Delayed APC/C activation extends the first mitosis of mouse embryos

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Ajduk, A 
Strauss, B 
Pines, J 
Zernicka-Goetz, Magdalena  ORCID logo

The correct temporal regulation of mitosis underpins genomic stability because it ensures the alignment of chromosomes on the mitotic spindle that is required for their proper segregation to the two daughter cells. Crucially, sister chromatid separation must be delayed until all the chromosomes have attached to the spindle; this is achieved by the Spindle Assembly Checkpoint (SAC) that inhibits the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. In many species the first embryonic M-phase is significantly prolonged compared to the subsequent divisions, but the reason behind this has remained unclear. Here, we show that the first M-phase in the mouse embryo is significantly extended due to a delay in APC/C activation. Unlike in somatic cells, where the APC/C first targets cyclin A2 for degradation at nuclear envelope breakdown (NEBD), we find that in zygotes cyclin A2 remains stable for a significant period of time after NEBD. Our findings that the SAC prevents cyclin A2 degradation, whereas over-expressed Plk1 stimulates it, support our conclusion that the delay in cyclin A2 degradation is caused by low APC/C activity. As a consequence of delayed APC/C activation cyclin B1 stability in the first mitosis is also prolonged, leading to the unusual length of the first M-phase.

Anaphase-Promoting Complex-Cyclosome, Animals, Biomarkers, Cyclin A2, Cyclin B1, Embryonic Development, Gene Expression, Gene Expression Regulation, Developmental, Genes, Reporter, M Phase Cell Cycle Checkpoints, Mice, Mitosis, Proteolysis, Transcriptional Activation
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Scientific Reports
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Nature Publishing Group
Wellcome Trust (098287/Z/12/Z)
Medical Research Council (G1000818)
Medical Research Council (G0701184)
Wellcome Trust (064421/Z/01/A)
Isaac Newton Trust (MINUTE 726(K))
We are grateful to the Wellcome Trust, which supported this work. AA was a beneficiary of the Kolumb programme and the subsequent Kolumb supporting grant of the Foundation for Polish Science. MZG is supported by the Wellcome Trust.