The role of APC/C inhibitor Emi2/XErp1 in oscillatory dynamics of early embryonic cell cycles.
Vinod PK., Zhou X., Zhang T., Mayer TU., Novak B.
The early embryonic Xenopus cell cycles are characterized by alternating oscillations of Cyclin-dependent kinase-1 (Cdk1) and Anaphase Promoting Complex/Cyclosome (APC/C) activities. The early cycles before midblastula transition lack significant inhibitory Cdk1 phosphorylations and are driven by periodic accumulation of Cyclin B before M phase and its degradation by APC/C at the end of M phase. Both experiments and mathematical modelling suggest that while Cdk1:CycB phosphorylation activates APC/C, it inhibits its co-activator Cdc20 (Fizzy). These interactions create an amplified negative-feedback loop which is at the heart of all cell cycle oscillations. Recent experiments find that the APC/C inhibitor, Emi2/XErp1 is essential for large amplitude and short period Cyclin B oscillations during early divisions in the intact Xenopus embryo. This finding is counter-intuitive since larger amplitudes should come with slower cycle times. We explain this paradox by analysing the amplified negative feedback model extended with APC/C inhibition by Emi2. We show that Emi2 interferes with the intrinsic time-delay in APC/C activation and inactivation to increase the amplitude as well as shorten the period of Cyclin B oscillation.