In 1982, Newport and Kirschner defined the midblastula transition (MBT), a key developmental event in Xenopus laevis and other animal embryos. The X. laevis embryo undergoes 12 rapid divisions after fertilization, with the thirteenth division initiating a new developmental program characterized by zygotic gene transcription and blastomere motility. Only fitful progress has been made in defining the molecules that regulate the MBT, but Jörg Grosshans and colleagues have now identified a protein that may have an important role (Dev. Cell 5, 285–294; 2003).

Previous work showed that although the pre-MBT X. laevis embryo is fully competent to initiate zygotic transcription, the rapid cell cycles of the first 12 cleavages don't allow enough time for such transcription to occur. Several groups have contributed to a model proposing that the increasing nucleocytoplasmic ratio in the blastomeres of the early embryo depletes factors that are required for DNA replication or cell cycle progression, thus lengthening interphase and allowing time for zygotic transcription. Such a model has also been suggested for the equivalent of the MBT in the Drosophila melanogaster embryo, in which zygotic transcription accompanies a checkpoint-dependent elongation of cell cycles 11–13. The fly embryo, which consists of shared cytoplasm up to this point, then pauses at cleavage cell cycle 14 and cellularizes. A central question that remains is the nature of the additional factors that link nucleocytoplasmic ratio with control of the cell cycle.

Grosshans et al. show that the cytoplasmic protein frühstart (meaning 'false start') has all the expected properties of a linchpin of the MBT in the fly embryo. Frühstart (frs) was originally identified as a mitotic inhibitor that delays division in cells of the ventral furrow during gastrulation. Noting that frs is first expressed coincident with the pause in the mitosis at cycle 14, the authors asked whether it might also delay mitosis at the MBT. As pictured here, injection of frs mRNA into the posterior end of the embryo (at right) during cycles 10–12 results in large patches where there are fewer cell divisions. Taking a closer look at frs-null embryos, they observed that a small fraction of them have patches of higher nuclear density, which the authors suggest is due to an extra cleavage before cellularization.

Is expression of frs regulated by the nucleocytoplasmic ratio? Expression of the gene, which peaks shortly after cycle 13, is delayed in haploid embryos. This and other lines of evidence lead the authors to argue that frs transcription is probably a direct readout of this ratio. Future work will focus on the identification of cis-acting regulatory elements that control expression of frs in response to the amount of DNA in the embryo as a whole.