Notch signaling specifies megakaryocyte development from hematopoietic stem cells.
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.
Mercher
Thomas
T
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 20115, USA. tmercher@rics.bwh.harvard.edu
Cornejo
Melanie G
MG
Sears
Christopher
C
Kindler
Thomas
T
Moore
Sandra A
SA
Maillard
Ivan
I
Pear
Warren S
WS
Aster
Jon C
JC
Gilliland
D Gary
DG
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
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch
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