title: Lunatic Fringe prolongs Delta/Notch-induced self-renewal of committed αβ T-cell progenitors.
abstract: Lunatic Fringe (Lfng) enhances Notch1 activation by Delta-like 4 (DL4) to promote Notch1-dependent T-lineage commitment of thymus-seeding progenitors. Subsequently, Notch1 and T-cell receptor-β (TCRβ)-containing pre-TCR complexes signal CD4/CD8 double-negative 3 (DN3) committed T-cell progenitors to survive, proliferate, and differentiate into CD4/CD8 double-positive (DP) αβ T-cell precursors. Few DP thymocytes develop without Notch1 or pre-TCR signals, whereas ectopic Notch1 activation causes T-cell leukemia. However, mechanisms of a Notch-pre-TCR collaboration during this "β-selection" process are poorly understood. We genetically manipulated Lfng to attenuate or enhance Notch1 activation in DN3 thymocytes without inducing leukemogenesis. We show that Lfng temporally sustains DL-induced Notch1 signaling to prolong proliferative self-renewal of pre-DP thymocytes. Pre-TCR signaling greatly augmented Notch trophic functions to promote robust proliferation of pre-DP progenitors. In contrast, in the absence of DL/Notch signaling, pre-TCR-expressing progenitors rapidly atrophied and differentiated into DP thymocytes. Thus, Lfng prolongs Notch1 signaling to promote self-renewal more than differentiation during the early stages of β-selection. Our data provide novel insights into the Notch-pre-TCR collaboration, and suggest that decreasing Lfng expression during the DN3-DP transition minimizes the potent leukemogenic potential of Notch1 signaling.
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, 101 College Street, Toronto, Ontario, Canada.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Yuan
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Tan
authors.forename: Ioana
authors.initials: I
authors.lastname: Visan
authors.forename: Irina R
authors.initials: IR
authors.lastname: Matei
authors.forename: Peter
authors.initials: P
authors.lastname: Urbanellis
authors.forename: Keli
authors.initials: K
authors.lastname: Xu
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016695:Glycosyltransferases; C498392:Lfng protein, mouse