Abstract
Oocytes from higher chordates, including man and nearly all mammals, arrest at metaphase of the second meiotic division before fertilization. This arrest is due to an activity that has been termed 'Cytostatic Factor'. Cytostatic Factor maintains arrest through preventing loss in Maturation-Promoting Factor (MPF; CDK1/cyclin B). Physiologically, Cytostatic Factor – induced metaphase arrest is only broken by a Ca2+ rise initiated by the fertilizing sperm and results in degradation of cyclin B, the regulatory subunit of MPF through the Anaphase-Promoting Complex/Cyclosome (APC/C). Arrest at metaphase II may therefore be viewed as being maintained by inhibition of the APC/C, and Cytostatic Factor as being one or more pathways, one of which inhibits the APC/C, consorting in the preservation of MPF activity.Many studies over several years have implicated the c-Mos/MEK/MAPK pathway in the metaphase arrest of the two most widely studied vertebrates, frog and mouse. Murine downstream components of this cascade are not known but in frog involve members of the spindle assembly checkpoint, which act to inhibit the APC/C. Interesting these downstream components appear not to be involved in the arrest of mouse eggs, suggesting a lack of conservation with respect to c-Mos targets. However, the recent discovery of Emi2 as an egg specific APC/C inhibitor whose degradation is Ca2+ dependent has greatly increased our understanding of MetII arrest. Emi2 is involved in both the establishment and maintenance of metaphase II arrest in frog and mouse suggesting a conservation of metaphase II arrest. Its identity as the physiologically relevant APC/C inhibitor involved in Cytostatic Factor arrest prompted us to re-evaluate the role of the c-Mos pathway in metaphase II arrest.This review presents a model of Cytostatic Factor arrest, which is primarily induced by Emi2 mediated APC/C inhibition but which also requires the c-Mos pathway to set MPF levels within physiological limits, not too high to induce an arrest that cannot be broken, or too low to induce parthenogenesis.
Highlights
Meiosis is a process in which two consecutive cell divisions (MI and MII) occur in the absence of an intervening S-phase
This review presents a model of Cytostatic Factor arrest, which is primarily induced by Emi2 mediated Anaphase-Promoting Complex/Cyclosome (APC/C) inhibition but which requires the c-Mos pathway to set Maturation-Promoting Factor (MPF) levels within physiological limits, not too high to induce an arrest that cannot be broken, or too low to induce parthenogenesis
A unifying hypothesis would be useful which invokes most of the Cytostatic Factor (CSF) candidates described in both mouse and
Summary
Meiosis is a process in which two consecutive cell divisions (MI and MII) occur in the absence of an intervening S-phase. It is possible to exit CSF mediated MetII arrest by inhibiting the CDK1 component of MPF [21,22], physiologically a sperm Ca2+ signal induces loss of cyclin B rather than CDK1 inactivation. Bub1 [34], Mad and Mad2 [35] all appear to be required downstream of c-Mos given that the immunodepletion of these proteins blocked the establishment of CSF arrest by c-Mos in frog egg extracts. Whilst the c-Mos/MEK/MAPK/p90rsk/(SAC proteins) pathway is well established in the frog, its role in mammalian eggs is less clear. The c-Mos/MEK/MAPK pathway acting independently of p90rsk is likely only to be involved in helping maintaining MetII arrest in mammals, rather than having a direct role in its establishment. Emi appears to be essential for the establishment of arrest in frog eggs [92,93] suggesting a conserved mechanism in vertebrates
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