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Studies on the establishment of the primitive streak region

原始条纹区建立研究

基本信息

批准号：
14380345
负责人：
SASAKI Hiroshi
金额：
$ 10.82万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14380345/
关键词：
axis formation primitive streak vertebrates TEF transcription factors shield マウス HNF3β Wnt Vestigial

项目摘要

Posterior extension of body axis is achieved by sequential addition of more posterior tissues in the primitive streak region, which consists of the node and the primitive streak. We previously found that core element of the node/notochord enhancer of Foxa2 gene drives gene expression specifically in the primitive streak region. Thus, to address the mechanism of establishment of the primitive streak region, we analyzed the regulatory mechanism of the core element. The core element is activated in the Wnt/β-catenin treated P19 cells, and this activation depends on the binding sites for two transcription factors. These binding sites are also essential for the in vivo activity of the node/notochord enhancer. One of the enhancer binding proteins is Tead, and inhibition of Tead activity by Tead-EnR in transgenic mouse embryos resulted in the loss of the notochord. Modulation of Tead activity in zebrafish embryos also altered foxa2 expression in the embryonic shield. These findings suggest that cooperation of Tead and a second factor is the central mechanism of Foxa2 expression in the node, and that this mechanism is evolutionally conserved. Since Tead is expressed widely, expression of the second factor should be restricted to the primitive streak region and this factor and Tead should cooperatively regulate gene expression in the primitive streak region. Tead family consists of four closely related proteins. To reveal the role of individual genes, we made knock out mice. Tead1 ; Tead2 double mutant embryos lack Foxa2 expression, and has defects in posterior body axis extension, suggesting that Tead1/2 play central roles in establishment of the central region.

体轴的后延是通过在由结节和原条组成的原条区内依次增加更多的后部组织来实现的。我们先前发现Foxa 2基因的节/脊索增强子的核心元件特异性地在原条区域驱动基因表达。因此，为了解决原条区的建立机制，我们分析了核心元件的调节机制。在Wnt/β-catenin处理的P19细胞中，核心元件被激活，并且这种激活依赖于两个转录因子的结合位点。这些结合位点对于结/脊索增强子的体内活性也是必需的。增强子结合蛋白之一是Tead，Tead-EnR在转基因小鼠胚胎中抑制Tead活性导致脊索丢失。斑马鱼胚胎中Tead活性的调节也改变了胚胎盾中foxa 2的表达。这些研究结果表明，合作的Tead和第二个因素是Foxa 2在节点中的表达的中心机制，这种机制是进化保守的。由于Tead广泛表达，第二个因子的表达应限于原条区域，并且该因子和Tead应协同调节原条区域中的基因表达。Tead家族由四种密切相关的蛋白质组成。为了揭示单个基因的作用，我们制造了基因敲除小鼠。Tead1 ; Tead 2双突变体胚胎Foxa 2表达缺失，体轴后部延伸缺陷，提示Tead 1/2在中央区的建立中起重要作用。