Genetic interactions between the CBFs and Notch signaling in the specification of HSCs, T cells, and NK cells in the fetus. Notch receptors and ligands are expressed on the aortic endothelial cells in the AGM region that give rise to HSCs.20 Notch signaling is required for Runx1 expression in endothelial cells and for the formation of HSCs19,20,23,24 ; thus, Notch is genetically upstream of Runx1 in HSC formation. — represent molecular interactions; ---- represent cell migrations. PB indicates peripheral blood. HSCs and progenitors are released into the circulation from their sites of formation and colonize the fetal liver. We speculate that Runx1 and/or Runx3 plus CBFβ are required to generate NKP from either a bipotent T/NK or another progenitor in the fetus, and perhaps in T/NK progenitors themselves. CBFs are also required for the NKP to iNK transition, based on data from the adult. Circulating progenitors expressing all 3 CBF complexes colonize the thymus where they encounter high levels of Notch ligands. CBFs confer on these progenitors the ability to respond to Notch signaling, which results in T-cell specification and progression to the ETP/DN2 stage accompanied by the expression of a suite of T cell–specific genes. Not shown are NKT cells, which differentiate from DP T cells in a Runx1-dependent manner.
