Spliceosomal component PRP-40 is a central regulator of microexon splicing.
Spliceosomal component PRP-40 is a central regulator of microexon splicing.
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DOI：
10.1016/j.celrep.2021.109464
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发表时间：
2021-08-03
期刊：
影响因子：
8.8
通讯作者：
Norris AD
中科院分区：
文献类型：
--
作者：
Choudhary B;Marx O;Norris AD
微外显子（≤27个核苷酸）在神经系统发育和功能中起着关键作用，但给剪接机制带来了独特的挑战。因此，微外显子调控机制备受关注。我们在秀丽隐杆线虫神经系统中对可变剪接调节因子进行了基因筛选，并鉴定出PRP - 40，它是U1小核核糖核蛋白的一个核心成分。RNA - seq显示，PRP - 40是包含可变剪接外显子（而非组成性剪接外显子）所必需的。PRP - 40对于包含神经元微外显子尤其重要，我们的数据表明PRP - 40是微外显子剪接的核心调节因子。通过人为增加外显子大小或减小侧翼内含子大小，可以使微外显子摆脱对PRP - 40的依赖，这表明PRP - 40是被常规大小内含子环绕的微外显子所特需的。在小鼠神经母细胞瘤细胞中敲低同源的PRPF40A会导致微外显子广泛失调，但常规大小的外显子不受影响。因此，PRP - 40对神经元微外显子的调控是一种广泛保守的现象。
微外显子在神经元功能中起关键作用，但给剪接体带来了机制上的挑战。乔杜里等人揭示，PRP - 40作为剪接体的一个核心成分，是秀丽隐杆线虫和哺乳动物细胞中包含微外显子所必需的。PRP - 40被认为是对难以通过外显子定义的外显子进行内含子定义的介质。
Microexons (≤27 nt) play critical roles in nervous system development and function but create unique challenges for the splicing machinery. The mechanisms of microexon regulation are therefore of great interest. We performed a genetic screen for alternative splicing regulators in the C. elegans nervous system and identify PRP-40, a core component of the U1 snRNP. RNA-seq reveals that PRP-40 is required for inclusion of alternatively spliced, but not constitutively spliced, exons. PRP-40 is particularly required for inclusion of neuronal microexons, and our data indicate that PRP-40 is a central regulator of microexon splicing. Microexons can be relieved from PRP-40 dependence by artificially increasing exon size or reducing flanking intron size, indicating that PRP-40 is specifically required for microexons surrounded by conventionally sized introns. Knockdown of the orthologous PRPF40A in mouse neuroblastoma cells causes widespread dysregulation of microexons but not conventionally sized exons. PRP-40 regulation of neuronal microexons is therefore a widely conserved phenomenon. Microexons play crucial roles in neuronal function but pose mechanistic challenges to the spliceosome. Choudhary et al. reveal that PRP-40, a core spliceosomal component, is required for microexon inclusion in C. elegans and mammalian cells. PRP-40 is proposed as a mediator of intron definition for exons refractory to exon definition.
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