T lymphocyte-specific gene targeting of Notch receptor glycosyltransferase fringe

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Notch1, one of Notch receptors, is essential for T cell development from lymphoid precursor. For instance, Notch1-deficient mice completely lack T cell development. Interactions between Notch receptors and their ligands are generally affected by glycosylation of Notch receptors, and enzymes to glycosylate them are fringes including three members in mammals : lunatic, manic and radical fringes. However, the role of glycosylation of Notch1 during T cell development has not been fully understood. By searching genes that dynamically change their expression during T cell development, we found that lunatic fringe (Lfg) showed different expression levels during the maturation process of thymocytes. To clarify an involvement of Lfg in T cell differentiation, we attempted to generate T lymphocyte-specifically Lfg-deficient mice using conditional gene targeting technology. Unfortunately the other group in Canada has produced the Lfg knockout mice in the way of our project. Finally, we changed our strategy to address our aim and we got the following results. The culture of CD4^-CD8^- thymocytes in which Lfg was ectopically expressed by using fetal thymic organ culture enhanced differentiation of immature CD8^+ T cells while inhibiting CD4^+CD8^- mature T-cell development. we found that Lfg that generally strengthens the interaction between Notch and Notch ligands (Delta family) regulates T cell development probably affecting the glycosylation of Notch1. Interestingly, the high expression of Lfg in lymphoid precursor regulates T cell development by strengthening Notch signaling of their own (cell autonomous) and inhibits the development toward T cells from neighboring precursors by competing limited amounts of Notch ligands in the thymus (non-autonomous). These results indicate that Lfg has novel roles to set the threshold of Notch signaling to promote T cell development in a cell autonomous and non-autonomous manner.