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

Patryk Poliński (), Marta Miret Cuesta, Alfonsa Zamora-Moratalla, Federica Mantica, Gerard Cantero-Recasens, Carlotta Viana, Miguel Sabariego-Navarro, Davide Normanno, Luis P. Iñiguez, Cruz Morenilla-Palao, Patricia Ordoño, Sophie Bonnal, Jonathan D. Ellis, Raúl Gómez-Riera, Hugo Fanlo-Ucar, Dominic S. Yap, María Martínez De Lagrán, Álvaro Fernández-Blanco, Cristina Rodríguez-Marin, Jon Permanyer, Orsolya Fölsz, Eduardo Dominguez-Sala, Cesar Sierra, Diana Legutko, José Wojnacki, Juan Luis Musoles Lleo, Maria Pia Cosma, Francisco José Muñoz, Benjamin J. Blencowe, Eloisa Herrera, Mara Dierssen () and Manuel Irimia ()
Additional contact information
Patryk Poliński: Barcelona Institute of Science and Technology
Marta Miret Cuesta: Barcelona Institute of Science and Technology
Alfonsa Zamora-Moratalla: Barcelona Institute of Science and Technology
Federica Mantica: Barcelona Institute of Science and Technology
Gerard Cantero-Recasens: Barcelona Institute of Science and Technology
Carlotta Viana: Barcelona Institute of Science and Technology
Miguel Sabariego-Navarro: Barcelona Institute of Science and Technology
Davide Normanno: Barcelona Institute of Science and Technology
Luis P. Iñiguez: Barcelona Institute of Science and Technology
Cruz Morenilla-Palao: Instituto de Neurociencias (CSIC-UMH)
Patricia Ordoño: Instituto de Neurociencias (CSIC-UMH)
Sophie Bonnal: Barcelona Institute of Science and Technology
Jonathan D. Ellis: University of Toronto
Raúl Gómez-Riera: Barcelona Institute of Science and Technology
Hugo Fanlo-Ucar: Universitat Pompeu Fabra
Dominic S. Yap: Barcelona Institute of Science and Technology
María Martínez De Lagrán: Barcelona Institute of Science and Technology
Álvaro Fernández-Blanco: Barcelona Institute of Science and Technology
Cristina Rodríguez-Marin: Barcelona Institute of Science and Technology
Jon Permanyer: Barcelona Institute of Science and Technology
Orsolya Fölsz: Barcelona Institute of Science and Technology
Eduardo Dominguez-Sala: Barcelona Institute of Science and Technology
Cesar Sierra: Barcelona Institute of Science and Technology
Diana Legutko: BRAINCITY
José Wojnacki: Barcelona Institute of Science and Technology
Juan Luis Musoles Lleo: Barcelona Institute of Science and Technology
Maria Pia Cosma: Barcelona Institute of Science and Technology
Francisco José Muñoz: Universitat Pompeu Fabra
Benjamin J. Blencowe: University of Toronto
Eloisa Herrera: Instituto de Neurociencias (CSIC-UMH)
Mara Dierssen: Barcelona Institute of Science and Technology
Manuel Irimia: Barcelona Institute of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59430-w

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