Embryonic M phase

Interestingly, prolonged duration of the first embryonic M phase is also observed in other mammalian and non-mammalian embryos. It was found in rabbit embryos (X. Yang M. Deng, personal communication) and in sea urchin embryos (J. Z. Kubiak P. Cormier, unpublished observation). Further studies will show whether it is a rule during animal development. 

FIG. 4. Hypothetical action of the cyclin A2-dependent mechanism retarding exit from the first embryonic M phase in the mouse. 

The very beginning of the first mitotic cell cycle of the mouse embryo seems to be controlled by the mechanisms characteristic for both meiotic and mitotic cell cycles. Active MAP kinase, its substrate p90rsk and the CSF activity itself could influence the cellular processes within the one-cell embryo. Indeed, we have observed that despite the entry into the interphase (as judged by the low activity of MPF) some proteins are actively phosphorylated as during the meiotic M phase (e.g. 35 kDa complex Howlett et al 1986, Szollosi et al 1993), the nuclei and the microtubule interphase network start to form only 1.5 hours after activation (Szollosi et al 1993). This delay in the phenomena characteristic for the interphase could be linked to the mixed meiotic/mitotic character of this early period. This delay probably allows the correct transformation of the sperm nucleus into the male pronucleus. In species like Xenopus or Drosophila the transitional period between the meiotic and the mitotic cell cycle control is probably much shorter since it is proportional to duration of the short first cell cycle of these rapidly cleaving embryos. Mammalian embryos are perhaps the most suitable to study this transition because of the exceptionally long first embryonic cell cycle. 

The entry into the first mitotic M phase at the end of the first embryonic cell cycle requires activation of MPF. In the mouse one-cell embryo this activation is fully autonomous from the nucleus (Ciemerych 1995, Ciemerych et al 1998). It proceeds within the cytoplasts obtained either by enucleation or by bisection of the embryo. Other autonomous phenomena are the cortical activity, or the deformation of the one-cell embryo, directly preceding the entry into first mitosis (Waksmundzka et al 1984) and the cyclic activity of K+ ion channels (Day et al 1998). The role of the cortical activity remains unknown however, the fact that it directly precedes the entry into the first mitotic M phase suggests that it could be linked to the activation... 

This suggests that cyclin A2 is not essential for the early embryonic cell cycles. Also D-type cyclins seem to be dispensable for the early mouse embryo cell cycle progression since embryonic stem (ES) cells do not express them at all before differentiation (Savatier et al 1996). We do not know, however, whether the D-type cyclins are also absent in the early embryo. These observations suggest that not only could the first cell cycles of the mouse embryo have specific modifications, but also further embryonic cell cycles are specifically modified as well. Mammalian embryonic cell cycles are probably modified often during development. Such studies could allow us to determine a profile of a minimal cell cycle in mammals which must, however, be much more complex than a simple S M phase embryonic cell cycle of amphibians or insects. 

Once the cycle has begun, the sequence of events is almost always completed in a time which is approximately constant for a given cell about 24 hours for a typical human cell. The largest variation in time occurs in the Gi phase. Very short cell cycles, 8 to 60 minutes, occur in early embryonic cells, during which cell division results in the formation of many smaller cells. In these cells, both the Gi and G2 phases are massively shortened, so that most of the time of cycling is spent in the S and M phases. 

In some cell types, such as early embryonal cells, the period between the S and M phases is reduced to the extent that discrete Gi and G2 phases cannot be identified. The duration of the cell cycle is then only 8-60 min. 

The cell cycle of somatic cells and mES cells differs markedly both in length and cell cycle phase distribution. The mES cells are characterised by a short cell cycle of 11 to 16 hours (Orford and Scadden, 2008). Cell cycle distribution analysis showed that 10%, 75% and 15% of mES cells are resjjectively in Gl, S and G2/M phase, indicating a very brief G1 phase ( 1.5h) compared to somatic cells ( 10h) (Savatier et al. 1996 Chuykin et al. 2008). In contrast, embryonic fibroblasts show a cell cycle distribution of 70%, 25%, and 5% of cells in Gl, S and G2/M phase, respectively. In this section an overview and comparison of the cell cycle control pathways that are at play in mES cells and somatic cells is given. 

Harazono, A., M. Ema, and Y. Ogawa. 1998. Evaluation of early embryonic loss induced by tributyltin chloride in rats phase- and dose-dependent antifertility effects. Arch, Environ. Contam. Toxicol. 34 94-99. 

The cell cycle is a key process that recurs in a periodic manner. Early cell cycles in amphibian embryos are driven by a mitotic oscillator. This oscillator produces the repetitive activation of the cyclin-dependent kinase cdkl, also known as cdc2 [131]. Cyclin synthesis is sufficient to drive repetitive cell division cycles in amphibian embryonic cells [132]. The period of these relatively simple cell cycles is of the order of 30 min. In somatic cells the cell cycle becomes longer, with durations of up to 24 h or more, owing to the presence of checkpoints that ensure that a cell cycle phase is properly completed before the cell progresses to the next phase. The cell cycle goes successively through the phases Gl, S (DNA replication), G2, and M (mitosis) before a new cycle starts in Gl. After mitosis cells can also enter a quiescent phase GO, from which they enter Gl under mitogenic stimulation. 

If the cell cycle in amphibian embryonic cells appears to be driven by a limit cycle oscillator, the question arises as to the precise dynamical nature of more complex cell cycles in yeast and somatic cells. Novak et al. [144] constructed a detailed bifurcation diagram for the yeast cell cycle, piecing together the diagrams obtained as a function of increasing cell mass for the transitions between the successive phases of the cell cycle. In these studies, cell mass plays the role of control parameter a critical mass has to be reached for cell division to occur, provided that it coincides with a surge in cdkl activity which triggers the G2/M transition. 

Yang, L., Zhang, H., Hu, G., Wang, H., Abate-Shen, C., Shen, M.M. 1998. An early phase of embryonic Dlx5 expression defines the rostral boundary of the neural plate. J. Neurosci. 18, 8322-8330. 

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