Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate

Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7839-44. doi: 10.1073/pnas.0801074105. Epub 2008 May 22.

Abstract

Mast cells are thought to participate in a wide variety of pathophysiological conditions. Mechanisms of regulation, however, of mast cell production and maturation are still to be elucidated. Mast cell developmental process is likely to be profoundly affected by cell-autonomous transcriptional regulators such as the GATA family and CCAAT/enhancer binding protein (C/EBP) family members. Extracellular regulators such as stem cell factor and IL-3 have essential roles in basal and inducible mast cell generation, respectively. The relationship, however, between the extracellular signaling and cellular transcriptional control is unclear, and the trigger of the mast cell development remains elusive. Notch signaling plays a fundamental role in the lymphopoietic compartment, but its role in myeloid differentiation is less clear. Here, we demonstrate that Notch signaling connects environmental cues and transcriptional control for mast cell fate decision. Delta1, an established Notch ligand, instructs bone marrow common myeloid progenitors and granulocyte-macrophage progenitors toward mast cell lineage at the expense of other granulocyte-macrophage lineages, depending on the function of the Notch2 gene. Notch2 signaling results in the up-regulation of Hes-1 and GATA3, whereas simultaneous overexpression of these transcription factors remarkably biases the progenitor fate toward the mast cell-containing colony-forming cells. C/EBPalpha mRNA was down-regulated in myeloid progenitors as a consequence of Hes-1 overexpression, in agreement with the recent proposal that the down-regulation of C/EBPalpha is necessary for mast cell fate determination. Taken together, signaling through Notch2 determines the fate of myeloid progenitors toward mast cell-producing progenitors, via coordinately up-regulating Hes-1 and GATA3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Lineage* / genetics
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism*
  • Granulocyte Precursor Cells / cytology
  • Granulocyte Precursor Cells / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mast Cells / cytology
  • Mast Cells / physiology*
  • Mice
  • Mice, Transgenic
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism*
  • Signal Transduction
  • Transcription Factor HES-1
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CCAAT-Enhancer-Binding Protein-alpha
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Notch2 protein, mouse
  • Receptor, Notch2
  • Transcription Factor HES-1