During the first week of mammalian development, the cells of the early embryo undertake two sequential cell fate decisions and segregate into the three lineages that make up the blastocyst. First, the trophectoderm (the precursor tissue to the placenta) becomes specified, occupying the outside of the embryo and surrounding uncommitted inner cell mass (ICM) cells. These subsequently segregate to Nanog-expressing epiblast (EPI; the embryo proper) and Gata6-expressing primitive endoderm (PE; yolk sac precursors).
In this issue, two research articles, one from the Ema lab and the second a collaboration between the Plusa and Piliszek labs, delve deeper into what governs the crucial EPI/PE cell fate specification event, which is well known to be reliant on FGF/ERK signalling. On p. 3706, Masatsugu Ema and colleagues provide evidence that the transcription factor Klf5 lies upstream of FGF/ERK signalling. They find that Fgf4 is upregulated in Klf5-knockout mouse embryos, which fail to specify EPI and can only generate PE. Conversely, when Klf5 is overexpressed, ICM cells fail to segregate, and continue to co-express both Nanog and Gata6. Furthermore, they find that Klf5 binds to the Fgf4 locus, suggesting that Fgf4 expression can be directly regulated by this transcription factor.
In the second study (p. 3719), Anna Piliszek et al. use a different model system – the rabbit – to investigate lineage specification in early embryos. Unlike the mouse embryo, they detect co-expression of NANOG and GATA6 in late blastocysts, suggesting that mutual co-repression does not function in the initiation of lineage specification in rabbit. Furthermore, they show that inhibition of FGF signalling is not sufficient to expand the population of EPI cells, and although the population of PE cells is reduced, GATA6 expression is unaffected. These results indicate that although the key transcription factors are conserved in early mammalian embryogenesis, the way they function, and the way they interact with signalling pathways, may differ between species.
Taken together, these data add to our understanding of how the earliest cell fate decisions are taken in the mammalian embryo, and how they vary across evolution.
