title: Notch signaling specifies megakaryocyte development from hematopoietic stem cells.
abstract: In the hematopoietic system, Notch signaling specifies T cell lineage fate, in part through negative regulation of B cell and myeloid lineage development. However, we unexpectedly observed the development of megakaryocytes when using heterotypic cocultures of hematopoietic stem cells with OP9 cells expressing Delta-like1, but not with parental OP9 cells. This effect was abrogated by inhibition of Notch signaling either with gamma-secretase inhibitors or by expression of the dominant-negative Mastermind-like1. The importance of Notch signaling for megakaryopoietic development in vivo was confirmed by using mutant alleles that either activate or inhibit Notch signaling. These findings indicate that Notch is a positive regulator of megakaryopoiesis and plays a more complex role in cell-fate decisions among myeloid progenitors than previously appreciated.
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 20115, USA. tmercher@rics.bwh.harvard.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Christopher
authors.initials: C
authors.lastname: Sears
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Moore
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch
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