Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0380, USA.
Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California 92093-0380, USA.
Nature. 2014 Aug 21;512(7514):319-23. doi: 10.1038/nature13623. Epub 2014 Aug 13.
Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-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. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish 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 (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the 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 dorsal aorta.
Notch 信号通路在脊椎动物发育过程中造血干细胞（HSCs）的生成中起着关键作用，需要信号发射细胞和信号接收细胞之间的密切接触，尽管对于这些细胞间事件何时、何地以及如何发生知之甚少。我们之前报道过，体节 Notch 配体 Dlc 和 Dld 对于 HSC 的特化是必不可少的。然而，这些体节的要求如何与 HSCs 后来从背主动脉中出现联系起来，目前仍不清楚。在这里，我们在斑马鱼中表明，Notch 信号通路在其共同的血管前体迁移穿过体节腹侧时建立了 HSC 命运，并且连接黏附分子（JAMs）介导了这种必需的 Notch 信号转导。HSC 前体表达 jam1a（也称为 f11r）并沿体节的腹侧轴向迁移，在该处表达 Jam2a 和 Notch 配体 Dlc 和 Dld。尽管 Notch 配体或受体基因的表达没有改变，但 jam1a 的功能丧失导致 Notch 信号的丧失和 HSCs 的丧失。在共享血管前体中强制激活 Notch 可挽救 jam1a 或 jam2a 缺陷胚胎中的 HSCs。总之，这些结果表明 Jam1a-Jam2a 相互作用促进了 Notch 信号从体节到 HSCs 前体的传递，并且这些事件发生在背主动脉形成之前。
