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′ UTR-splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3′ UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity.
Highlights
De novo transcription and translation of the immediate-early gene (IEG) activity-regulated cytoskeleton-associated protein (Arc) is triggered by neuronal activity and results in profound alterations of synaptic properties underlying learning and memory processes (Plath et al, 2006; Shepherd and Bear, 2011; Nikolaienko et al, 2017)
Even a short (5 min) initial pulse with brain-derived neurotrophic factor (BDNF) is sufficient to trigger a significant upregulation of Arc 5 untranslated region (UTR) constructs after 4 h of incubation in media, quantitatively comparable to that observed upon 4 h of chronic BDNF treatment. These results indicate that the 3 UTR region of Arc messenger RNA (mRNA) is alone able to confer responsiveness to BDNF, even to a short pulse of the neurotrophin, and that the observed upregulation is dependent on splicing of Arc 3 UTR introns
Arc mRNA 3 UTR is interesting as it harbors two conserved introns, which regulate its abundance targeting it for destruction via the nonsense mediated decay (NMD) (Giorgi et al, 2007; Steward et al, 2018)
Summary
De novo transcription and translation of the IEG Arc is triggered by neuronal activity and results in profound alterations of synaptic properties underlying learning and memory processes (Plath et al, 2006; Shepherd and Bear, 2011; Nikolaienko et al, 2017). As an IEG, transcription of Arc mRNA is rapidly induced by patterns of synaptic activity that elicit LTP (Steward et al, 1998; Rao et al, 2006) and a portion is transported and locally translated in dendrites (Steward and Worley, 2001; Dynes and Steward, 2012; Farris et al, 2014; Na et al, 2016; Wang et al, 2016). Recent groundbreaking studies have revealed that segments of Arc protein resemble retroviral Gag domains and mediate Arc assembly into virus-like capsids. These vesicles can capture RNA transcripts, including Arc’s own mRNA, and transfer them to post-synaptic cells. Arc is involved in intercellular signaling and trafficking of mRNAs (Zhang et al, 2015; Ashley et al, 2018; Pastuzyn et al, 2018)
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