Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification
Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification
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DOI：
10.1242/dev.087387
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发表时间：
2013-04-15
期刊：
影响因子：
4.6
通讯作者：
Merrill, Bradley J.
中科院分区：
文献类型：
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作者：
Hoffman, Jackson A.;Wu, Chun-I;Merrill, Bradley J.
胚胎干细胞(ESCs)的核心基因调控网络(GRN)整合了促自我更新因子Oct4(Pou5f1)、Sox2和Nanog以及自我更新抑制因子Tcf7l1(Tcf3)的活性。Tcf7l1的抑制功能依赖于细胞外Wnt/β-catenin的信号活性，使其在ESC GRN中的胚胎作用尚不清楚。通过分析完整的小鼠胚胎，我们证明了Tcf7l1的功能对于细胞谱系的指定是必要的，同时伴随着原肠胚三维身体计划的制定。在Tcf711(-/-)胚胎中，中胚层的指定被延迟，有效地将其从原始条纹的诱导中分离出来。在多能细胞对Wnt/β-catenin刺激的反应中，Tcf7l1的抑制活性是必需的，从自我更新反应到中胚层规范反应。这些结果证实，Tcf7l1是多能细胞为谱系指定做准备所必需的独特因子。我们认为Tcf7l1在哺乳动物中的作用是抑制GRN，以确保谱系特征与原肠形成过程中发生的动态细胞事件的协调。
The core gene regulatory network (GRN) in embryonic stem cells (ESCs) integrates activities of the pro-self-renewal factors Oct4 (Pou5f1), Sox2 and Nanog with that of an inhibitor of self-renewal, Tcf7l1 (Tcf3). The inhibitor function of Tcf7l1 causes dependence on extracellular Wnt/beta-catenin signaling activity, making its embryonic role within the ESC GRN unclear. By analyzing intact mouse embryos, we demonstrate that the function of Tcf7l1 is necessary for specification of cell lineages to occur concomitantly with the elaboration of a three-dimensional body plan during gastrulation. In Tcf7l1(-/-) embryos, specification of mesoderm is delayed, effectively uncoupling it from the induction of the primitive streak. Tcf7l1 repressor activity is necessary for a rapid switch in the response of pluripotent cells to Wnt/beta-catenin stimulation, from one of self-renewal to a mesoderm specification response. These results identify Tcf7l1 as a unique factor that is necessary in pluripotent cells to prepare them for lineage specification. We suggest that the role of Tcf7l1 in mammals is to inhibit the GRN to ensure the coordination of lineage specification with the dynamic cellular events occurring during gastrulation.