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The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands

¹ Department of Biological Chemistry, Geffen School of Medicine
² Department of Psychiatry and Behavioral Sciences, Geffen School of Medicine
³ Department of Molecular and Medical Pharmacology, Geffen School of Medicine
⁴ The Molecular Biology Institute, Geffen School of Medicine
⁵ Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles (UCLA), Los Angeles, CA 90095
⁶ The Salk Institute for Biological Studies, La Jolla, CA 92186

Correspondence to Gerry Weinmaster: gweinmaster{at}mednet.ucla.edu

Mutations in the DSL (Delta, Serrate, Lag2) Notch (N) ligand Delta-like (Dll) 3 cause skeletal abnormalities in spondylocostal dysostosis, which is consistent with a critical role for N signaling during somitogenesis. Understanding how Dll3 functions is complicated by reports that DSL ligands both activate and inhibit N signaling. In contrast to other DSL ligands, we show that Dll3 does not activate N signaling in multiple assays. Consistent with these findings, Dll3 does not bind to cells expressing any of the four N receptors, and N1 does not bind Dll3-expressing cells. However, in a cell-autonomous manner, Dll3 suppressed N signaling, as was found for other DSL ligands. Therefore, Dll3 functions not as an activator as previously reported but rather as a dedicated inhibitor of N signaling. As an N antagonist, Dll3 promoted Xenopus laevis neurogenesis and inhibited glial differentiation of mouse neural progenitors. Finally, together with the modulator lunatic fringe, Dll3 altered N signaling levels that were induced by other DSL ligands.

Abbreviations used in this paper: Dll, Delta-like; GFAP, glial fibrillary acidic protein; LFng, lunatic fringe; mDll, mouse Dll; MLC2, myosin light chain 2; NICD, Notch intracellular domain; NRARP, Notch-regulated ankyrin repeat protein; NSC, neural stem cell; NT-DSL, NH₂-terminal and DSL domains; PSM, presomitic mesoderm; rDll, rat Dll; SAV, streptavidin; WCL, whole cell lysate.

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