A highly conserved neuronal microexon in DAAM1 controls actin dynamics, RHOA/ROCK signaling, and memory formation
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.
Authors
- Cristina Rodríguez-Marin (ORCID: https://orcid.org/0000-0001-6772-4853)
- Davide Normanno (ORCID: https://orcid.org/0000-0003-4740-5542)
- C. S. da Costa Viana (ORCID: https://orcid.org/0000-0002-7160-5491)
- Miguel Sabariego-Navarro (ORCID: https://orcid.org/0000-0001-6869-8095)
- Mara Dierssen (ORCID: https://orcid.org/0000-0003-0853-6865)
- Hugo Fanlo-Ucar (ORCID: https://orcid.org/0000-0001-7420-6501)
- Maria Pia Cosma (ORCID: https://orcid.org/0000-0003-4207-5097)
- Jon Permanyer (ORCID: https://orcid.org/0000-0001-7641-4451)
- Manuel Irimia (ORCID: https://orcid.org/0000-0002-2179-2567)
- Diana Legutko (ORCID: https://orcid.org/0000-0002-9463-640X)
- Alfonsa Zamora‐Moratalla (ORCID: https://orcid.org/0000-0002-1870-1003)
- Orsolya Fölsz
- Patryk Poliński (ORCID: https://orcid.org/0000-0002-1733-7983)
- Benjamin J. Blencowe (ORCID: https://orcid.org/0000-0002-4461-0340)
- Damian Yap (ORCID: https://orcid.org/0000-0002-5370-4592)
- Eduardo Dominguez (ORCID: https://orcid.org/0000-0002-8436-9993)
- L. Iñiguez (ORCID: https://orcid.org/0000-0002-1470-9024)
- María Martínez de Lagrán (ORCID: https://orcid.org/0000-0002-0836-6491)
- Cruz Morenilla‐Palao (ORCID: https://orcid.org/0000-0002-8159-1206)
- Álvaro Fernández‐Blanco (ORCID: https://orcid.org/0000-0001-6451-1094)
- Gerard Cantero-Recasens (ORCID: https://orcid.org/0000-0001-6452-782X)
- Sophie Bonnal (ORCID: https://orcid.org/0000-0001-6096-3042)
- Cèsar Sierra (ORCID: https://orcid.org/0000-0002-4544-9149)
- Juan Luis Musoles Lleó (ORCID: https://orcid.org/0000-0002-2474-0009)
- Francisco José Muñoz (ORCID: https://orcid.org/0000-0002-0426-2118)
- José Wojnacki (ORCID: https://orcid.org/0000-0002-1659-8698)
- Eloı́sa Herrera (ORCID: https://orcid.org/0000-0001-9525-5441)
- Marta Miret-Cuesta (ORCID: https://orcid.org/0000-0002-1083-5904)
- Federica Mantica (ORCID: https://orcid.org/0000-0001-9794-9770)
- Patricia Ordoño (ORCID: https://orcid.org/0000-0002-4140-7750)
- Raúl Gómez (ORCID: https://orcid.org/0000-0003-4197-180X)
- Jonathan D. Ellis
Institutions
- Centre National de la Recherche Scientifique (FR)
- Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
- Universitat Pompeu Fabra (ES)
- University of Toronto (CA)
- Université de Montpellier (FR)
- Instituto de Neurociencias (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Institut Català de Ciències del Clima (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centre for Genomic Regulation (ES)
- Institut de Génétique Humaine (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s41467-025-59430-w
- Citations
- 7
- Primary Topic
- Advanced Fluorescence Microscopy Techniques
- Type
- article
- Field-Weighted Citation Impact
- 9.80
Funders
- Centres de Recerca de Catalunya
- European Commission
- Generalitat de Catalunya
- University of Toronto
- Ministerio de Ciencia e Innovación
- National Institutes of Health
- Canadian Institutes of Health Research
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Agencia Estatal de Investigación