Notch in Hematopoiesis: Cell Fate Decisions and Self-Renewal of Progenitors

摘要

The Notch family comprises a group of highly conserved cell-surface receptors that mediate cell fate decisions in many developmental processes, from worms and flies to mammalian systems. Cell-cell signaling through Notch permits multipotent progenitors in the same environmental context to respond differently to developmental signals, facilitating the establishment of distinct cell types. Over the past several years major advances have been made in denning the molecular mechanisms involved in Notch signaling, understanding the complex interactions of Notch with other signaling pathways, and establishing the central role of Notch in mammalian development. Here we present evidence supporting a conserved role for Notch in hematopoietic regulation. Notch1 and Notch2 are both expressed by hematopoietic progenitors and the Notch ligand, Jagged1, is expressed by a subset of bone marrow stromal cells. Using 32D myeloid progenitors, we show that activation of Notch1 by Jagged1 inhibits G-CSF-induced granulocytic differentiation and permits the maintenance of undifferentiated cells. We also demonstrate that Notch1 and Notch2 have distinct intracellular activities that permit modulation of myeloid differentiation specifically in response to G-CSF or GM-CSF. We speculate that Notch plays a central role in the regulation of cell fate determination and self-renewal of progenitors during hematopoiesis.