title: Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival.
abstract: Intrathymic T-cell maturation critically depends on the selective expansion of thymocytes expressing a functionally rearranged T-cell receptor (TCR) beta chain. In addition, TCR-independent signals also contribute to normal T-cell development. It is unclear whether and how signals from the 2 types of pathways are integrated. Here, we show that T-cell factor-1 (TCF-1), a nuclear effector of the canonical wingless/int (wnt)/catenin signaling pathway, ensures the survival of proliferating, pre-TCR(+) thymocytes. The survival of pre-TCR(+) thymocytes requires the presence of the N-terminal catenin-binding domain in TCF-1. This domain can bind the transcriptional coactivator beta-catenin and may also bind gamma-catenin (plakoglobin). However, in the absence of gamma-catenin, T-cell development is normal, supporting a role for beta-catenin. Signaling competent beta-catenin is present prior to and thus arises independently from pre-TCR signaling and does not substantially increase on pre-TCR signaling. In contrast, pre-TCR signaling significantly induces TCF-1 expression. This coincides with the activation of a wnt/catenin/TCF reporter transgene in vivo. Collectively, these data suggest that efficient TCF-dependent transcription requires that pre-TCR signaling induces TCF-1 expression, whereas wnt signals may provide the coactivator such as beta-catenin. The 2 pathways thus have to cooperate to ensure thymocyte survival at the pre-TCR stage.
authors.affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, Ch des Boveresses 155, 1066 Epalinges, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Goux
authors.forename: Jérôme D
authors.initials: JD
authors.lastname: Coudert
authors.forename: Diane
authors.initials: D
authors.lastname: Maurice
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scarpellino
authors.forename: Grégoire
authors.initials: G
authors.lastname: Jeannet
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
authors.forename: Kathleen
authors.initials: K
authors.lastname: Weston
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.forename: Werner
authors.initials: W
authors.lastname: Held
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology*; D051180:Desmoplakins; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013329:Structure-Activity Relationship; D051822:T Cell Transcription Factor 1; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000276:immunology*; D051153:Wnt Proteins; D051185:gamma Catenin
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051180:Desmoplakins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C495293:Jup protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D011948:Receptors, Antigen, T-Cell; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051185:gamma Catenin; C064658:RAG-1 protein