The first definitive haematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E)10.5-11 aorta-gonad-mesonephros (AGM) region. Notch signalling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signalling regulates HSCs formation in the embryo is poorly understood. We demonstrate here that Notch signalling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually down-regulated while they progress towards dHSCs at E11.5. This down-regulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation programme. Our data indicate that fine stagedependent tuning of Notch signalling may be required for the generation of definitive HSCs from pluripotent cells.
- Notch pathway