DAAM1中一个高度保守的神经元微小外显子控制肌动蛋白动力学、RHOA/ROCK信号传导和记忆形成。

A highly conserved neuronal microexon in DAAM1 controls actin dynamics, RHOA/ROCK signaling, and memory formation.

作者信息

Poliński Patryk, Miret Cuesta Marta, Zamora-Moratalla Alfonsa, Mantica Federica, Cantero-Recasens Gerard, Viana Carlotta, Sabariego-Navarro Miguel, Normanno Davide, Iñiguez Luis P, Morenilla-Palao Cruz, Ordoño Patricia, Bonnal Sophie, Ellis Jonathan D, Gómez-Riera Raúl, Fanlo-Ucar Hugo, Yap Dominic S, Martínez De Lagrán María, Fernández-Blanco Álvaro, Rodríguez-Marin Cristina, Permanyer Jon, Fölsz Orsolya, Dominguez-Sala Eduardo, Sierra Cesar, Legutko Diana, Wojnacki José, Musoles Lleo Juan Luis, Cosma Maria Pia, Muñoz Francisco José, Blencowe Benjamin J, Herrera Eloisa, Dierssen Mara, Irimia Manuel

机构信息

Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.

Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.

出版信息

Nat Commun. 2025 May 6;16(1):4210. doi: 10.1038/s41467-025-59430-w.

DOI:10.1038/s41467-025-59430-w

PMID:40328765

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12056172/

Abstract

Actin cytoskeleton dynamics is essential for proper nervous system development and function. A conserved set of neuronal-specific microexons influences multiple aspects of neurobiology; however, their roles in regulating the actin cytoskeleton are unknown. Here, we study a microexon in DAAM1, a formin-homology-2 (FH2) domain protein involved in actin reorganization. Microexon inclusion extends the linker region of the DAAM1 FH2 domain, altering actin polymerization. Genomic deletion of the microexon leads to neuritogenesis defects and increased calcium influx in differentiated neurons. Mice with this deletion exhibit postsynaptic defects, fewer immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These phenotypes are associated with increased RHOA/ROCK signaling, which regulates actin-cytoskeleton dynamics, and are partially rescued by treatment with a ROCK inhibitor. This study highlights the role of a conserved neuronal microexon in regulating actin dynamics and cognitive functioning.

摘要

肌动蛋白细胞骨架动力学对于神经系统的正常发育和功能至关重要。一组保守的神经元特异性微小外显子影响神经生物学的多个方面；然而，它们在调节肌动蛋白细胞骨架中的作用尚不清楚。在这里，我们研究了DAAM1中的一个微小外显子，DAAM1是一种参与肌动蛋白重组的formin同源2（FH2）结构域蛋白。微小外显子的包含扩展了DAAM1 FH2结构域的连接区，改变了肌动蛋白聚合。该微小外显子的基因组缺失导致分化神经元的神经突发生缺陷和钙内流增加。具有这种缺失的小鼠表现出突触后缺陷、更少的未成熟树突棘、长时程增强受损以及记忆形成缺陷。这些表型与调节肌动蛋白细胞骨架动力学的RHOA/ROCK信号增加有关，并且通过用ROCK抑制剂治疗可部分挽救。这项研究突出了一个保守的神经元微小外显子在调节肌动蛋白动力学和认知功能中的作用。