UC San Diego

Hematopoietic stem cells (HSCs) originate from a specialized subset of arterial endothelial cells termed hemogenic endothelium (HE) within the dorsal aorta (DA) during early embryonic development. Notch signaling is known to be required for the specification of HSCs. However, little is still known about the specific Notch receptor-ligand interactions that are required for the specification of the HE. Previous work has shown that Notch ligands Dlc, Dld, and the Notch3 receptor, are required non-cell-autonomously in the somites to specify HSCs. However, whether Notch3 functions exclusively in the somites to regulate HE specification, and through which ligand(s), is debatable. By contrast, the Notch1b receptor has been shown to function only in a cell-autonomous manner for HE specification, but the Notch ligand(s) that are required to signal through Notch1b are still unknown. Here, we confirm the non-cell-autonomous requirement for Notch3 in the somites to regulate HSC specification. Combinatorial low-dose knockdown experiments also revealed that Dlc and Dld act synergistically through Notch1b, in a cell-autonomous manner, for the proper specification of HSCs.