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 Notch1~(12f) allele and an inactive Notch1 allele die at approximately embryonic day (E)12 with a typical Notchi null phenotype. Homozygous Notch1~(12f/12f) mice are viable and fertile but grow somewhat more slowly than littermates after weaning. Notch1~(12f/12f) thymocytes bind less Delta1 and exhibit reduced Notchi signaling. The number of double-positive (DP) and single-positive (SP) T cells are decreased in Notch1~(12f/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 Notchi is required for optimal Notchi signaling and T cell development in mammals.