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

Changhui Ge, Pamela Stanley

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1539-1544
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number5
DOIs
StatePublished - Feb 5 2008

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Fucose
Embryonic Development
Polysaccharides
Ligands
T-Lymphocytes
Weaning
Thymus Gland
Alleles
Thymocytes
Heterozygote
Mammals
Phenotype
Growth

Keywords

  • Hypomorphic mutation
  • Notch signaling
  • O-fucosylation mutant

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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abstract = "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.",
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AU - Stanley, Pamela

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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.

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