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

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• dc.contributor.author Poliński, Patryk
• dc.contributor.author Miret-Cuesta, Marta
• dc.contributor.author Zamora Moratalla, Alfonsa
• dc.contributor.author Mantica, Federica
• dc.contributor.author Cantero Recasens, Gerard, 1984-
• dc.contributor.author Viana, Carlotta
• dc.contributor.author Sabariego Navarro, Miguel
• dc.contributor.author Normanno, Davide
• dc.contributor.author Iñiguez, Luis P.
• dc.contributor.author Bonnal, Sophie
• dc.contributor.author Gómez-Riera, Raúl
• dc.contributor.author Fanlo-Ucar, Hugo
• dc.contributor.author Yap, Dominic S.
• dc.contributor.author Martínez de Lagrán Cabredo, María
• dc.contributor.author Fernández-Blanco, Álvaro
• dc.contributor.author Rodríguez-Marin, Cristina
• dc.contributor.author Permanyer, Jon
• dc.contributor.author Fölsz, Orsolya
• dc.contributor.author Domínguez-Sala, Eduardo
• dc.contributor.author Sierra, Cesar
• dc.contributor.author Wojnacki, José
• dc.contributor.author Musoles Lleo, Juan Luis
• dc.contributor.author Cosma, Maria Pia
• dc.contributor.author Muñoz López, Francisco José, 1964-
• dc.contributor.author Dierssen, Mara
• dc.contributor.author Irimia Martínez, Manuel
• dc.date.accessioned 2025-06-05T17:01:47Z
• dc.date.available 2025-06-05T17:01:47Z
• dc.date.issued 2025
• dc.description.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.
• dc.description.sponsorship The research has been funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERCCoG-LS2-101002275 to M.I.), Spanish Ministry of Science and Innovation (PID2020-115040GB-I00 to M.I., PID2022−141900OB-I00 to M.D., PID2020- 114080GB-I00 to M.P.C., PID2023-1497670B-I00 to F.J.M. and PID2022-138245NB-I00 to E.H), the European Union’s Horizon 2020 research and innovation program under grant agreements No 964342 to M.P.C., 721890 to P.P. and 848077 to A.Z.M., the National Institutes of Health (NIH) (1R01NS137222-01 to M.D.) and AGAUR grants from Secretaria d’Universitats i Recerca del Departament d’Empresa iConeixement de la Generalitat de Catalunya to M.I., M.D. and M.P.C.. CRG acknowledges support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA program. M.S.N. received an FPU fellowship (FPU19/04789) from Ministerio de Universidades. This research was in part supported by grants from the Simons Foundation and Canadian Institutes of Health Research to B.J.B., who also holds the University of Toronto Banbury Chair in Medical Research and the Canada Research Chair in RNA Biology and Genomics.
• dc.format.mimetype application/pdf
• dc.identifier.citation Poliński P, Miret Cuesta M, Zamora-Moratalla A, Mantica F, Cantero-Recasens G, Viana C, et al. A highly conserved neuronal microexon in DAAM1 controls actin dynamics, RHOA/ROCK signaling, and memory formation. Nat Commun. 2025 May 6;16(1):4210. DOI: 10.1038/s41467-025-59430-w
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-025-59430-w
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/70629
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2025 May 6;16(1):4210
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/101002275
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-115040GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022−141900OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114080GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2023-1497670B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-138245NB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/964342
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/721890
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/848077
• dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Biochemistry
• dc.subject.keyword Learning and memory
• dc.subject.keyword Molecular biology
• dc.subject.keyword Molecular neuroscience
• dc.subject.keyword RNA splicing
• dc.title A highly conserved neuronal microexon in DAAM1 controls actin dynamics, RHOA/ROCK signaling, and memory formation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion