Upf1 regulates neurite outgrowth and branching by transcriptional and post-transcriptional modulation of .

A large number of neuronal proteins must show correct spatiotemporal localization in order to carry out their critical functions. The mRNA transcript for the somatodendritic protein activity-regulated cytoskeleton-associated protein (Arc; also known as Arg3.1) contains two conserved introns in the 3' untranslated region (UTR), and was proposed to be a natural target for nonsense-mediated mRNA decay (NMD). However, a well-known NMD component Upf1 has differential roles in transcriptional and translational regulation of gene expression. Specifically, Upf1 suppresses transcription by enhancing destabilization of mRNAs encoding various transcription factors, including Mef2a. Upf1 also binds to the 3'UTR, resulting in suppression of translation. Surprisingly, the transcript escapes from Upf1-mediated NMD by binding to Ago2 (also known as miRISC), which blocks NMD and further suppresses mRNA translation. Upf1 knockdown triggered sustained Arc expression, which contributes to Cofilin (also known as Cfl1) hyperphosphorylation and abnormal neuronal outgrowth and branching. Collectively, these data reveal that multiple levels of Upf1-mediated inhibition of gene expression may allow neurons to more effectively respond to changes in neuronal activity.