Jam1a – Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling

Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development(1-3) and requires intimate contact between signal emitting and receiving cells, although little is known regarding when, where, and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification(4). It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta (DA). Here we show that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that Junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a and migrate axially across the ventral somite, where Jam2a and Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a – Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the DA.