title: Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions.
abstract: Notch signaling is essential for lymphocyte development and is also implicated in myelopoiesis. Notch receptors are modified by O-fucosylation catalyzed by protein O-fucosyltransferase 1 (Pofut1). Fringe enzymes add N-acetylglucosamine to O-fucose and modify Notch signaling by altering the sensitivity of Notch receptors to Notch ligands. To address physiologic functions in hematopoiesis of Notch modified by O-fucose glycans, we examined mice with inducible inactivation of Pofut1 using Mx-Cre. These mice exhibited a reduction in T lymphopoiesis and in the production of marginal-zone B cells, in addition to myeloid hyperplasia. Restoration of Notch1 signaling rescued T lymphopoiesis and the marrow myeloid hyperplasia. After marrow transfer, both cell-autonomous and environmental cues were found to contribute to lymphoid developmental defects and myeloid hyperplasia in Pofut1-deleted mice. Although Pofut1 deficiency slightly decreased cell surface expression of Notch1 and Notch2, it completely abrogated the binding of Notch receptors with Delta-like Notch ligands and suppressed downstream Notch target activation, indicating that O-fucose glycans are critical for efficient Notch-ligand binding that transduce Notch signals. The combined data support a key role for the O-fucose glycans generated by Pofut1 in Notch regulation of hematopoietic homeostasis through modulation of Notch-ligand interactions.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Yao
authors.forename: Yuanshuai
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Huang
authors.forename: Weihuan
authors.initials: W
authors.lastname: Wang
authors.forename: Quanjian
authors.initials: Q
authors.lastname: Yan
authors.forename: Lebing
authors.initials: L
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.forename: Stanton
authors.initials: S
authors.lastname: Gerson
authors.forename: Pamela
authors.initials: P
authors.lastname: Stanley
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005643:Fucose / Q000378:metabolism; D005647:Fucosyltransferases / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D006965:Hyperplasia / Q000201:enzymology / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008024:Ligands; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D038042:Myelopoiesis / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology
chemical_list: D008024:Ligands; D012333:RNA, Messenger; D051880:Receptors, Notch; D005643:Fucose; D005647:Fucosyltransferases; C539426:Pofut1 protein, mouse; C045073:Cre recombinase; D019426:Integrases; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase