The Protein Arginine Methyltransferase PRMT8 and Substrate G3BP1 Control Rac1-PAK1 Signaling and Actin Cytoskeleton for Dendritic Spine Maturation

Excitatory synapses of neurons are located on dendritic spines. Spine maturation is essential for the stability of synapses and memory consolidation, and overproduction of the immature filopodia is associated with brain disorders. The structure and function of synapses can be modulated by protein post-translational modification (PTM). Arginine methylation is a major PTM that regulates chromatin structure, transcription, and splicing within the nucleus. Here we find that the protein arginine methyltransferase PRMT8 is present at neuronal synapses and its expression is upregulated in the hippocampus when dendritic spine maturation occurs. Depletion of PRMT8 leads to overabundance of filopodia and mis-localization of excitatory synapses. Mechanistically, PRMT8 promotes dendritic spine morphology through methylation of the dendritic RNA-binding protein G3BP1 and suppression of the Rac1-PAK1 signaling pathway to control synaptic actin dynamics. Our findings unravel arginine methylation as a crucial regulatory mechanism for actin cytoskeleton during synapse development.