Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10.
Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10.
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DOI：
10.3233/jad-180882
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发表时间：
2018-12
期刊：
影响因子：
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通讯作者：
Jianlan Gu;Feng Chen;Dandan Chu;Ying Lu;K. Iqbal;C. Gong;Fei Liu
中科院分区：
文献类型：
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作者：
Jianlan Gu;Feng Chen;Dandan Chu;Ying Lu;K. Iqbal;C. Gong;Fei Liu
tau外显子10的选择性剪接产生具有3或4个微管结合重复序列的tau同工异构体，3R-tau或4R-tau，它们受到发育调节。tau外显子10剪接的失调足以引起神经退行性疾病。RNA结合Fox3 (Rbfox3)，被鉴定为NeuN，调控RNA加工。然而，Rbfox3/NeuN是否调控tau外显子10剪接尚不清楚。在本研究中，我们发现4R-tau的发育表达与Rbfox3在大鼠脑中的表达一致。Rbfox3增强了tau外显子10的内含。Tau内含子10含有Rbfox3的保守结合序列UGCAUG。Rbfox3/NeuN共免疫沉淀tau前mrna内含子10。Rbfox3/NeuN中RNA识别基序（RRM）或RRM的三个RNA结合位点的缺失突变体未能增强tau外显子10的包含。Rbfox3在胎儿大脑中特异性表达，不影响tau外显子10剪接。Rbfox3/NeuN水平降低，并与kainic酸诱导的兴奋性中毒小鼠脑内4R-tau/3R-tau比值相关。这些发现表明Rbfox3/NeuN调控tau外显子10的选择性剪接，Rbfox3/NeuN的降低可能会降低4R-tau/3R-tau的比例。
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau.