Abstract Naïve pluripotency is a transient state during mammalian development that can be recapitulated indefinitely in vitro by inhibition of the mitogen-activated protein kinase (MAPK/Erk) signalling and activation of STAT and Wnt pathways. How Erk is inhibited in vivo to promote naïve pluripotency remains largely unknown. By combining live cell imaging and quantitative proteomics we found that FGF2, a known Erk activator and pro-differentiation cue, induces instead long-term Erk inhibition in both ES cells and mouse embryos. We show that Erk inhibition results from a FGF2-induced incoherent feedforward loop. Importantly, we see that FGF2 induces up-regulation of naïve pluripotency factors, down-regulation of DNA methylation by suppression of de novo DNA methylases thereby helping maintain naïve pluripotency. We show that FGF2 is expressed maternally and propose that integration of signals from the embryo’s niche may contribute to the generation of embryonic lineages with the right cell proportions. We suggest that feedforward regulation may play a role driving transient, reversible developmental transitions.

A FGF2-mediated incoherent feedforward loop induces Erk inhibition and promotes naïve pluripotency