A beta-catenin/engrailed chimera selectively suppresses Wnt signaling.
A beta-catenin/engrailed chimera selectively suppresses Wnt signaling.
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发表时间：
2000-05
影响因子：
4
通讯作者：
W. T. Montross;H. Ji;P. McCrea
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文献类型：
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作者：
W. T. Montross;H. Ji;P. McCrea
β-连环蛋白通过将粘附连接的钙粘蛋白复合物连接到下面的肌动蛋白细胞骨架而在细胞-细胞粘附中起着不可或缺的作用。此外，β-连环蛋白在Wnt发育途径内转导细胞内信号，这对胚胎轴的正确建立和早期中胚层和外胚层的模式形成至关重要。例如，在早期非洲爪蟾胚胎的确定的背侧“组织者”区域的背景下，β-连环蛋白进入细胞核并与HMG（高迁移率组）Lef/Tcf蛋白家族的转录因子相关联。因此，基因如siamois，一个同源异型盒基因有助于规范的背前轴，被激活。为了进一步研究β-连环蛋白在Wnt信号传导中的作用，我们产生了一种嵌合蛋白，β-Engrailed（β-Eng），其中β-连环蛋白的C-末端反式激活结构域被果蝇Engrailed的转录抑制结构域取代。这种mRNA在早期爪蟾胚胎的背侧过度表达导致组织特异性分子标记物如siamois，Xnr-3和goosecoid的抑制，与胚胎的戏剧性形态学腹侧化相对应。胚胎发育的胚胎进一步表现出Wnt途径活性降低，如脊索/组织者标记物脊索蛋白的丧失所示。重要的是，β-Eng通常与钙粘蛋白复合物的已知组分相关联并起作用，这提供了抑制β-连环蛋白的信号传导功能的实验机会，除了其在钙粘蛋白介导的细胞-细胞粘附中的作用之外。
beta-catenin plays an integral role in cell-cell adhesion by linking the cadherin complex of the adherens junction to the underlying actin cytoskeleton. In addition, beta-catenin transduces intracellular signals within the Wnt developmental pathway that are crucial to the proper establishment of embryonic axes and pattern formation of early mesoderm and ectoderm. For example, in the context of a defined dorsal 'organizer' region of early Xenopus embryos, beta-catenin enters the nucleus and associates with transcription factors of the HMG (High Mobility Group) Lef/Tcf protein family. Consequently, genes such as siamois, a homeobox gene contributing to the specification of the dorsoanterior axis, are activated. To further examine the role that beta-catenin plays in Wnt signaling, we generated a chimeric protein, beta-Engrailed (beta-Eng), in which the C-terminal trans-activation domain of beta-catenin is replaced with the transcriptional repression domain of Drosophila Engrailed. Dorsal overexpression of this mRNA in early Xenopus embryos leads to suppression of organizer-specific molecular markers such as siamois, Xnr-3 and goosecoid, corresponding with the dramatic morphological ventralization of embryos. Ventralized embryos further exhibit reduced activity of the Wnt pathway, as indicated by the loss of the notochord/organizer marker, chordin. Importantly, beta-Eng associates and functions normally with the known components of the cadherin complex, providing the experimental opportunity to repress beta-catenin's signaling function apart from its role in cadherin-mediated cell-cell adhesion.