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Aurora-A kinase (AURKA), a member of the serine/threonine protein kinase family, is involved in multiple steps of mitotic progression. It regulates centrosome maturation, mitotic spindle formation, and cytokinesis. While studied extensively in somatic cells, little information is known about AURKA in the early cleavage mouse embryo with respect to acentrosomal spindle assembly. In vitro experiments in which AURKA was inactivated with specific inhibitor MLN8237 during the early stages of embryogenesis documented gradual arrest in the cleavage ability of the mouse embryo. In the AURKA-inhibited 1-cell embryos, spindle formation and anaphase onset were delayed and chromosome segregation was defective. AURKA inhibition increased apoptosis during early embryonic development. In conclusion these data suggest that AURKA is essential for the correct chromosome segregation in the first mitosis as a prerequisite for normal later development after first cleavage.
Polo-like kinase 1 (PLK1) is involved in essential events of cell cycle including mitosis in which it participates in centrosomal microtubule nucleation, spindle bipolarity establishment and cytokinesis. Although PLK1 function has been studied in cycling cancer cells, only limited data are known about its role in the first mitosis of mammalian zygotes. During the 1-cell stage of mouse embryo development, the acentriolar spindle is formed and the shift from acentriolar to centrosomal spindle formation progresses gradually throughout the preimplantation stage, thus providing a unique possibility to study acentriolar spindle formation. We have shown previously that PLK1 activity is not essential for entry into first mitosis, but is required for correct spindle formation and anaphase onset in 1-cell mouse embryos. In the present study, we extend this knowledge by employing quantitative confocal live cell imaging to determine spindle formation kinetics in the absence of PLK1 activity and answer the question whether metaphase arrest at PLK1-inhibited embryos is associated with low anaphase-promoting complex/cyclosome (APC/C) activity and consequently high securin level. We have shown that inhibition of PLK1 activity induces a delay in onset of acentriolar spindle formation during first mitosis. Although these PLK1-inhibited 1-cell embryos were finally able to form a bipolar spindle, not all chromosomes were aligned at the metaphase equator. PLK1-inhibited embryos were arrested in metaphase without any sign of APC/C activation with high securin levels. Our results document that PLK1 controls the onset of spindle assembly and spindle formation, and is essential for APC/C activation before anaphase onset in mouse zygotes.
The cell-cycle regulators that control meiotic divisions also regulate the events that accompany the oocyte-to-zygote transition. Thus, the meiotic machinery functions as an internal pacemaker that propels the oocyte toward embryogenesis. The preimplantation embryo expresses a number of receptors that are important for initial activity of the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt/PKB) pathway. The complete PI3K-Akt/PKB-CDK1 cascade is implicated as a key regulator of a number of cellular functions. Selective inhibition of protein kinase B (Akt/PKB) with inhibitor SH6 and cyclin-dependent kinase 1 (CDK1) with inhibitor roscovitine arrest development of the 1-cell preimplantation mouse embryo before entry into the first mitosis. The pronuclei of these inhibited embryos migrate to one another, but do not progress to pronuclei envelope breakdown and pronuclear fusion running immediately before the onset of mitosis. SH6-treated 1-cell mouse embryos showed a high occurrence of apoptosis features (nuclear fragmentation, positive terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), active caspase-3 in both cytoplasm and nucleoplasm). In the Akt/PKB-inhibited embryos, the active phosphorylated form Ser473Akt/PKB was not detected in pronuclear areas when compared with inhibitor-free controls. Although CDK1-inhibited 1-cell embryos also failed to enter into the first mitosis, the presence of apoptotic cell death features was not observed. In the roscovitine-treated embryos, Ser473Akt/PKB was detected in the pronuclei independently of CDK1 activity. We conclude that Akt/PKB plays an important role during entry of the 1-cell mouse embryo into the first mitosis, and probably functions as a relay in the cell-cycle stage. We assume that Akt/PKB is the primary target responsible for mediating anti-apoptotic signals in the 1-cell mouse embryo.
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