Regulation of Notch signaling during T‐ and B‐cell development by O‐fucose glycans

Summary:  Notch signaling is required for the development of all T cells and marginal zone (MZ) B cells. Specific roles in T‐ and B‐cell differentiation have been identified for different Notch receptors, the canonical Delta‐like (Dll) and Jagged (Jag) Notch ligands, and downstream effectors of Notch signaling. Notch receptors and ligands are post‐translationally modified by the addition of glycans to extracellular domain epidermal growth factor‐like (EGF) repeats. The O‐fucose glycans of Notch cell‐autonomously modulate Notch–ligand interactions and the strength of Notch signaling. These glycans are initiated by protein O‐fucosyltransferase 1 (Pofut1), and elongated by the transfer of N‐acetylglucosamine (GlcNAc) to the fucose by β1,3GlcNAc‐transferases termed lunatic, manic, or radical fringe. This review discusses T‐ and B‐cell development from progenitors deficient in O‐fucose glycans. The combined data show that Lfng and Mfng regulate T‐cell development by enhancing the interactions of Notch1 in T‐cell progenitors with Dll4 on thymic epithelial cells. In the spleen, Lfng and Mfng cooperate to modify Notch2 in MZ B progenitors, enhancing their interaction with Dll1 on endothelial cells and regulating MZ B‐cell production. Removal of O‐fucose affects Notch signaling in myelopoiesis and lymphopoiesis, and the O‐fucose glycan in the Notch1 ligand‐binding domain is required for optimal T‐cell development.