Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00145/full |
| _version_ | 1818316499592413184 |
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| author | Chiara Paolantoni Chiara Paolantoni Simona Ricciardi Simona Ricciardi Veronica De Paolis Veronica De Paolis Chinenye Okenwa Caterina Catalanotto Maria T. Ciotti Antonino Cattaneo Antonino Cattaneo Carlo Cogoni Corinna Giorgi |
| author_facet | Chiara Paolantoni Chiara Paolantoni Simona Ricciardi Simona Ricciardi Veronica De Paolis Veronica De Paolis Chinenye Okenwa Caterina Catalanotto Maria T. Ciotti Antonino Cattaneo Antonino Cattaneo Carlo Cogoni Corinna Giorgi |
| author_sort | Chiara Paolantoni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T09:22:24Z |
| format | Article |
| id | doaj.art-505d26d55e964976a2da721fa3db14c7 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-13T09:22:24Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-505d26d55e964976a2da721fa3db14c72022-12-21T23:52:43ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-04-011110.3389/fnmol.2018.00145339134Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF SignalingChiara Paolantoni0Chiara Paolantoni1Simona Ricciardi2Simona Ricciardi3Veronica De Paolis4Veronica De Paolis5Chinenye Okenwa6Caterina Catalanotto7Maria T. Ciotti8Antonino Cattaneo9Antonino Cattaneo10Carlo Cogoni11Corinna Giorgi12European Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyDepartment of Biology and Biotechnology, Sapienza University of Rome, Rome, ItalyEuropean Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyDepartment of Biology and Biotechnology, Sapienza University of Rome, Rome, ItalyEuropean Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyDepartment of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, ItalyEuropean Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyDepartment of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, ItalyInstitute of Cell Biology and Neurobiology, National Research Council, Rome, ItalyEuropean Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyBio@SNS Laboratory, Scuola Normale Superiore, Pisa, ItalyDepartment of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, ItalyEuropean Brain Research Institute Rita Levi-Montalcini Rome, Rome, ItalyActivity-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.http://journal.frontiersin.org/article/10.3389/fnmol.2018.00145/fullArcEJCsplicingBDNFplasticitypost-transcriptional regulation |
| spellingShingle | Chiara Paolantoni Chiara Paolantoni Simona Ricciardi Simona Ricciardi Veronica De Paolis Veronica De Paolis Chinenye Okenwa Caterina Catalanotto Maria T. Ciotti Antonino Cattaneo Antonino Cattaneo Carlo Cogoni Corinna Giorgi Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling Frontiers in Molecular Neuroscience Arc EJC splicing BDNF plasticity post-transcriptional regulation |
| title | Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling |
| title_full | Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling |
| title_fullStr | Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling |
| title_full_unstemmed | Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling |
| title_short | Arc 3′ UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling |
| title_sort | arc 3 utr splicing leads to dual and antagonistic effects in fine tuning arc expression upon bdnf signaling |
| topic | Arc EJC splicing BDNF plasticity post-transcriptional regulation |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00145/full |
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