Inhibition of granulocytic differentiation by mNotch1.
Effective hematopoiesis requires the commitment of pluripotent and multipotent stem cells to distinct differentiation pathways, proliferation and maturation of cells in the various lineages, and preservation of pluripotent progenitors to provide continuous renewal of mature blood cells. While the importance of positive and negative cytokines in regulating proliferation and maturation of hematopoietic cells has been well documented, the factors and molecular processes involved in lineage commitment and self-renewal of multipotent progenitors have not yet been defined. In other developmental systems, cellular interactions mediated by members of the Notch gene family have been shown to influence cell fate determination by multipotent progenitors. We previously described the expression of the human Notch1 homolog, TAN-1, in immature hematopoietic precursors. We now demonstrate that constitutive expression of the activated intracellular domain of mouse Notch1 in 32D myeloid progenitors inhibits granulocytic differentiation and permits expansion of undifferentiated cells, findings consistent with the known function of Notch in other systems.
Milner
L A
LA
Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle 98104, USA.
Bigas
A
A
Kopan
R
R
Brashem-Stein
C
C
Bernstein
I D
ID
Martin
D I
DI
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D006098:Granulocytes / Q000166:cytology* / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D016133:Polymerase Chain Reaction; D021382:Protein Sorting Signals / Q000737:chemistry; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D012190:Retroviridae; D014157:Transcription Factors; D014162:Transfection
D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D021382:Protein Sorting Signals; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014157:Transcription Factors