Signaling in the DN to DP thymocyte transition

DN 至 DP 胸腺细胞转变中的信号传导

• 批准号: 6868943
• 负责人: Fotini Gounari
• 金额: $ 36.68万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868943
• 关键词: CD antigens; CD3 molecule; CD4 molecule; CD44 molecule; CD8 molecule; T cell receptor; T lymphocyte; biological signal transduction; cadherins; cell differentiation; laboratory mouse; microarray technology

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.

描述（由申请人提供）：TCR-β 基因在胸腺细胞发育的 CD44-CD25+ (DN3) 阶段进行生产性重排，并与不变的前 TCR-α 和 CD3 亚基组装，导致在胸腺细胞上形成前 TCR 复合物。细胞表面。细胞自主和配体独立的前 TCR 信号传导触发一系列复杂的信号传导事件，导致未成熟胸腺细胞的存活、增殖和分化。在 TCR 前活性开始后的阶段中发挥重要作用的级联之一是 wnt/β-连环蛋白途径。 β-连环蛋白是 wnt 信号传导的中心介质，其对该通路激活的反应稳定，导致其转运至细胞核，在细胞核中结合并激活 TCF/LEF 转录因子。 TCF-1 和 LEF-1（淋巴细胞特异性 β-连环蛋白调节转录因子）的缺乏，会导致胎儿胸腺器官培养物 (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-连环蛋白与 TCF-1 的相互作用对于该蛋白在 DN 到 DP 转变过程中的作用是必要的，并且 β-连环蛋白的体细胞稳定可以在没有 pre-TCR 和 ab-TCR 信号传导的情况下介导发育进程。参与该发育阶段的wnt/β-连环蛋白途径的确切功能机制以及分子成分和特定靶点仍有待阐明。鉴于这种发育转变依赖于前 TCR 信号传导，因此专门检查前 TCR 和 wnt/β-连环蛋白信号级联之间的相互作用变得很重要。本提案的重点是剖析 DN 到 DP 胸腺细胞转变中对 wnt/β-连环蛋白信号传导的需求，以及确定前 TCR 和 wnt/β-连环蛋白信号级联之间的相互作用。