Roles of Wnt/β-catenin/TCF signal transduction pathway in early T cell development

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Wnt/β-catenin/TCF signaling is important for murine early T cell development. However, our understanding of each transmitting molecule is incomplete. As the result of this study, a member of the Frizzled (Fz) family, Fz3, to which secreted Wnt protein binds, is revealed to be one of key factors in the pathway. I have also established a method efficiently transducing gene into murine hematopoietic progenitors.The expression level of Fz genes in fetal and adult thymus was examined by RT-PCR.We found that Fz3 is exclusively transcribed in fetal thymocytes, and that the highest expression is observed at the developmental stage after which rearrangement of T cell receptor (TCR) β chain gene occurs. In order to investigate the function of Fz3 during early T cell development, a dominant negative form retaining only Fz3 extracellular domain (sFz3) was forced to express in hematopoietic progenitors and the cells were cultured under the conditions suitable for T cell development. For the transduction, a retroviral vector with GFP gene as a marker was used. The number of cells recovered after the culture was far less than that obtained from the vector-transduced sample. Surprisingly, immature CD3^-CD4^-CD8^-CD44^-CD25^+ T cells still existed in the sFz3-transduced sample. Additionally, Fz3 is not expressed in TCR^+ T cells. Taken together, my data strongly suggest that the signal mediated by Fz3 is indispensable for differentiation and proliferation of T progenitors which rearranged TCR β but not α chain gene, and that the signal is partly responsible for multiplying more primitive T progenitors with unrearranged TCR β chain loci. In the future, Wnt molecules that bind to Fz3 in the T progenitors should be determined. In addition, analysis of target genes regulated by the Fz3 signaling will be required to comprehend the molecular mechanisms of early T cell development.