The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development

摘要

Mechanisms by which the extracellular domain of Notch1 controls Notch1 signaling are not well defined. Here, we show that the O-fucose glycan in the Notch1 ligand-binding domain regulates the strength of Notch1 signaling during embryogenesis, postweaning growth, and T cell development in the mouse. Heterozygotes carrying a Notch112f allele and an inactive Notch1 allele die at approximately embryonic day (E)12 with a typical Notch1 null phenotype. Homozygous Notch112f/12f mice are viable and fertile but grow somewhat more slowly than littermates after weaning. Notch112f/12f thymocytes bind less Delta1 and exhibit reduced Notch1 signaling. The number of double-positive (DP) and single-positive (SP) T cells are decreased in Notch112f/12f thymus, and DP T cells are more apoptotic. By contrast, proportionately more SP cells have matured, and SP-to-DP ratios are increased in mutant thymus. Thus, the O-fucose glycan in EGF12 of mouse Notch1 is required for optimal Notch1 signaling and T cell development in mammals.