title: The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Ena
authors.initials: E
authors.lastname: Ladi
authors.forename: James T
authors.initials: JT
authors.lastname: Nichols
authors.forename: Weihong
authors.initials: W
authors.lastname: Ge
authors.forename: Alison
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Christine
authors.initials: C
authors.lastname: Yao
authors.forename: Liang-Tung
authors.initials: LT
authors.lastname: Yang
authors.forename: Jim
authors.initials: J
authors.lastname: Boulter
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.forename: Chris
authors.initials: C
authors.lastname: Kintner
authors.forename: Gerry
authors.initials: G
authors.lastname: Weinmaster
mesh_terms: D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D018920:Coculture Techniques; D047108:Embryonic Development; D016695:Glycosyltransferases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007739:L Cells; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D014404:Tubulin; C064045:delta protein; D008156:Luciferases; D016695:Glycosyltransferases; C498392:Lfng protein, mouse