title: Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development.
abstract: Signals of Notch transmembrane receptors function to regulate a wide variety of developmental cell fates. Here we investigate the role of Notch signaling in the development of mesodermal cell types by expressing a tamoxifen-inducible, activated form of Notch1 in embryonic stem cells (ESC). For differentiation of ESC into first mesodermal progenitor cells and then endothelial, mural, cardiac muscle and hematopoietic cells, the OP9 stroma co-culture system was used. Timed activation of Notch signaling by the addition of tamoxifen at various stages during differentiation of ESC into mesodermal cell lineages results in profound alterations in the generation of all of these cells. Differentiation of ESC into Flk1(+) mesodermal cells is inhibited by activated Notch. When Notch signaling is activated in mesodermal cells, generation of cardiac muscle, endothelial and hematopoietic cells is inhibited, favoring the generation of mural cells. Activation of Notch signaling in hematopoietic cells reduces colony formation and maintenance of hematopoiesis. These data suggest that Notch signaling plays a regulatory role in mesodermal development, cardiomyogenesis, the balanced generation of endothelial versus mural cells of blood vessels and hematopoietic development.
authors.affiliation: Institute for Clinical Molecular Biology and Tumor Genetics, GSF - National Research Center for Environment and Health, Marchioninistr. 25, 81377 München, Germany. timm.schroeder@gsf.de
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.forename: Franziska
authors.initials: F
authors.lastname: Meier-Stiegen
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwanbeck
authors.forename: Hanna
authors.initials: H
authors.lastname: Eilken
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Ursula
authors.initials: U
authors.lastname: Just
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1