title: FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation.
abstract: Here, we show that as human embryonic stem cells (ESCs) exit the pluripotent state, NANOG can play a key role in determining lineage outcome. It has previously been reported that BMPs induce differentiation of human ESCs into extraembryonic lineages. Here, we find that FGF2, acting through the MEK-ERK pathway, switches BMP4-induced human ESC differentiation outcome to mesendoderm, characterized by the uniform expression of T (brachyury) and other primitive streak markers. We also find that MEK-ERK signaling prolongs NANOG expression during BMP-induced differentiation, that forced NANOG expression results in FGF-independent BMP4 induction of mesendoderm, and that knockdown of NANOG greatly reduces T induction. Together, our results demonstrate that FGF2 signaling switches the outcome of BMP4-induced differentiation of human ESCs by maintaining NANOG levels through the MEK-ERK pathway.
authors.affiliation: Morgridge Institute for Research, Madison, WI 53715-7365, USA.
authors.forename: Pengzhi
authors.initials: P
authors.lastname: Yu
authors.forename: Guangjin
authors.initials: G
authors.lastname: Pan
authors.forename: Junying
authors.initials: J
authors.lastname: Yu
authors.forename: James A
authors.initials: JA
authors.lastname: Thomson
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D000071317:Nanog Homeobox Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases