Notch signaling in embryonic and adult myelopoiesis

Notch signaling is a highly conserved mechanism of intercellular communication that controls the developmental fate in all animal species studied to date. Specific transmembrane ligands activate Notch receptors on neighboring cells, thereby inducing proteolytic cleavage and nuclear translocation of the Notch intracellular domain (Notch(IC)). Notch(IC) associates with the transcriptional repressor RBP-J (recombination recognition sequence binding protein at the J kappa site), also known as CSL [CBF1/Su(H)/Lag-1], and converts it to an activator. In conjunction with chromatin remodeling enzymes, components of the transcriptional machinery and the activity of other cofactors, Notch(IC) induces transcription of downstream target genes, including genes of the Hes (hairy and enhancer of split) and Hey (also called Hes-related repressor Herp, Hesr, Hrt, CHF, gridlock) family. Recent evidence has shown that the Notch pathway is involved in multiple aspects of hematopoietic development. In this review, we summarize the current knowledge of the components and mechanisms of the Notch signaling pathway and discuss the role of Notch in embryonic and adult myelopoiesis. Finally, we will focus on mediators of Notch signaling in the hematopoietic system. We propose that besides suppression of differentiation mediated by the Hes/Hey family, Notch/ RBP-J signaling mediates lineage decisions by direct activation of transcription factors such as PU.1, that are critically involved in directing cells along certain cell lineages, and further influences maturation by activation of functional genes, for example beta-globin.