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

Cell Rep. 2019 Nov 12;29(7):2054-2066.e6
Ashutosh Pandey 1 , Beth M Harvey 2 , Mario F Lopez 1 , Atsuko Ito 3 , Robert S Haltiwanger 4 , Hamed Jafar-Nejad 5
Ashutosh Pandey 1 , Beth M Harvey 2 , Mario F Lopez 1 , Atsuko Ito 3 , Robert S Haltiwanger 4 , Hamed Jafar-Nejad 5
+ et al

[No authors listed]

Author information
  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
  • 3 Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
  • 4 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA. Electronic address: rhalti@uga.edu.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hamedj@bcm.edu.

摘要

Fringe glycosyltransferases differentially modulate the binding of Notch receptors to Delta/DLL versus Serrate/Jagged ligands by adding GlcNAc to O-linked fucose on Notch epidermal growth factor-like (EGF) repeats. Although Notch has 22 O-fucosylation sites, the biologically relevant sites affecting Notch activity during animal development in vivo in the presence or absence of Fringe are not known. Using a variety of assays, we find important roles in Drosophila Notch signaling for GlcNAc-fucose-O glycans on three sites: EGF8, EGF9, and EGF12. O-Fucose monosaccharide on EGF12 (in the absence of Fringe) is essential for Delta-mediated lateral inhibition in embryos. However, wing vein development depends on the addition of GlcNAc to EGF8 and EGF12 by Fringe, with a minor contribution from EGF9. Fringe modifications of EGF8 and EGF12 together prevent Notch from cis-inhibiting Serrate, thereby promoting normal wing margin formation. Our work shows the combinatorial and context-dependent roles of GlcNAc-fucose-O glycans on these sites in Drosophila Notch-ligand interactions.

KEYWORDS: Drosophila, Pofut1, cis-inhibition, fringe, glycosylation, notch signaling

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