FGF/MAPK signaling sets the switching threshold of a mutual repressor circuit controlling cell fate decisions in ES cells

Abstract

Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. We study this question in the context of the fate decision between embryonic epiblast (Epi) and extraembryonic primitive endoderm (PrE) that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell system to model this decision in culture, we find that FGF/MAPK signaling determines the threshold concentration of GATA transcription factors required for PrE-like differentiation, and thereby controls the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression circuit modulated by FGF/MAPK signaling. This may be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.