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

Abstract

Neuronal microexon; Actin; Memory

Microexón neuronal; Actina; Memoria

Microexó neuronal; Actina; Memòria

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.

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.