FMRP-dependent production of large dosage-sensitive proteins is highly conserved.

IF 3.3 3区 生物学 Genetics Pub Date : 2022-07-30 DOI:10.1093/genetics/iyac094
Keegan Flanagan, Alireza Baradaran-Heravi, Qi Yin, Khanh Dao Duc, Allan C Spradling, Ethan J Greenblatt
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引用次数: 6

Abstract

Mutations in FMR1 are the most common heritable cause of autism spectrum disorder. FMR1 encodes an RNA-binding protein, FMRP, which binds to long, autism-relevant transcripts and is essential for normal neuronal and ovarian development. In contrast to the prevailing model that FMRP acts to block translation elongation, we previously found that FMRP activates the translation initiation of large proteins in Drosophila oocytes. We now provide evidence that FMRP-dependent translation is conserved and occurs in the mammalian brain. Our comparisons of the mammalian cortex and Drosophila oocyte ribosome profiling data show that translation of FMRP-bound mRNAs decreases to a similar magnitude in FMRP-deficient tissues from both species. The steady-state levels of several FMRP targets were reduced in the Fmr1 KO mouse cortex, including a ∼50% reduction of Auts2, a gene implicated in an autosomal dominant autism spectrum disorder. To distinguish between effects on elongation and initiation, we used a novel metric to detect the rate-limiting ribosome stalling. We found no evidence that FMRP target protein production is governed by translation elongation rates. FMRP translational activation of large proteins may be critical for normal human development, as more than 20 FMRP targets including Auts2 are dosage sensitive and are associated with neurodevelopmental disorders caused by haploinsufficiency.

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依赖于fmrp的大剂量敏感蛋白的产生是高度保守的。
FMR1基因突变是自闭症谱系障碍最常见的遗传原因。FMR1编码一种rna结合蛋白FMRP,该蛋白与自闭症相关的长转录本结合,对正常的神经元和卵巢发育至关重要。与FMRP阻断翻译延伸的主流模型相反,我们之前发现FMRP激活果蝇卵母细胞中大蛋白的翻译起始。我们现在提供的证据表明,依赖于fmrp的翻译是保守的,发生在哺乳动物的大脑中。我们对哺乳动物皮层和果蝇卵母细胞核糖体分析数据的比较表明,在两种物种的fmrp缺陷组织中,fmrp结合mrna的翻译减少到相似的程度。在Fmr1 KO小鼠皮层中,几个FMRP靶点的稳态水平降低,包括与常染色体显性自闭症谱系障碍有关的基因Auts2减少约50%。为了区分对延伸和起始的影响,我们使用了一种新的度量来检测限速核糖体失速。我们发现没有证据表明FMRP靶蛋白的产生受翻译延伸率的支配。FMRP大蛋白的翻译激活可能对正常的人类发育至关重要,因为包括Auts2在内的20多种FMRP靶点是剂量敏感的,并且与单倍体功能不全引起的神经发育障碍有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genetics
Genetics 生物-遗传学
CiteScore
6.20
自引率
6.10%
发文量
177
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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