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Glycan‐dependent Control of Myelopoiesis
Author(s) -
Lowe John,
Yao David,
Petryniak Bronia,
Shim Jeongsup,
Stanley Pamela,
Zhou Lan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.335.1
Subject(s) - fucosylation , notch signaling pathway , notch proteins , myelopoiesis , microbiology and biotechnology , hes3 signaling axis , biology , signal transduction , chemistry , fucose , progenitor cell , biochemistry , stem cell , glycoprotein
Notch1 is modified by O‐fucosylation catalyzed by Protein O‐fucosyltransferase 1 (Pofut1). The Fringe family of glycosyltransferases extend Notch‐borne O‐fucose moieties, and modulate Notch1 signaling by altering the sensitivity of Notch receptors to Notch ligands. To address the physiologic function Notch O‐fucosylation in myelopoiesis, we characterized myelopoiesis in mice carrying a deficiency in fucosylation (the FX(−/−) mouse), or with an inducible deficiency of Pofut1. In either strain, loss of Notch fucosylation yields a myeloid hyperplasia phenotype. Restoration of Notch1 signaling suppresses myeloid hyperplasia. Loss of fucosylation in FX(−/−) mice or in Pofut1‐deficient mice is associated with diminished cell surface expression of Notch family members, loss of binding of Notch ligands to the fucosylation‐deficient cells in the mice, and suppressed activation of Notch target genes. Surface plasmon resonance experiments indicate that Fringe‐mediated elongation of O‐fucosylated Notch modulates binding of Notch ligands to Notch1, corresponding to Fringe‐dependent modulation of Notch1‐dependent signal transduction. These observations indicate that Pofut1‐dependent Notch fucosylation is required for myelopoietic homeostasis via proper (i) cell surface localization of Notch1, (ii) binding of Notch ligands to Notch1, and (iii) Fringe‐dependent modulation of Notch1 signaling.