title: Overexpression of ICAT highlights a role for catenin-mediated canonical Wnt signalling in early T cell development.
abstract: Transcription factors of the T cell factor/lymphoid enhancing factor (Tcf/Lef) family are key regulators in the development of T cell precursors to the CD4+8+ stage. These factors are known targets of the canonical Wnt signalling pathway, and regulate transcription of Wnt target genes following interaction with the armadillo repeat-containing protein beta-catenin. However, as recent studies show normal thymocyte maturation in the absence of either beta-catenin or its homologue gamma-catenin, the role of Wnt signalling in Tcf/Lef activation during T cell development is controversial. To directly investigate the importance of catenin-mediated Wnt signalling in early thymocytes, we have compared the expression of beta- and gamma-catenin and analysed distinct stages of T cell precursor maturation following overexpression of inhibitor of beta-catenin and Tcf (ICAT), which inhibits Wnt signalling by preventing binding of armadillo repeat-containing proteins to Tcf/Lef. By direct retroviral gene targeting of CD4-8- and CD4+8+ precursors, we show that ICAT overexpression inhibits the CD4-8--to-CD4+8+ transition, but not the CD4+8+-to-CD4+8- or -CD4-8+ transition. Collectively, our data support a model in which canonical Wnt signalling influences T cell development in the thymus by playing an essential role in the maturation of CD4-8- but not CD4+8+ thymocytes.
authors.affiliation: MRC Centre for Immune Regulation, Division of Immunity and Infection, Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Judit E
authors.initials: JE
authors.lastname: Pongracz
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.forename: Terry
authors.initials: T
authors.lastname: Jones
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D051177:Catenins / Q000096:biosynthesis* / Q000276:immunology; D018797:Cell Cycle Proteins / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology*; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism; D051153:Wnt Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; D016827:CD8 Antigens; D051177:Catenins; D018797:Cell Cycle Proteins; C498785:Ctnnbip1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins