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 decision between the embryonic epiblast (Epi) and the extraembryonic primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell model, we discover two successive roles of Fgf/MAPK signaling in this decision. First, this pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors. In a second step, the level of 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.
