Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions
Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions
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DOI：
10.1016/j.molcel.2020.01.006
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发表时间：
2020-03-19
期刊：
影响因子：
16
通讯作者：
Blencowe, Benjamin J.
中科院分区：
文献类型：
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作者：
Gonatopoulos-Pournatzis, Thomas;Niibori, Rieko;Blencowe, Benjamin J.
微外显子是选择性剪接中保守性最强的一类，但人们对其功能了解甚少。在此，我们聚焦于翻译起始因子eIF4G1和eIF4G3中与朊病毒样结构域重叠的密切相关的神经元微外显子，它们的剪接具有活性依赖性，且在自闭症中经常受到干扰。通过CRISPR - Cas9技术删除这些微外显子会选择性地上调控制神经元活动和可塑性的突触蛋白，并进一步触发一个与激活神经元相似的基因表达程序。缺失Eif4g1微外显子的小鼠表现出社交行为、学习和记忆缺陷，同时伴有海马突触可塑性改变。我们提供的证据表明，eIF4G微外显子通过促使核糖体停滞而起到翻译制动的作用，这是因为它们易于促进与翻译抑制相关的细胞质颗粒成分的聚集，包括脆性X智力低下蛋白FMRP。因此，这些结果揭示了一种在自闭症中被破坏的机制，即选择性剪接使神经元翻译特化以控制高阶认知功能。
Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively upregulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning, and memory deficits, accompanied by altered hippocampal synaptic plasticity. We provide evidence that the eIF4G microexons function as a translational brake by causing ribosome stalling, through their propensity to promote the coalescence of cytoplasmic granule components associated with translation repression, including the fragile X mental retardation protein FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes neuronal translation to control higher order cognitive functioning.