Notch ligands transduce different magnitudes of signaling critical for determination of T-cell fate

Abstract

Notch signaling mediated by Delta-like (Dll) 4 is essential and sufficient for T-cell development in vivo. Stromal cells expressing Dll4 or Dll1, but not Jagged1, support T lymphopoiesis in vitro, but the molecular basis of this functional divergence among Notch ligands remains to be clarified. To examine this, we constructed chimeric variants composed of Dll4 and Jagged1. The intracellular regions were necessary, but interchangeable, for signal induction, and the extracellular regions determined the unique characteristics of the ligands. While Jagged1 induced minimal Notch signaling, Jagged2 elicited substantial levels of Hes1 transcripts and promoted T lymphopoiesis in vitro. Dll4 and Jagged2 showed a quantitative advantage when bound to fringe-modified Notch; this was not due to the Delta-Serrate-Lag2 domain, an extracellular region essential for interaction with Notch. These results suggest that different Notch ligands possess distinct potentials for the induction of Notch signaling through unique interactions of their extracellular regions with fringe-modified Notch. Furthermore, the magnitude of Notch signaling induced is critical for the determination of T-cell fate.