A novel regulatory mechanism of actin cytoskeleton dynamics through a neural microexon in DAAM1 is important for proper memory formation

Actin cytoskeleton dynamics is crucial for neurogenesis and neuronal function. Precise quantitative and qualitative regulation of actin polymerization is achieved by multiple actin-binding proteins, among which formins are particularly versatile. Here, we investigate how neuronal-specific splicing e...

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Published inbioRxiv
Main Authors Polinski, Patryk, Miret-Cuesta, Marta, Zamora-Moratalla, Alfonsa, Mantica, Federica, Cantero-Recasens, Gerard, Normanno, Davide, Iniguez-Rabago, Luis, Cruz Morenilla-Palao, Ordono, Patricia, Bonnal, Sophie, Gomez-Riera, Raul, Martinez De Lagran, Maria, Fernandez-Blanco, Alvaro, Rodriguez-Marin, Cristina, Permanyer, Jon, Folsz, Orsolya, Sierra, Cesar, Legutko, Diana, Wojnacki, Jose, Musoles-Lleo, Juan Luis, Herrera, Eloisa, Dierssen, Mara, Irimia, Manuel
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.03.2023
Subjects
Actin
ARC protein
Axonogenesis
Calcium influx
Cytoskeleton
Dendritic spines
Gene regulation
Long-term potentiation
Neurogenesis
Polymerization
Post-transcription
RhoA protein
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Summary:Actin cytoskeleton dynamics is crucial for neurogenesis and neuronal function. Precise quantitative and qualitative regulation of actin polymerization is achieved by multiple actin-binding proteins, among which formins are particularly versatile. Here, we investigate how neuronal-specific splicing expands formin's functional diversity in the brain. We uncovered a highly conserved microexon in DAAM1, whose inclusion extends the linker region of the FH2 domain, and leads to remarkable changes in actin polymerization rates and structure. Microexon deletion causes neuritogenesis defects and increased calcium influx in in vitro differentiated neurons, and mice carrying this deletion exhibit deficient memory formation. These memory defects were associated with higher activity of DAAM1's interactor RhoA, increased ARC protein levels, postsynaptic deficiencies, fewer dendritic spines and impaired long-term potentiation. In summary, precise post-transcriptional regulation of DAAM1's FH2 domain is a novel mechanism for modulating actin dynamics in neurons, and is essential for proper brain function.Competing Interest StatementThe authors have declared no competing interest.Footnotes* A few wording changes in one section of results and Discussion, and minor missing details.
DOI:10.1101/2023.01.12.523772