A novel regulatory mechanism of actin cytoskeleton dynamics through a neural microexon in DAAM1 is necessary for memory formation
Actin cytoskeleton dynamics is critical for nervous system development and function, yet the role of alternative splicing in controlling these processes is poorly understood. A highly conserved subset of neuronal-specific microexons coordinates fundamental aspects of nervous system biology. A subset of these exons is enriched in genes involved in actin cytoskeleton, yet their functions are unknown. Here, we focus on a microexon in DAAM1, a member of the formin-homology-2 (FH2) domain class of proteins, which have diverse functions associated with the reorganization of the actin cytoskeleton. Remarkably, splicing of the microexon extends the linker region of the DAAM1 FH2 domain and leads to qualitative and quantitative changes in actin polymerization. Deletion of the microexon results in neuritogenesis defects and increased calcium influx in differentiated neurons. Moreover, mice harboring the deletion exhibit postsynaptic defects, reduced number of immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These deficits are associated with increased RHOA/ROCK signaling, pivotal in controlling actin-cytoskeleton dynamics, and were rescued by treatment with a ROCK inhibitor. We thus demonstrate that a conserved neuronal microexon in DAAM1 is critical for controlling actin dynamics through the RHOA/ROCK signaling pathway and is necessary for normal cognitive functioning.