RNA 结合蛋白 EIF4A3 通过直接控制细胞骨架促进轴突发育。
The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton.
发表日期：2024 Aug 23
作者：
Fernando C Alsina, Bianca M Lupan, Lydia J Lin, Camila M Musso, Federica Mosti, Carly R Newman, Lisa M Wood, Aussie Suzuki, Mark Agostino, Jeffrey K Moore, Debra L Silver
来源：
Cell Reports
摘要：
由 EIF4A3 成核的外显子连接复合物 (EJC) 对于真核生物中 mRNA 的命运和功能是不可或缺的。我们发现 EIF4A3 直接控制微管，独立于 RNA，这对神经线路至关重要。虽然发育中的小鼠大脑皮层中的神经元存活取决于完整的 EJC，但轴突束的发育仅需要 Eif4a3。使用人类皮质类器官，我们发现 EIF4A3 疾病突变也会损害神经元生长，突出显示与神经发育病理学相关的保守功能。生长神经元的实时成像表明 EIF4A3 对于微管动力学至关重要。利用生物化学和竞争实验，我们证明 EIF4A3 直接与微管结合，与 EJC 相互排斥。最后，体外重建测定和救援实验表明，EIF4A3 足以促进微管聚合，并且 EIF4A3-微管关联是轴突生长的主要贡献者。这揭示了神经元重新利用核心基因表达机制来直接控制细胞骨架的基本机制。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. We discover that EIF4A3 directly controls microtubules, independent of RNA, which is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract development requires only Eif4a3. Using human cortical organoids, we show that EIF4A3 disease mutations also impair neuronal growth, highlighting conserved functions relevant for neurodevelopmental pathology. Live imaging of growing neurons shows that EIF4A3 is essential for microtubule dynamics. Employing biochemistry and competition experiments, we demonstrate that EIF4A3 directly binds to microtubules, mutually exclusive of the EJC. Finally, in vitro reconstitution assays and rescue experiments demonstrate that EIF4A3 is sufficient to promote microtubule polymerization and that EIF4A3-microtubule association is a major contributor to axon growth. This reveals a fundamental mechanism by which neurons re-utilize core gene expression machinery to directly control the cytoskeleton.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.