Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia
Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia
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DOI：
10.1046/j.1471-4159.2000.740490.x
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发表时间：
2000-02-01
影响因子：
4.7
通讯作者：
Andreadis, A
中科院分区：
文献类型：
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作者：
Gao, QS;Memmott, J;Andreadis, A
Tau 是一种微管相关蛋白，其转录物在哺乳动物神经系统中经历复杂的调控剪接。该基因的外显子 10 是成人特异性的选择性剪接盒，编码微管结合域。最近，影响外显子 10 剪接的突变已被证明会导致遗传性额颞叶痴呆 (FTDP)。在这项研究中，我们建立了人体组织中外显子 10 的内源性表达模式；通过在外显子 10 的同源环境中重建天然存在的 FTDP 突变体，我们表明外显子 10 剪接调节的顺式决定因素包括外显子内的外显子沉默子、其 5' 剪接位点以及其侧翼外显子与其的相对亲和力。通过体内共转染，我们证明了几种剪接调节因子通过抑制外显子 10 包含来影响 tau 异构体的比例。
Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and that codes for a microtubule binding domain. Recently, mutations that affect splicing of exon 10 have been shown to cause inherited frontotemporal dementia (FTDP), In this study, we establish the endogenous expression patterns of exon 10 in human tissue; by reconstituting naturally occurring FTDP mutants in the homologous context of exon 10, we show that the cis determinants of exon 10 splicing regulation include an exonic silencer within the exon, its 5' splice site, and the relative affinities of its flanking exons to it. By cotransfections in vivo, we demonstrate that several splicing regulators affect the ratio of tau isoforms by inhibiting exon 10 inclusion.