

MII Arrest

Ubiquitin/proteasome

Ca2+(eg. CaM/CaMKII) dependent proteins

Cortical granule release

Active MPF Ca2+ Oscillations

Polar Body

APC/C

Cdk1

Cyclin B1

Cdk1

Cdk1

UU

UUU

Cyc lin B1

Cyclin B1 CSF

MAPK

Fig. 1.4 Schematic illustration of the signaling pathway, downstream of the sperm-induced Ca2+
release, that triggers meiotic resumption and the initiation of embryo development (From Kashir
et al. 2012 , with permission)

1 Egg Activation at Fertilization

http://www.ebook3000.com