SAM68-regulated ALE selection of Pcdh15 maintains proper synapse development and function
SAM68-regulated ALE selection of Pcdh15 maintains proper synapse development and function
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SAM68 调节的 Pcdh15 ALE 选择维持适当的突触发育和功能
DOI：
10.1101/2023.04.04.535307
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Iijima Takatoshi
中科院分区：
文献类型：
--
作者：
Darwish Mohamed;Ito Masatoshi;Takase Akinori;Ayukawa Noriko;Suzuki Satoko;Tanaka Masami;Iijima Yoko;Iijima Takatoshi
数以千计的哺乳动物基因在其3‘非翻译区(3’UTR)编码交替剪接的异构体。另一种3‘非编码区的多样性可能对发育中的和成人大脑的几个神经过程有贡献。SAM68是通过选择性最后外显子(ALE)选择调控神经元3‘非编码区异构体多样性的关键剪接调控因子。然而，控制3‘端剪接的机制及其在神经系统中的功能仍不清楚。在这里，我们证明了神经元SAM68依赖的ALE剪接受到依赖于其目标转录的调控。例如，原钙粘附素-15(PCDH15)基因的选择在很大程度上依赖于SAM68的表达，SAM68的表达部分通过CaMK途径调节，但不依赖于U1小核核糖核蛋白。我们发现，Pcdh15的异常ALE导致产生的蛋白从膜到可溶性的异构体转化，并扰乱了其向兴奋性和抑制性突触的定位。此外，可溶性PCDH15(SPCDH15)的神经元表达优先影响抑制性突触的数量。在人工突触形成试验中，sPCDH15进一步减少了神经连接素-2诱导的抑制性突触，但不是兴奋性突触。我们的发现为3‘非编码区亚型选择在突触发育中的作用提供了洞察力。
Thousands of mammalian genes encode alternatively spliced isoforms in their 3’ untranslated region (3’UTR). Alternative 3’UTR diversity may contribute to several neurological processes in developing and adult brains. SAM68 is the key splicing regulator for the diversity of neuronal 3’UTR isoforms through alternative last exon (ALE) selection. However, the mechanisms underlying the control of splicing at the 3’ end and its function in the nervous system remain unclear. Here, we show that neuronal SAM68-dependent ALE splicing is regulated depending on its target transcripts. For example, the selection of the ALE ofprotocadherin-15(Pcdh15), a gene implicated in Usher syndrome and several neuropsychiatric disorders, is largely dependent on the expression of SAM68, partially regulated via the CaMK pathway, but independent of the U1 small nuclear ribonucleoprotein. We found that the aberrant ALEs ofPcdh15caused membrane-to-soluble isoform conversion of the produced protein and disrupted its localization into excitatory and inhibitory synapses. In addition, the neuronal expression of the soluble form of PCDH15 (sPCDH15) preferentially affected the number of inhibitory synapses. sPCDH15 further reduced neuroligin-2-induced inhibitory, but not excitatory, synapses in artificial synapse formation assays. Our findings provide insights into the role of alternative 3’UTR isoform selections in synapse development.
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影响因子：
9.8
作者：
Ahmed, ZM;Riazuddin, S;Wilcox, ER
通讯作者：
Wilcox, ER
影响因子：
3.5
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9.8
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影响因子：
5.6
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Sánchez-Jiménez F;Sánchez-Margalet V
通讯作者：
Sánchez-Margalet V
影响因子：
16
作者：
Taliaferro JM;Vidaki M;Oliveira R;Olson S;Zhan L;Saxena T;Wang ET;Graveley BR;Gertler FB;Swanson MS;Burge CB
通讯作者：
Burge CB