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. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem cell (ESC) model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ESCs. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control 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 might 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.
Highlights
To ensure the faithful development of multicellular organisms, cell fate decisions in populations of undifferentiated cells have to be tightly balanced
This question is of particular importance in one of the first cell fate decisions in the mammalian preimplantation embryo, where a small number of inner cell mass (ICM) cells have to reliably populate both the epiblast (Epi) lineage that will give rise to the embryo proper, as well as the primitive endoderm (PrE) lineage, which differentiates into tissues that function in patterning and nutrient supply of the embryo (Rossant and Tam, 2009)
An embryonic stem cell (ESC) model system to investigate PrE-like fate choice in culture To model in culture the transition from GATA6/NANOG coexpression to mutually exclusive expression of Epi and PrE markers that characterizes the Epi-versus-PrE fate decision (Plusa et al, 2008), we used a doxycycline-inducible system to transiently express GATA6-FLAG in ESCs (Beard et al, 2006; Mulvey et al, 2015; Wamaitha et al, 2015) (Fig. 1A)
Summary
To ensure the faithful development of multicellular organisms, cell fate decisions in populations of undifferentiated cells have to be tightly balanced. It is well established that transcriptional networks and extracellular signals together control these decisions, but how their interactions determine the proportions of cells differentiating along particular lineages is often not known This question is of particular importance in one of the first cell fate decisions in the mammalian preimplantation embryo, where a small number of inner cell mass (ICM) cells have to reliably populate both the epiblast (Epi) lineage that will give rise to the embryo proper, as well as the primitive endoderm (PrE) lineage, which differentiates into tissues that function in patterning and nutrient supply of the embryo (Rossant and Tam, 2009). How the activities of the transcriptional networks are integrated with the activity of the FGF/MAPK signaling pathway, and how these inputs together control the proportion of cells differentiating along either lineage has not been systematically investigated
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