Notch signaling induces multilineage myeloid differentiation and up-regulates PU.1 expression

Timm Schroeder, Hella Kohlhof, Nikolaus Rieber, Ursula Just

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5538-5548
Number of pages11
JournalJournal of Immunology
Volume170
Issue number11
DOIs
StatePublished - 1 Jun 2003
Externally publishedYes

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