TY - JOUR
T1 - The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development
AU - Ge, Changhui
AU - Stanley, Pamela
PY - 2008/2/5
Y1 - 2008/2/5
N2 - 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, post-weaning 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. 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 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.
AB - 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, post-weaning 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. 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 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.
KW - Hypomorphic mutation
KW - Notch signaling
KW - O-fucosylation mutant
UR - http://www.scopus.com/inward/record.url?scp=40349089637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40349089637&partnerID=8YFLogxK
U2 - 10.1073/pnas.0702846105
DO - 10.1073/pnas.0702846105
M3 - Article
C2 - 18227520
AN - SCOPUS:40349089637
SN - 0027-8424
VL - 105
SP - 1539
EP - 1544
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -