Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing.
Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing.
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通过重定向选择性剪接上调小鼠和人类神经元中的 SYNGAP1 表达。
DOI：
10.1016/j.neuron.2023.02.021
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发表时间：
2023
期刊：
影响因子：
16.2
通讯作者：
Zhang,
中科院分区：
文献类型：
--
作者：
Yang,Runwei;Feng,Xinran;Arias-Cavieres,Alejandra;Mitchell,RobinM;Polo,Ashleigh;Hu,Kaining;Zhong,Rong;Qi,Cai;Zhang,RachelS;Westneat,Nathaniel;Portillo,CristabelA;Nobrega,MarceloA;Hansel,Christian;GarciaIii,AlfredoJ;Zhang,
Ras GTP酶激活蛋白SYNGAP 1在突触可塑性中起着核心作用，而新生SYNGAP 1突变是自闭症和智力残疾的最常见原因。SYNGAP 1在发育过程中如何调节以及如何治疗SYNGAP 1相关的单倍不足仍然是具有挑战性的问题。在这里，我们描述了SYNGAP 1的一个选择性3′剪接位点（A3 SS），它在小鼠和人类神经发育中诱导无义介导的mRNA衰变（A3 SS-NMD）。我们证明PTBP 1/2直接结合并促进SYNGAP 1A 3SS的包含。小鼠中Syngap 1A 3SS基因缺失上调Syngap 1蛋白，并消除由Syngap 1敲除等位基因引起的长时程增强和膜兴奋性缺陷我们进一步报道了一种剪接转换寡核苷酸（SSO），它可以将SYNGAP 1非生产性亚型转化为人类iPSC衍生神经元中的功能性形式。本研究描述了SYNGAP 1A 3SS-NMD的调节和功能，异源Syngap 1基因敲除小鼠的遗传拯救，以及SSO的开发，以潜在地消除SYNGAP 1相关的单倍不足。
The Ras GTPase-activating proteinSYNGAP1plays a central role in synaptic plasticity, andde novo SYNGAP1mutations are among the most frequent causes of autism and intellectual disability. HowSYNGAP1is regulated during development and how to treatSYNGAP1-associated haploinsufficiency remain challenging questions. Here, we characterize an alternative 3′ splice site (A3SS) ofSYNGAP1that induces nonsense-mediated mRNA decay (A3SS-NMD) in mouse and human neural development. We demonstrate that PTBP1/2 directly bind to and promoteSYNGAP1A3SS inclusion. Genetic deletion of theSyngap1A3SS in mice upregulates Syngap1 protein and alleviates the long-term potentiation and membrane excitability deficits caused by aSyngap1knockout allele. We further report a splice-switching oligonucleotide (SSO) that convertsSYNGAP1unproductive isoform to the functional form in human iPSC-derived neurons. This study describes the regulation and function ofSYNGAP1A3SS-NMD, the genetic rescue of heterozygousSyngap1knockout mice, and the development of an SSO to potentially alleviateSYNGAP1-associated haploinsufficiency.