Dendritic transport element of human arc <scp>mRNA</scp> confers <scp>RNA</scp> degradation activity in a translation‐dependent manner

Ninomiya, K.; Ohno, Masatomi; Kataoka, Naoyuki

doi:10.1111/gtc.12439

Cited by 12 publications

(15 citation statements)

References 25 publications

(62 reference statements)

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“…Next, we investigated known cis -acting elements within Arc 3′ UTR that may contribute to the observed splicing-dependent upregulation. One candidate element we analyzed is the primary 3′ UTR-encoded DTE region which was recently suggested to participate in human Arc mRNA translation-dependent decay in SH-SY5Y cells ( Ninomiya et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, spatial and temporal restriction of Arc expression is also achieved by rapid decay of Arc mRNA upon its translational activation ( Giorgi et al, 2007 ; Soule et al, 2012 ; Farris et al, 2014 ; Ninomiya et al, 2016 ). This ensures that activity-dependent expression of the mRNA decays after 1–2 h from the initial stimulus ( Bateup et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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

Paolantoni

Ricciardi

Paolis

et al. 2018

Front. Mol. Neurosci.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Paolantoni

Ricciardi

Paolis

et al. 2018

Front. Mol. Neurosci.

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“…Although our results indicate that the presence of introns plays a role in regulating mRNA decay, EGFP-Arc mRNA is degraded, albeit with a slower time course, indicating that mechanisms other than NMD also contribute. In this regard, it is noteworthy that a recent study reports that the presence of the 3′UTR sequence called the “dendritic targeting element (DTE)” in fusion transcripts also confers destabilizing activity independent of NMD (Ninomiya et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Delayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Mice

Steward

Yee

Farris

et al. 2018

Front. Mol. Neurosci.

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Arc is a unique immediate early gene (IEG) whose expression is induced as synapses are modified during learning. Newly-synthesized Arc mRNA is rapidly transported throughout dendrites and localizes near recently activated synapses. Arc mRNA levels are regulated by rapid degradation, which is accelerated by synaptic activity in a translation-dependent process. One possible mechanism is nonsense-mediated mRNA decay (NMD), which depends on the presence of a splice junction in the 3′UTR. Here, we test this hypothesis using transgenic mice that express EGFP-Arc. Because the transgene was constructed from Arc cDNA, it lacks intron structures in the 3′UTR that are present in the endogenous Arc gene. NMD depends on the presence of proteins of the exon junction complex (EJC) downstream of a stop codon, so EGFP-Arc mRNA should not undergo NMD. Assessment of Arc mRNA rundown in the presence of the transcription inhibitor actinomycin-D confirmed delayed degradation of EGFP-Arc mRNA. EGFP-Arc mRNA and protein are expressed at much higher levels in transgenic mice under basal and activated conditions but EGFP-Arc mRNA does not enter dendrites efficiently. In a physiological assay in which cycloheximide (CHX) was infused after induction of Arc by seizures, there were increases in endogenous Arc mRNA levels consistent with translation-dependent Arc mRNA decay but this was not seen with EGFP-Arc mRNA. Taken together, our results indicate: (1) Arc mRNA degradation occurs via a mechanism with characteristics of NMD; (2) rapid dendritic delivery of newly synthesized Arc mRNA after induction may depend in part on prior splicing of the 3′UTR.

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“…S2C,D). This finding is also supported by the results of Ninomiya et al (2016). To analyze the mechanism for human ARC mRNA degradation, the authors constructed an ARC genome-type 3′UTR fused to an EGFP reporter and then removed the termination codons, in order to inhibit NMD targeting of this construct.…”

Section: Role Of Ago2 In Nmd Of Arc Mrnamentioning

confidence: 53%

“…This implies a role for other mRNA decay processes in ARC mRNA regulation. Importantly, ARC mRNA localization is mediated by a dendritic-targeting element (DTE) in the ARC 3′UTR, which also has a cis-acting element for destabilizing ARC mRNA, independent of the NMD pathway (Ninomiya et al, 2016). Besides, this DTE alone was able to promote degradation of the reporter RNA, dependent on translation.…”

Section: Role Of Ago2 In Nmd Of Arc Mrnamentioning

confidence: 99%

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

Ryu

Seo

Jung

et al. 2019

Journal of Cell Science

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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 nonsensemediated mRNA decay (NMD). However, a well-known NMD component Upf1 has differential roles in transcriptional and translational regulation of Arc gene expression. Specifically, Upf1 suppresses Arc transcription by enhancing destabilization of mRNAs encoding various transcription factors, including Mef2a. Upf1 also binds to the Arc 3′UTR, resulting in suppression of translation. Surprisingly, the Arc transcript escapes from Upf1-mediated NMD by binding to Ago2 (also known as miRISC), which blocks NMD and further suppresses Arc 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 Arc gene expression may allow neurons to more effectively respond to changes in neuronal activity.

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Dendritic transport element of human arc mRNA confers RNA degradation activity in a translation‐dependent manner

Cited by 12 publications

References 25 publications

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

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

Delayed Degradation and Impaired Dendritic Delivery of Intron-Lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc Transgenic Mice

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

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