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Published online 6 September 2005. doi:10.1083/jcb.200503113
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 6, 983-992
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Article

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

Ena Ladi1, James T. Nichols1, Weihong Ge2,3, Alison Miyamoto1, Christine Yao1, Liang-Tung Yang1, Jim Boulter2, Yi E. Sun2,3, Chris Kintner6, and Gerry Weinmaster1,4,5

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.

E. Ladi's present address is Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, CA 94720.

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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