Overexpression of ICAT highlights a rolefor catenin-mediated canonical Wnt signalling in early T cell development

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.