Arc 3' UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling

Frontiers in Molecular Neuroscience
Chiara PaolantoniCorinna Giorgi

Abstract

Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3' UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3' UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3' UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2α dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3...Continue Reading

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Citations

Sep 14, 2018·Frontiers in Molecular Neuroscience·Catia AndreassiAntonella Riccio
Nov 10, 2018·Nature Reviews. Neuroscience·Samie R Jaffrey, Miles F Wilkinson
Dec 4, 2020·Neural Regeneration Research·Dae Young YooIn Koo Hwang
May 7, 2021·ELife·Sibylle Mitschka, Christine Mayr

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