An environmental Wnt16/Notch pathway specifies haematopoietic stem cells

Haematopoietic stem cells (HSCs) are a self-renewing population that continuously replenish all blood and immune cells during the lifetime of an individual(1, 2). HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune compatible donors remain serious problems. These concerns have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in specification of HSCs during embryonic development. Here we demonstrate that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signaling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are in turn required for establishment of definitive haematopoiesis. Notch signalling downstream of Dlc/Dld is earlier than, and distinct from known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium.