The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development.
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 Notch1 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 Notch1 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 Notch1 is required for optimal Notch1 signaling and T cell development in mammals.
Ge
Changhui
C
Deparment of Cell Biology, Albert Einstein College of Medicine of Yeshiva University, New York, NY 10461, USA.
Stanley
Pamela
P
D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D005643:Fucose / Q000032:analysis / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D011134:Polysaccharides / Q000032:analysis / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
C497762:Notch1 protein, mouse; D011134:Polysaccharides; D051881:Receptor, Notch1; D005643:Fucose