Notch signaling induces multilineage myeloid differentiation and up-regulates PU.1 expression.
Hemopoietic commitment is initiated by and depends on activation of transcription factors. However, it is unclear whether activation of lineage-affiliated transcription factors is extrinsically regulated by to date unknown agents or is the result of a cell autonomous program. Here we show that signaling by the Notch1 transmembrane receptor instructively induces myeloid differentiation of multipotent hemopoietic progenitor cells and concomitantly up-regulates the expression of the transcription factor PU.1. Transient activation of Notch1 signaling is sufficient to irreversibly reduce self-renewal of multipotent progenitor cells accompanied by increased and accelerated differentiation along the granulocyte, macrophage, and dendritic cell lineages. Activated Notch1 has no direct influence on apoptosis of multipotent progenitor cells, shows a weak inhibition of proliferation, and does not substitute for survival and proliferation signals provided by cytokines. Activated Notch1 directly increases PU.1 RNA levels, leading to a high concentration of PU.1 protein, which has been shown to direct myeloid differentiation. These findings identify Notch as an extrinsic regulator of myeloid commitment, and the lineage-affiliated transcription factor PU.1 as a specific direct target gene of Notch.
Schroeder
Timm
T
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Munich, Germany.
Kohlhof
Hella
H
Rieber
Nikolaus
N
Just
Ursula
U
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002135:Calcium-Binding Proteins; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D002999:Clone Cells; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology; D006098:Granulocytes / Q000166:cytology / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology* / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D002135:Calcium-Binding Proteins; D016207:Cytokines; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse