T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling
T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling
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DOI：
10.1073/pnas.1110230108
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发表时间：
2011-12-13
影响因子：
11.1
通讯作者：
Gounari, Fotini
中科院分区：
文献类型：
--
作者：
Germar, Kristine;Dose, Marei;Gounari, Fotini
尽管已经描述了与T细胞特化和定型相关的转录程序，但功能层次结构和关键调控因子在构建/编排这些程序中的作用仍不清楚。通过胸腺基质激活未定型前体中的Notch信号传导启动T细胞分化程序。首先在这些前体中诱导的一种调节剂是DNA结合蛋白T细胞因子1（Tcf-1），其是Wnt信号传导的T细胞特异性介体。然而，Tcf-1对早期T细胞发育的具体贡献以及在这些细胞中诱导它的信号仍然不清楚。在这里，我们分配的功能意义Tcf-1作为T细胞命运的看门人，并表明Tcf-1是直接激活的Notch信号。Tcf-1在T细胞决定的最早阶段是必需的，以便在早期胸腺祖细胞阶段之后进展。Tcf-1缺陷的祖细胞的整体表达谱表明，DNA代谢的基本过程在其缺失的情况下被下调，并且被阻断的T细胞祖细胞变得流产并通过凋亡而死亡。因此，我们的数据为T细胞发育的路线图添加了重要的功能关系。
Although transcriptional programs associated with T-cell specification and commitment have been described, the functional hierarchy and the roles of key regulators in structuring/orchestrating these programs remain unclear. Activation of Notch signaling in uncommitted precursors by the thymic stroma initiates the T-cell differentiation program. One regulator first induced in these precursors is the DNA-binding protein T-cell factor 1 (Tcf-1), a T-cell-specific mediator of Wnt signaling. However, the specific contribution of Tcf-1 to early T-cell development and the signals inducing it in these cells remain unclear. Here we assign functional significance to Tcf-1 as a gatekeeper of T-cell fate and show that Tcf-1 is directly activated by Notch signals. Tcf-1 is required at the earliest phase of T-cell determination for progression beyond the early thymic progenitor stage. The global expression profile of Tcf-1-deficient progenitors indicates that basic processes of DNA metabolism are down-regulated in its absence, and the blocked T-cell progenitors become abortive and die by apoptosis. Our data thus add an important functional relationship to the road-map of T-cell development.