The divergent DSL ligand Dll3 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 (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.
Ladi
Ena
E
Department of Biological Chemistry, Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Nichols
James T
JT
Ge
Weihong
W
Miyamoto
Alison
A
Yao
Christine
C
Yang
Liang-Tung
LT
Boulter
Jim
J
Sun
Yi E
YE
Kintner
Chris
C
Weinmaster
Gerry
G
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
D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D014404:Tubulin; C064045:delta protein; D008156:Luciferases; D016695:Glycosyltransferases; C498392:Lfng protein, mouse