The divergent DSL ligand DII3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands.

Mutations in the DSL (Delta, Serrate, Lag2) Notch (N) ligand Delta-like (DII) 3 cause skeletal abnormalities in spondylocostal dysostosis, which is consistent with a critical role for N signaling during somitogenesis. Understanding how DII3 functions is complicated by reports that DSL ligands both activate and inhibit N signaling. In contrast to other DSL ligands, we show that DII3 does not activate N signaling in multiple assays. Consistent with these findings, DII3 does not bind to cells expressing any of the four N receptors, and N1 does not bind DII3-expressing cells. However, in a cell-autonomous manner, DII3 suppressed N signaling, as was found for other DSL ligands. Therefore, DII3 functions not as an activator as previously reported but rather as a dedicated inhibitor of N signaling. As an N antagonist, DII3 promoted Xenopus laevis neurogenesis and inhibited glial differentiation of mouse neural progenitors. Finally, together with the modulator lunatic fringe, DII3 altered N signaling levels that were induced by other DSL ligands. [ABSTRACT FROM AUTHOR]