title: FGF signalling inhibits neural induction in human embryonic stem cells.
abstract: Human embryonic stem cells (hESCs) can exit the self-renewal programme, through the action of signalling molecules, at any given time and differentiate along the three germ layer lineages. We have systematically investigated the specific roles of three signalling pathways, TGFβ/SMAD2, BMP/SMAD1, and FGF/ERK, in promoting the transition of hESCs into the neuroectoderm lineage. In this context, inhibition of SMAD2 and ERK signalling served to cooperatively promote exit from hESC self-renewal through the rapid downregulation of NANOG and OCT4. In contrast, inhibition of SMAD1 signalling acted to maintain SOX2 expression and prevent non-neural differentiation via HAND1. Inhibition of FGF/ERK upregulated OTX2 that subsequently induced the neuroectodermal fate determinant PAX6, revealing a novel role for FGF2 in indirectly repressing PAX6 in hESCs. Combined inhibition of the three pathways hence resulted in highly efficient neuroectoderm formation within 4 days, and subsequently, FGF/ERK inhibition promoted rapid differentiation into peripheral neurons. Our study assigns a novel, biphasic role to FGF/ERK signalling in the neural induction of hESCs, which may also have utility for applications requiring the rapid and efficient generation of peripheral neurons.
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
authors.forename: Philippe
authors.initials: P
authors.lastname: Coulon
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Sören
authors.initials: S
authors.lastname: Moritz
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
authors.forename: Arnoldo José
authors.initials: AJ
authors.lastname: Müller-Molina
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Pape
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D000071317:Nanog Homeobox Protein; D054258:Neural Plate / Q000166:cytology* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D051857:Otx Transcription Factors / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051899:Smad2 Protein / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C497659:OTX2 protein, human; D050814:Octamer Transcription Factor-3; D051857:Otx Transcription Factors; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; C494173:POU5F1 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; D051898:Smad1 Protein; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors
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