FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells.
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.
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK cs684@cam.ac.uk ama11@cam.ac.uk.
Christian
C
Schröter
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Pau
P
Rué
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Jonathan Peter
JP
Mackenzie
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK cs684@cam.ac.uk ama11@cam.ac.uk.
Alfonso
A
Martinez Arias
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000097573:Red Fluorescent Protein
D015415:Biomarkers; D005346:Fibroblast Growth Factors; D050991:GATA4 Transcription Factor; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein
Cell fate decision; Dynamic systems; Embryonic stem cells; GATA factor; Live cell imaging; Preimplantation development