We are interested in understanding signaling events in the thymus that regulate T cell development. Current efforts are aimed at delineating the role of evolutionarily conserved Wnt-beta-catenin-TCF pathway. To this end, we have manipulated the transcription factor TCF1 gene and the beta-catenin gene, which mediate the canonical Wnt signaling pathway. In this study we have used TCF1-deficient (TCF1-KO) mice, (beta-CAT) mice expressing transgenic beta-catenin. T cells develop in the thymus from a progenitor population that migrate via blood from the bone marrow to the thymus. Earliest thymic precursor (ETP) has been identified as giving rise to majority of developing thymocytes. Recently, it was shown that Notch signals, which are required for commitment to T lineage activate expression of TCF1 in the ETP. These cells develop to a stage defined as the CD4-CD8- double negative (DN) 2 stage followed by development to the DN3 stage. We have found that failure to induce TCF1 expression in TCF1-KO thymocytes leads to a profound block in T cell development such that ETP cells fail to develop to the DN2 stage. These cells fail to survive and gene expression profile suggests that TCF1 and beta-catenin dependent transcription induces the expression of genes essential for maturation. Future studies are aimed to understand the molecular basis for TCF1 and beta-catenin dependent T cell development in the thymus.
