Tissue-Specific Alternative Splicing of Tak1 Is Conserved in Deuterostomes
Tissue-Specific Alternative Splicing of Tak1 Is Conserved in Deuterostomes
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DOI：
10.1093/molbev/msr193
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发表时间：
2012-01-01
影响因子：
10.7
通讯作者：
Tazi, Jamal
中科院分区：
文献类型：
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作者：
Venables, Julian P.;Vignal, Emmanuel;Tazi, Jamal
选择性剪接允许生物体快速调节蛋白质功能以适应生理变化，因此代表了高度通用的适应性过程。我们研究了RNA结合剪接因子（RBFOX）的“Fox”家族的进化历史的保守性，以及它们控制的基因的调节性选择性剪接的保守性。我们发现，RBFOX蛋白是保守的所有后生动物检查。在人类中，Fox蛋白控制许多基因的肌肉特异性选择性剪接，但尽管剪接因子的保守性，但在人类和非脊椎动物物种之间从未证明过选择性剪接的调节的保守性。因此，我们研究了40个已知的Fox-regulated人类外显子，发现其中22个在肌肉和心脏中具有组织特异性剪接模式。其中，11个在小鼠组织中以相同的组织特异性方式剪接，4个在青蛙非洲爪蟾的肌肉和心脏中以组织特异性方式剪接。在蝌蚪发育过程中，这些替代外显子中的两个也被下调。在起始组中的40个中，最保守的选择性剪接事件是转化生长因子（TGF）β激活的激酶Tak 1（MAP 3 K7），因为这在尿索动物和Ambulacraria（最古老的后口动物分支）中也是肌肉特异性的。我们发现Tak 1的肌肉特异性外显子的排除本身在细胞培养物中受TGF β的控制，并且TGF β始终引起Fox 2（RBFOX 2）表达的上调。选择性外显子编码激酶和已知的TAK 1调节结构域之间的27个氨基酸，在所有生物体中含有保守特征，包括潜在的磷酸化位点，并且可能在TGF β信号传导和发育中具有重要的保守功能。这项研究证实，后口动物有一个显着保守的生理过程，该过程涉及剪接因子和靶基因组织特异性亚型的表达，从而加速了高度保守的信号通路。
Alternative splicing allows organisms to rapidly modulate protein functions to physiological changes and therefore represents a highly versatile adaptive process. We investigated the conservation of the evolutionary history of the "Fox" family of RNA-binding splicing factors (RBFOX) as well as the conservation of regulated alternative splicing of the genes they control. We found that the RBFOX proteins are conserved in all metazoans examined. In humans, Fox proteins control muscle-specific alternative splicing of many genes but despite the conservation of splicing factors, conservation of regulation of alternative splicing has never been demonstrated between man and nonvertebrate species. Therefore, we studied 40 known Fox-regulated human exons and found that 22 had a tissue-specific splicing pattern in muscle and heart. Of these, 11 were spliced in the same tissue-specific manner in mouse tissues and 4 were tissue-specifically spliced in muscle and heart of the frog Xenopus laevis. The inclusion of two of these alternative exons was also downregulated during tadpole development. Of the 40 in the starting set, the most conserved alternative splicing event was in the transforming growth factor (TGF) beta-activated kinase Tak1 (MAP3K7) as this was also muscle specific in urochordates and in Ambulacraria, the most ancient deuterostome clade. We found exclusion of the muscle-specific exon of Tak1 was itself under control of TGF beta in cell culture and consistently that TGF beta caused an upregulation of Fox2 (RBFOX2) expression. The alternative exon, which codes for an in-frame 27 amino acids between the kinase and known regulatory domain of TAK1, contains conserved features in all organisms including potential phosphorylation sites and likely has an important conserved function in TGF beta signaling and development. This study establishes that deuterostomes share a remarkable conserved physiological process that involves a splicing factor and expression of tissue-specific isoforms of a target gene that expedites a highly conserved signaling pathway.