An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons
An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons
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DOI：
10.1101/gad.1837009
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发表时间：
2009-10-01
影响因子：
10.5
通讯作者：
Black, Douglas L.
中科院分区：
文献类型：
--
作者：
Lee, Ji-Ann;Tang, Zhen-Zhi;Black, Douglas L.
神经元去极化和CaM激酶IV信号改变离子通道、神经递质受体和其他突触蛋白转录本中多个外显子的剪接。这些剪接的变化部分介导的特殊钙调蛋白激酶响应的RNA元件，内或附近的外显子被压抑在慢性去极化的初始阶段。许多神经元转录物的剪接也受到Fox（X上的雌性化基因）蛋白家族成员的调节，并且这些Fox靶点通常也是影响突触活性的蛋白质。我们发现Fox-1/共济失调蛋白2结合蛋白1（A2 BP 1），一种与多种神经系统疾病有关的蛋白质，可以抵消慢性去极化对剪接的影响。我们发现Fox-1的外显子19本身被去极化抑制。缺失外显子19的Fox-1转录物编码Fox-1的核同种型，当细胞保持去极化培养基时，其逐渐取代细胞质Fox-1同种型。核Fox-1的增加导致许多Fox-1靶外显子的再活化，包括NMDA受体1的外显子5，其最初被高KCl培养基抑制。这些结果揭示了一种新的机制，缓慢调制的剪接细胞适应慢性刺激：亚细胞定位的剪接调节通过自己的选择性剪接控制。
Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated in a variety of neurological diseases, can counteract the effects of chronic depolarization on splicing. We find that exon 19 of Fox-1 is itself repressed by depolarization. Fox-1 transcripts missing exon 19 encode a nuclear isoform of Fox-1 that progressively replaces the cytoplasmic Fox-1 isoform as cells are maintained depolarizing media. The resulting increase in nuclear Fox-1 leads to the reactivation of many Fox-1 target exons, including exon 5 of the NMDA receptor 1, that were initially repressed by the high-KCl medium. These results reveal a novel mechanism for the slow modulation of splicing as cells adapt to chronic stimuli: The subcellular localization of a splicing regulator is controlled through its own alternative splicing.