title: Different Concentrations of FGF Ligands, FGF2 or FGF8 Determine Distinct States of WNT-Induced Presomitic Mesoderm.
abstract: Presomitic mesoderm (PSM) cells are the precursors of the somites, which flank both sides of the neural tube and give rise to the musculo-skeletal system shaping the vertebrate body. WNT and FGF signaling control the formation of both the PSM and the somites and show a graded distribution with highest levels in the posterior PSM. We have used reporters for the mesoderm/PSM control genes T, Tbx6, and Msgn1 to investigate the differentiation of mouse ESCs from the naïve state via EpiSCs to PSM cells. Here we show that the activation of WNT signaling by CHIR99021 (CH) in combination with FGF ligand induces embryo-like PSM at high efficiency. By varying the FGF ligand concentration, the state of PSM cells formed can be altered. High FGF concentration supports posterior PSM formation, whereas low FGF generates anterior/differentiating PSM, in line with in vivo data. Furthermore, the level of Msgn1 expression depends on the FGF ligand concentration. We also show that Activin/Nodal signaling inhibits CH-mediated PSM induction in EpiSCs, without affecting T-expression. Inversely, Activin/Nodal inhibition enhances PSM induction by WNT/high FGF signaling. The ability to generate PSM cells of either posterior or anterior PSM identity with high efficiency in vitro will promote the investigation of the gene regulatory networks controlling the formation of nascent PSM cells and their switch to differentiating/somitic paraxial mesoderm. Stem Cells 2016;34:1790-1800.
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Smita
authors.initials: S
authors.lastname: Sudheer
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marks
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Koch
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Department of Biology, Chemistry and Pharmacy, Free University Berlin, Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Anurin
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Scholze
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Anna Dorothea
authors.initials: AD
authors.lastname: Senft
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Wittler
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Karol
authors.initials: K
authors.lastname: Macura
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Grote
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008648:Mesoderm / Q000166:cytology / Q000196:embryology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D019170:Somites / Q000166:cytology / Q000196:embryology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D028341:Activins; D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D051524:Fibroblast Growth Factor 8; D008024:Ligands; D051153:Wnt Proteins; C422405:activin A
keywords: Brachyury; CHIR99021; Differentiation; Embryonic stem cells; Epiblast stem cells; FGF; Mesogenin; Paraxial mesoderm; TBX6; WNT