PT - JOURNAL ARTICLE AU - Borzo Gharibi AU - Emanuel Gonçalves AU - Buhe Nashun AU - Alex Montoya AU - Katherine Mankalow AU - Stephanie Strohbuecker AU - Rahuman S M Sheriff AU - Alessandro Cicarrelli AU - Joana Carvalho AU - Emma Nye AU - Holger Kramer AU - Ian Rosewell AU - Petra Hajkova AU - Pedro Beltrao AU - Silvia D. M. Santos TI - A FGF2-mediated incoherent feedforward loop induces Erk inhibition and promotes naïve pluripotency AID - 10.1101/2020.11.11.378869 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.11.11.378869 4099 - http://biorxiv.org/content/early/2020/11/11/2020.11.11.378869.short 4100 - http://biorxiv.org/content/early/2020/11/11/2020.11.11.378869.full AB - 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.Competing Interest StatementThe authors have declared no competing interest.