Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila
Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila
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DOI：
10.1242/dev.057729
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发表时间：
2011-03-01
期刊：
影响因子：
4.6
通讯作者：
Jimenez, Gerardo
中科院分区：
文献类型：
--
作者：
Ajuria, Leiore;Nieva, Claudia;Jimenez, Gerardo
RTK/RAS/MAPK信号通路在后生动物的发育中起着关键作用，但它们如何控制下游基因的表达尚不清楚。在果蝇中，通常认为对RTK信号激活的大多数转录反应依赖于ETS家族蛋白与靶增强子中特定的顺式作用位点的结合。在这里，我们证明了几个果蝇RTK途径通过共同的八聚体元件控制下游基因的表达，这些八聚体元件是HMG-box因子Capicua的结合部位，HMG-box因子Capicua是一种转录抑制因子，在不同的上下文中被RTK信号下调。我们发现，躯干RTK依赖于躯干RTK对早期胚胎末端GAP基因表达的调节关键依赖于CapicuA八聚体位点，而Capicua与这些位点的结合对于Groucho共抑制子在体内招募到huckebein增强子是必不可少的。然后，我们证明了胚胎神经外胚层中EGFR RTK通路的随后激活通过下调Capicua蛋白来控制背腹基因的表达，并且这种控制也依赖于Capicua八聚体基序。因此，RTK调节的类似机制在胚轴的前后部和背腹部的细分过程中起作用。我们还发现，相同的DNA八聚体介导了发育中翅膀中另一个EGFR靶标的Capicua依赖调节。值得注意的是，激活物结合位点和Capicua基序的简单组合足以在不同组织中建立响应躯干和EGFR激活的复杂基因表达模式。我们的结论是，Capicua八聚体是果蝇RTK信号的一般反应元件。
RTK/Ras/MAPK signaling pathways play key functions in metazoan development, but how they control expression of downstream genes is not well understood. In Drosophila, it is generally assumed that most transcriptional responses to RTK signal activation depend on binding of Ets-family proteins to specific cis-acting sites in target enhancers. Here, we show that several Drosophila RTK pathways control expression of downstream genes through common octameric elements that are binding sites for the HMG-box factor Capicua, a transcriptional repressor that is downregulated by RTK signaling in different contexts. We show that Torso RTK-dependent regulation of terminal gap gene expression in the early embryo critically depends on Capicua octameric sites, and that binding of Capicua to these sites is essential for recruitment of the Groucho co-repressor to the huckebein enhancer in vivo. We then show that subsequent activation of the EGFR RTK pathway in the neuroectodermal region of the embryo controls dorsal-ventral gene expression by downregulating the Capicua protein, and that this control also depends on Capicua octameric motifs. Thus, a similar mechanism of RTK regulation operates during subdivision of the anterior-posterior and dorsal-ventral embryonic axes. We also find that identical DNA octamers mediate Capicua-dependent regulation of another EGFR target in the developing wing. Remarkably, a simple combination of activator-binding sites and Capicua motifs is sufficient to establish complex patterns of gene expression in response to both Torso and EGFR activation in different tissues. We conclude that Capicua octamers are general response elements for RTK signaling in Drosophila.