Activity-induced synaptic plasticity is important for long-term learning and memory, and involves alterations in the expression of immediate early genes, such as the somatodentritic protein Arc (also known as Arg3.1). Nonsense-mediated RNA decay (NMD) has been implicated in the regulation of Arc expression to prevent its synthesis at inappropriate times or locations. In this work (Ryu et al., 2019), Kyong-Tai Kim and co-workers investigate in more detail the role of the essential NMD component Upf1 for Arc expression in mouse neuroblastoma Neuro 2a cells and primary hippocampal neurons. Interestingly, they find that Upf1 functions both at the transcriptional and translational level to inhibit the expression of Arc. Upf1 limits Arc transcription by downregulating transcription factors that promote Arc expression, including Mef2a, while it inhibits translation of Arc mRNA by binding to its 3′ untranslated region. Furthermore, Arc transcripts can escape from NMD by binding to Ago2/miRISC and become subject to microRNA‐mediated gene silencing. Finally, the authors show that knockdown of Upf1 in hippocampal neurons resulted in sustained Arc expression and led to abnormal neuronal outgrowth and branching. Thus, these findings not only present a novel, NMD-independent, role for Upf1 in the transcriptional regulation of Arc, but also imply that Arc expression is inhibited at multiple levels to allow cells to react rapidly to activity-dependent changes in synaptic strength.
