Glycosylation of Specific Notch EGF Repeats by O-Fut1 and Fringe Regulates Notch Signaling in Drosophila

摘要

Fringe glycosyltransferases differentially modulatethe binding of Notch receptors to Delta/DLL versusSerrate/Jagged ligands by adding GlcNAc to Olinkedfucose on Notch epidermal growth factorlike(EGF) repeats. Although Notch has 22 O-fucosylationsites, the biologically relevant sites affectingNotch activity during animal development in vivoin the presence or absence of Fringe are not known.Using a variety of assays, we find important roles inDrosophila Notch signaling for GlcNAc-fucose-Oglycans on three sites: EGF8, EGF9, and EGF12.O-Fucose monosaccharide on EGF12 (in theabsence of Fringe) is essential for Delta-mediatedlateral inhibition in embryos. However, wing veindevelopment depends on the addition of GlcNActo EGF8 and EGF12 by Fringe, with a minor contributionfrom EGF9. Fringe modifications of EGF8and EGF12 together prevent Notch from cis-inhibitingSerrate, thereby promoting normal wing marginformation. Our work shows the combinatorial andcontext-dependent roles of GlcNAc-fucose-O glycanson these sites in Drosophila Notch-ligand interactions.