Pleiotropic Notch functions in the hematopoietic system. (A) Notch is required during hematopoietic development to generate HSCs in the AGM. This process takes place in the aorta endothelium and is dependent on the Jagged1 ligand and the Notch1 receptor. Endothelial-like pre-HSCs or HSCs are the putative target of Notch activation (light green). (B-C) Models of Notch signaling in hematopoietic differentiation. (B) Notch is involved at different steps of differentiation of the hematopoietic lineages. The classic hierarchical model of the hematopoietic tree is here adapted to the concept that a gradient of Notch activation or signaling determines the different types of hematopoietic cells. (C) A hematopoietic potential restriction model¹⁰⁷  in which lineage restriction is determined by Notch doses. HSCs progressively lose their capacity to generate different lineages concomitantly to different exposure to Notch doses. Intensity of the blue color represents a speculative gradient of Notch activity. Dashed lines represent cell potential to become a specific cell type. Solid lines represent progression through normal hematopoietic development. LT-HSC indicates long-term HSCs; CMP, common myeloid progenitor; LMPP, lymphoid/myeloid potential progenitor; CME, common megakaryocyte-erythroid progenitor; ETP, early T-progenitor; Ery, erythrocyte; Meg, megakaryocyte; and M/Gr, macrophage/granulocyte.