Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium.
Blood. 2011 Apr 28;117(17):4449-59. doi: 10.1182/blood-2010-06-290049. Epub 2011 Mar 3.
Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe- mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.
Notch 信号通路在各种造血谱系的决定中起着关键作用，在哺乳动物中，Notch 配体通过 Notch 配体被诱导，这些配体根据与果蝇配体 Delta 和 Serrate 的结构同源性，分为 2 个家族，Delta-like（Delta-like-1、-3 和 -4）和 Jagged（Jagged1 和 Jagged2）。由于哺乳动物 Notch 配体之间的功能差异仍不清楚，我们研究了它们对早期人类造血的影响，并表明 Jagged2 对造血谱系的决定非常类似于 Delta-like-1 和 -4，但与 Jagged1 非常不同。OP9 共培养实验表明，Jagged2 与 Delta-like 配体一样，诱导 T 细胞谱系分化，并抑制 B 细胞和髓系发育。然而，剂量依赖性 Notch 激活研究、基因表达分析和启动子激活测定表明，Jagged2 作为 Notch1 激活剂的能力比 Delta-like 配体弱，揭示了哺乳动物 Notch 配体中 Notch1 特定的信号强度层次结构。引人注目的是，Lunatic-Fringe 介导的 Notch1 糖基化通过 Delta-like 配体增强了 Notch 信号，Jagged2 也是如此，而 Jagged1 则不是。因此，我们的研究结果揭示了 Jagged1 在阻止造血干细胞中 T 细胞谱系分化诱导中的独特作用，并显示了 Jagged2 和 Delta-like 配体之间出人意料的功能相似性。
