Signaling in the DN to DP thymocyte transition

描述(由申请人提供)：在胸腺细胞发育的CD44-CD25+(DN3)阶段，TCR-β基因与不变的前TCR-α和CD3亚单位的有效重排导致在细胞表面形成前TCR复合体。细胞自主和配体非依赖的Pre-TCR信号触发一系列复杂的信号事件，导致未成熟胸腺细胞的存活、增殖和分化。WNT/β-连环蛋白途径是在TCR前活性开始后的各个阶段中发挥重要作用的级联反应之一。β-连环蛋白是WNT信号转导的中枢调节因子，该信号通路激活后的稳定导致其转运到细胞核，在那里它与TCF/Lef转录因子结合并激活。缺乏TCF-1和LEF-1(淋巴细胞特异性β-连环素调节的转录因子)导致胎儿胸腺器官培养(FTOC)中胎儿胸腺细胞发育完全受阻，处于未成熟的单一阳性阶段。β-catenin与Tcf-1的相互作用是该蛋白在糖尿病肾病向DP转变过程中所必需的，在缺乏前TCR和ab-TCR信号的情况下，β-catenin的体细胞稳定可以介导发育进程。WNT/β-catenin途径的确切作用机制以及参与该发育阶段的分子组成和特异靶点仍有待阐明。鉴于这一发育转变依赖于前TCR信号，因此特别研究前TCR和WNT/β-catenin信号级联之间的相互作用变得重要。目前的建议集中在解剖WNT/β-连环蛋白信号在糖尿病肾病到DP胸腺细胞的转变中的需求，以及确定前TCR和WNT/β-连环蛋白信号级联之间的相互作用。

DESCRIPTION (provided by applicant): 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.