RNA 结合蛋白 Nab2 可调节 RhoGEF Trio 的水平,从而控制轴突和树突的形态。

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
ACS Applied Electronic Materials Pub Date : 2024-08-01 Epub Date: 2024-07-10 DOI:10.1091/mbc.E24-04-0150
Carly L Lancaster, Pranav S Yalamanchili, Jordan N Goldy, Sara W Leung, Anita H Corbett, Kenneth H Moberg
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引用次数: 0

摘要

果蝇 RNA 结合蛋白(RBP)Nab2 在神经元中调节神经发育,与人类智障相关 RBP ZC3H14 同源。Nab2 部分通过调节 150 个 mRNA 的剪接事件来控制蘑菇体神经元的轴突投射,并限制第四类感觉神经元的树突轴化。对性致死(Sxl)mRNA的分析表明,Nab2促进了外显子跳转事件,并通过Mettl3甲基转移酶调节Sxl前mRNA上的m6A甲基化。Mettl3 杂合子能广泛地挽救 Nab2 缺失的表型,这意味着 Nab2 通过类似的机制作用于其他 RNA,包括参与神经发育的未知靶标。在这里,我们发现 Nab2 和 Mettl3 能够调节三体前核糖核酸(trio pre-mRNA)中 5'UTR 内含子的移除。Trio 利用两个 GEF 结构域来平衡 Rac 和 RhoGTPase 的活性。耐人寻味的是,在 Nab2 缺失的神经组织中,仅含有 RhoGEF 结构域的 Trio 异构体 GEF2 被耗尽。表达 Trio-GEF2 能挽救 Nab2null 轴突和树突的投射缺陷,而 GEF1 Rac1 调节结构域则会加剧这些缺陷,这表明 Nab2 介导了对 Trio-GEF 活性的调节。总之,这些数据表明,Nab2-调控的Trio处理对于平衡Trio-GEF1和-GEF2的活性至关重要,并表明Nab2、Mettl3和Trio在塑造轴突和树突形态的共同途径中发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The RNA-binding protein Nab2 regulates levels of the RhoGEF Trio to govern axon and dendrite morphology.

The Drosophila RNA-binding protein (RBP) Nab2 acts in neurons to regulate neurodevelopment and is orthologous to the human intellectual disability-linked RBP, ZC3H14. Nab2 governs axon projection in mushroom body neurons and limits dendritic arborization of class IV sensory neurons in part by regulating splicing events in ∼150 mRNAs. Analysis of the Sex-lethal (Sxl) mRNA revealed that Nab2 promotes an exon-skipping event and regulates m6A methylation on Sxl pre-mRNA by the Mettl3 methyltransferase. Mettl3 heterozygosity broadly rescues Nab2null phenotypes implying that Nab2 acts through similar mechanisms on other RNAs, including unidentified targets involved in neurodevelopment. Here, we show that Nab2 and Mettl3 regulate the removal of a 5'UTR (untranslated region) intron in the trio pre-mRNA. Trio utilizes two GEF domains to balance Rac and RhoGTPase activity. Intriguingly, an isoform of Trio containing only the RhoGEF domain, GEF2, is depleted in Nab2null nervous tissue. Expression of Trio-GEF2 rescues projection defects in Nab2null axons and dendrites, while the GEF1 Rac1-regulatory domain exacerbates these defects, suggesting Nab2-mediated regulation Trio-GEF activities. Collectively, these data indicate that Nab2-regulated processing of trio is critical for balancing Trio-GEF1 and -GEF2 activity and show that Nab2, Mettl3, and Trio function in a common pathway that shapes axon and dendrite morphology.

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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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