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: 7034667
• 负责人: Fotini Gounari
• 金额: $ 35.81万
• 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/7034667
• 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）：在CD44-CD25+（DN3）胸腺细胞发育和组装中，与不变的TCR-Alpha和CD3亚基的组装在CD44-CD25+（DN3）阶段的生产性重排导致细胞表面上的Pre-TCR复合物形成。细胞自主和配体独立的TRE-TCR信号传导触发了一系列复杂的信号事件级联，导致未成熟胸腺细胞的存活，增殖和分化。 Wnt/beta-catenin途径是在TRE-TCR活动开始后在阶段中发挥至关重要的级联作用之一。 β-catenin是Wnt信号传导的中心介体，其稳定对该途径的激活导致其转运到细胞核，并在该核中与TCF/LEF转录因子结合并激活。 TCF-1和LEF-1，淋巴细胞特异性β-catenin调节转录因子的缺乏，在未成熟的单个阳性阶段在胎儿胸腺器官培养物（FTOC）中导致胎儿胸腺细胞发育的完整块。 β-catenin与TCF-1的相互作用对于在DN到DP过渡过程中该蛋白的作用是必要的，而在没有前TCR和AB-TCR信号传导的情况下，β-catenin的体稳定可以介导发展进展。该发育阶段涉及的Wnt/beta-catenin途径的功能以及分子成分和特定靶标的确切机制尚待阐明。鉴于这种发育过渡取决于TRE-TCR信号传导的事实，特异性检查前TCR与Wnt/beta- catenin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中Wnt/beta-catenin信号传导的需求，并确定前TCR和Wnt/beta-catenin信号级联的相互作用。