Productive rearrangement of TCR-beta genes at the CD44- CD25+ (DN3) stage of thymocyte development and assembly with the invariant pre-TCR-alpha and CD3 subunits leads to the formation of a pre-TCR complex on the cell surface. Cell autonomous and ligand independent pre-TCR signaling triggers a complex cascade of signaling events leading to the survival, proliferation and differentiation of immature thymocytes. One of the cascades that play an essential role in the stages following the onset of pre-TCR activity is the wnt/beta-catenin pathway. Beta-catenin is the central mediator of wnt signaling, whose stabilization in response to activation of this pathway results to its transport to the nucleus, where it binds to and activates the TCF/LEF transcription factors. Deficiency for both TCF-1, and LEF-1, lymphocyte specific beta-catenin regulated transcription factors, results in a complete block of fetal thymocyte development in fetal thymic organ cultures (FTOC) at the immature single positive stage. Interaction of beta-catenin with TCF-1 is necessary for the action of this protein during the DN to DP transition, and somatic stabilization of beta-catenin can mediate developmental progression in the absence of pre-TCR and ab-TCR signaling. The exact mechanism of function as well as the molecular components and specific targets of the wnt/beta-catenin pathway involved in this developmental stage remain to be elucidated. In view of the fact that this developmental transition depends on pre-TCR signaling it becomes important to specifically examine the interaction between the pre-TCR and the wnt/beta- catenin signaling cascades. The present proposal focuses at dissecting the requirement for wnt/beta-catenin signaling in the DN to DP thymocyte transition as well as determining the interaction between pre-TCR and wnt/beta-catenin signaling cascades.

R01AI059676

2004-04-01

2010-03-31