SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth.
SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth.
复制标题
srrm4依赖性神经元特异性替代剪接的突出蛋白转录物调节神经突生长。
DOI：
10.1038/srep41130
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发表时间：
2017-01-20
影响因子：
4.6
通讯作者：
Nakayama KI
中科院分区：
文献类型：
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作者：
Ohnishi T;Shirane M;Nakayama KI
选择性剪接引起蛋白质组的多样性，并且它在哺乳动物神经系统中特别普遍。事实上，许多控制剪接过程的因素支配着神经系统的发育。在这些因子中，SRRM 4是神经分化包括神经突生长的重要调节因子。然而，SRRM 4调节神经突生长的机制仍然知之甚少。我们现在表明，SRRM 4调节神经元细胞中Zfyve 27基因转录本的剪接。SRRM 4被发现促进剪接的residin前mRNA，以包括一个微外显子（外显子L）编码七个氨基酸的神经元特异性的方式。所产生的蛋白质（Escheridin-L）在神经发生期间促进神经突生长。在Neuro 2A细胞中SRRM 4的消耗损害了Escheridin mRNA中外显子L的包含，导致产生较短的蛋白质同种型（Escheridin-S），其在促进神经突延伸方面不太有效。SRRM 4被发现识别UGC基序，该基序位于外显子L的上游，并且是将外显子L包含在成熟转录物中所必需的。Neuro 2A或胚胎干细胞中外显子L的缺失抑制神经突生长。我们的研究结果表明，SRRM 4控制神经突起的生长，通过调节选择性剪接的转录。
Alternative splicing gives rise to diversity of the proteome, and it is especially prevalent in the mammalian nervous system. Indeed, many factors that control the splicing process govern nervous system development. Among such factors, SRRM4 is an important regulator of aspects of neural differentiation including neurite outgrowth. The mechanism by which SRRM4 regulates neurite outgrowth has remained poorly understood, however. We now show that SRRM4 regulates the splicing of protrudin gene (Zfyve27) transcripts in neuronal cells. SRRM4 was found to promote splicing of protrudin pre-mRNA so as to include a microexon (exon L) encoding seven amino acids in a neuron-specific manner. The resulting protein (protrudin-L) promotes neurite outgrowth during neurogenesis. Depletion of SRRM4 in Neuro2A cells impaired inclusion of exon L in protrudin mRNA, resulting in the generation of a shorter protein isoform (protrudin-S) that is less effective at promoting neurite extension. SRRM4 was found to recognize a UGC motif that is located immediately upstream of exon L and is necessary for inclusion of exon L in the mature transcript. Deletion of exon L in Neuro2A or embryonic stem cells inhibited neurite outgrowth. Our results suggest that SRRM4 controls neurite outgrowth through regulation of alternative splicing of protrudin transcripts.