Rescue of a Wnt mutation by an activated form of LEF-1:: Regulation of maintenance but not initiation of Brachyury expression
Rescue of a Wnt mutation by an activated form of LEF-1:: Regulation of maintenance but not initiation of Brachyury expression
复制标题
DOI：
10.1073/pnas.151258098
复制
发表时间：
2001-07-17
影响因子：
11.1
通讯作者：
Grosschedl, R
中科院分区：
文献类型：
--
作者：
Galceran, J;Hsu, SC;Grosschedl, R
LEF-1/TCF家族转录因子的成员通过与β-连环蛋白结合而参与介导对Wnt信号的核应答，与此观点一致，先前发现在Wnt 3a基因或转录因子基因Lef 1和Tcf 1中携带突变的小鼠在原肠胚形成小鼠胚胎中显示出相似的近轴中胚层形成缺陷.此外，Brachyury基因（LEF-1的直接转录靶基因）的突变显示会导致中胚层缺陷。然而，LEF-1和Brachyury在Wnt 3a信号传导中的作用的直接证据是有限的。在这项研究中，我们从遗传学角度研究了LEF-1在调节Brachyury表达和Wnt 3a信号传导中的功能。对Brachyury在Lef 1（-/-）Tcf 1（-/-）小鼠中表达的分析和对含有野生型或突变型LEF-1结合位点的Brachyury：lacZ转基因的研究表明，Lef 1是启动子，但对于Brachyury表达的维持是必需的。我们还表明，表达活化形式的LEF-1，含有β-连环蛋白活化结构域融合的氨基末端的LEF-1，可以挽救Wnt 3a突变。总之，这些数据提供了遗传证据，即Lef 1介导Wnt 3a信号并调节原肠胚形成期间Brachyury表达的稳定维持。
Members of the LEF-1/TCF family of transcription factors have been implicated in mediating a nuclear response to Wnt signals by association with beta -catenin, consistent with this view, mice carrying mutations in either the Wnt3a gene or in both transcription factor genes Lef1 and Tcf1 were previously found to show a similar defect in the formation of paraxial mesoderm in the gastrulating mouse embryo. In addition, mutations in the Brachyury gene, a direct transcriptional target of LEF-1, were shown to result in mesodermal defects. However, direct evidence for the role of LEF-1 and Brachyury in Wnt3a signaling has been limiting. In this study, we genetically examine the function of LEF-1 in the regulation of Brachyury expression and in signaling by Wnt3a. Analysis of the expression of Brachyury in Lef1(-/-)Tcf1(-/-) mice and studies of Brachyury:lacZ transgenes containing wild type or mutated LEF-1 binding sites indicate that Lef1 is dispensable for the initiation, but is required for the maintenance of Brachyury expression. We also show that the expression of an activated form of LEF-1, containing the beta -catenin activation domain fused to the amino terminus of LEF-1, can rescue a Wnt3a mutation. Together, these data provide genetic evidence that Lef1 mediates the Wnt3a signal and regulates the stable maintenance of Brachyury expression during gastrulation.