Rem2 signaling affects neuronal structure and function in part by regulation of gene expression

The central nervous system has the remarkable ability to convert changes in the environment in the form of sensory experience into long-term alterations in synaptic connections and dendritic arborization, in part through changes in gene expression. Surprisingly, the molecular mechanisms that translate neuronal activity into changes in neuronal connectivity and morphology remain elusive. Rem2, a member of the Rad/Rem/Rem2/Gem/Kir (RGK) subfamily of small Ras-like GTPases, is a positive regulator of synapse formation and negative regulator of dendritic arborization. Here we identify that one output of Rem2 signaling is the regulation of gene expression. Specifically, we demonstrate that Rem2 signaling modulates the expression of genes required for a variety of cellular processes from neurite extension to synapse formation and synaptic function. Our results highlight Rem2 as a unique molecule that transduces changes in neuronal activity detected at the cell membrane to morphologically relevant changes in gene expression in the nucleus. •Rem2 signaling regulates gene expression.•Rem2 signaling promotes the expression of known synaptogenic factors Lrrtm4 and Gpc5.•The Gpc5 ligand functions in the postsynaptic neuron to regulate excitatory synapse formation.•Rem2 both promotes and represses gene expression in the context of neuronal depolarization.•Rem2 knockdown modulates activity-dependent transcriptional pathways.