Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions.,Molecular Cell

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Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-01-25 , DOI: 10.1016/j.molcel.2020.01.006
Thomas Gonatopoulos-Pournatzis ₁ , Rieko Niibori ₂ , Eric W Salter ₃ , Robert J Weatheritt ₄ , Brian Tsang ₅ , Shaghayegh Farhangmehr ₆ , Xinyi Liang ₇ , Ulrich Braunschweig ₁ , Jonathan Roth ₈ , Shen Zhang ₂ , Tyler Henderson ₉ , Eesha Sharma ₆ , Mathieu Quesnel-Vallières ₆ , Jon Permanyer ₁₀ , Stefan Maier ₂ , John Georgiou ₂ , Manuel Irimia ₁₁ , Nahum Sonenberg ₁₂ , Julie D Forman-Kay ₅ , Anne-Claude Gingras ₉ , Graham L Collingridge ₁₃ , Melanie A Woodin ₇ , Sabine P Cordes ₉ , Benjamin J Blencowe ₆

Affiliation

Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Centre for Genomic Regulation, Barcelona 08003, Spain.
Centre for Genomic Regulation, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain; ICREA, Barcelona 08010, Spain.
Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 1A8, Canada.

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.

中文翻译：

自闭症失控的eIF4G微外显子控制突触翻译和高阶认知功能。

Microexon代表了最高度保守的替代剪接类，但对其功能的了解却很少。在这里，我们专注于紧密相关的神经元微外显子，在翻译起始因子eIF4G1和eIF4G3中重叠病毒样结构域，其剪接是活动依赖性的，并且在自闭症中经常受到干扰。这些微外显子的CRISPR-Cas9缺失选择性地上调了控制神经元活动和可塑性的突触蛋白，并进一步触发了与活化神经元相似的基因表达程序。缺乏Eif4g1 microexon的小鼠表现出社交行为，学习和记忆缺陷，并伴有海马突触可塑性改变。我们提供的证据表明，eIF4G微外显子通过引起核糖体失速而起翻译制动器的作用，通过它们促进与翻译抑制相关的细胞质颗粒成分（包括脆弱的X智力障碍蛋白FMRP）的融合。结果因此揭示了一种自闭症破坏机制，通过该机制，选择性剪接使神经元翻译专门控制高阶认知功能。

更新日期：2020-01-29

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