PI3K/AKT signalling regulates mouse Inner Cell Mass (ICM) progenitor specification [FLASH-seq]

The inner cell mass (ICM) of early mouse embryos is specified into Epiblast (Epi) and primitive endoderm (PrE) lineages during blastocyst formation. The antagonistic transcription factors (TFs) NANOG and GATA6 in combination with FGF/ERK signaling are central actors in ICM fate choice. However, what initiates the specification of the bipotent ICM progenitor and whether other factors are involved in this process is not fully understood yet. Here, we report the key role of PI3K in mouse ICM progenitors specification. Surprisingly, while the PI3K/AKT signaling pathway is known for almost two decades to participate to the maintenance of pluripotency in stem cells, no role for this pathway in ICM cell fate decisions has been reported so far. This is likely due to the dynamic and asynchronous nature of ICM specification combined with the pleiotropic and rapidly evolving functions mediated by PI3K/AKT. By limiting the perturbations of the pathway to a short time-window corresponding to the early phase of ICM specification, we unravelled a dual role of PI3K in ICM progenitor, being required on the one hand for the maintenance of pluripotency TFs and, on the other hand, for the competence to engage into PrE differentiation in response to FGF signaling. Thus, our work identifies PI3K as a novel critical regulator of ICM progenitor specification in the mouse embryo.