title: Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors.
abstract: The bone marrow and thymus, although both hemopoietic environments, induce very distinct differentiation outcomes. The former supports hemopoietic stem cell self-renewal and multiple hemopoietic lineages, while the latter supports T lymphopoiesis almost exclusively. This distinction suggests that the thymic environment acts to restrict the hemopoietic fates available to thymic immigrants. In this study, we demonstrate that the addition of the Notch ligand Delta-like-1 (Dll-1) to an in vitro system that otherwise supports myelopoiesis, greatly reduces the myelopoietic potential of stem cells or uncommitted progenitors. In contrast, committed myeloid progenitors mature regardless of the presence of Dll-1. The block in myelopoiesis is the direct result of Notch signaling within the hemopoietic progenitor, and Dll-1-induced signals cause a rapid increase in the expression of the zinc finger transcription factor GATA-2. Importantly, in the absence of GATA-2, Dll-1-induced signals fail to inhibit commitment to the myeloid fate. Taken together, our results support a role for GATA-2 in allowing Dll-1 to restrict non-T cell lineage differentiation outcomes.
authors.affiliation: Department of Immunology, University of Toronto, Sunnybrook and Women's Research Institute, 2075 Bayview Avenue, Toronto, Ontario, Canada.
authors.forename: Renée F
authors.initials: RF
authors.lastname: de Pooter
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schmitt
authors.forename: José Luis
authors.initials: JL
authors.lastname: de la Pompa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
mesh_terms: D002478:Cells, Cultured; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D038042:Myelopoiesis; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050989:GATA2 Transcription Factor; D051880:Receptors, Notch; D014157:Transcription Factors