Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity
Open accessAbstract
Circular RNAs (circRNAs) have re-emerged as an interesting RNA species. Using deep RNA profiling in different mouse tissues, we observed that circRNAs were substantially enriched in brain and a disproportionate fraction of them were derived from host genes that encode synaptic proteins. Moreover, on the basis of separate profiling of the RNAs localized in neuronal cell bodies and neuropil, circRNAs were, on average, more enriched in the neuropil than their host gene mRNA isoforms. Using high-resolution in situ hybridization, we visualized circRNA punctae in the dendrites of neurons. Consistent with the idea that circRNAs might regulate synaptic function during development, many circRNAs changed their abundance abruptly at a time corresponding to synaptogenesis. In addition, following a homeostatic downscaling of neuronal activity many circRNAs exhibited substantial up- or downregulation. Together, our data indicate that brain circRNAs are positioned to respond to and regulate synaptic function.
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circHomer1 derived from the homer scaffolding protein 1 pre-RNA can regulate synaptic structure during development and neuronal plasticity.
“circHomer1 derived from the homer scaffolding protein 1 pre-RNA can regulate some synaptic structure during the development and neuronal plasticity.297”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [297]
The Results identify circHomer1_a as derived from the Homer1 scaffolding transcript and report that it is up-regulated after induced neuronal plasticity. The Discussion proposes that its production could affect Homer1b/c and synaptic downscaling, but does not establish that circHomer1_a regulates synaptic structure. The developmental Results describe changes in circRNAs generally, not a developmental structural effect of circHomer1_a. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredcircRNAs were observed to be linked to neurotransmitter function and synaptic plasticity and have higher expression in the neuropil area compared to their mRNA isoforms.
“circRNAs were also observed to be linked to neurotransmitter function and synaptic plasticity and have a higher expression in the neuropil area compared to their mRNA isoforms.297”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [297]
The Abstract and Results ('circRNAs: synaptic gene origin and dendritic localization'; page unavailable) report that circRNAs are, on average, more enriched in neuropil than their host-gene mRNA isoforms, and that many arise from synapse-related genes. The Results ('Neuronal plasticity changes circRNA expression'; page unavailable) show changes following induced synaptic plasticity. The paper suggests a role in synaptic transmission, but does not establish a specific link to neurotransmitter function or show higher absolute circRNA expression than mRNA expression in neuropil. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany host genes of circRNA were enriched in the pathway of synaptic activities and neurotransmitter secretion.
“many host genes of circRNA were enriched in the pathway of synaptic activities and neurotransmitter secretion.289,297,298”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [297]
The Results section (“circRNAs: synaptic gene origin and dendritic localization”; page unavailable) reports that genes hosting brain-expressed circRNAs are enriched for synapse-related Gene Ontology groups, including presynaptic active zone and presynaptic membrane. It does not report enrichment specifically for a neurotransmitter-secretion pathway, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCompared with other cytoplasmic RNAs, circRNAs seem to be more prone to being localized in synapses and their expression is correlated with neural plasticity.
“Compared with other cytoplasmic RNAs, circRNAs seem to be more prone to being localized in synapses and their expression is correlated with neural plasticity, which further supports an important function of circRNAs in synaptic transmission [50,62].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [50]
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Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · see citing works
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome
Li, B., & Dewey, C. N. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-323 · Cited by 22,179 · see citing works
MicroRNAs: Target Recognition and Regulatory Functions
Bartel, D. P. (2009) · Cell · doi:10.1016/j.cell.2009.01.002 · Cited by 20,068 · see citing works
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108 · see citing works
Circular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990 · see citing works
Natural RNA circles function as efficient microRNA sponges
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013) · Nature · doi:10.1038/nature11993 · Cited by 7,985 · see citing works
Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans.
Squire, L. R. (1992) · Psychological Review · doi:10.1037/0033-295x.99.2.195 · Cited by 5,376 · see citing works
Circular RNAs are abundant, conserved, and associated with ALU repeats
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013) · RNA · doi:10.1261/rna.035667.112 · Cited by 4,388 · see citing works
Genome Regulation by Long Noncoding RNAs
Rinn, J. L., & Chang, H. Y. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-051410-092902 · Cited by 4,011 · see citing works
Detecting and characterizing circular RNAs
Jeck, W. R., & Sharpless, N. E. (2014) · Nature Biotechnology · doi:10.1038/nbt.2890 · Cited by 2,685 · see citing works
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. J., & Brown, P. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030733 · Cited by 2,457 · see citing works
Griffiths-Jones, S. (2004) · Nucleic Acids Res. · doi:10.1093/nar/gkh023 · Cited by 2,446 · see citing works
Gene silencing by microRNAs: contributions of translational repression and mRNA decay
Huntzinger, E., & Izaurralde, E. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2936 · Cited by 2,339 · see citing works
Activity-dependent scaling of quantal amplitude in neocortical neurons
Turrigiano, G. G., Leslie, K. R., Desai, N. S., Rutherford, L. C., & Nelson, S. B. (1998) · Nature · doi:10.1038/36103 · Cited by 2,226 · see citing works
Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing Signals
Yeo, G. W.-M., & Burge, C. B. (2004) · Journal of Computational Biology · doi:10.1089/1066527041410418 · Cited by 2,042 · see citing works
Cell-Type Specific Features of Circular RNA Expression
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003777 · Cited by 1,955 · see citing works
lincRNAs act in the circuitry controlling pluripotency and differentiation
Guttman, M., Donaghey, J., Carey, B. W., Garber, M. G., Grenier, J. K., Munson, G., Young, G., Lucas, A. B., Ach, R. A., Bruhn, L., et al. (2011) · Nature · doi:10.1038/nature10398 · Cited by 1,845 · see citing works
Expanded identification and characterization of mammalian circular RNAs
Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014) · Genome biology · doi:10.1186/s13059-014-0409-z · Cited by 1,578 · see citing works
Ingolia, N. T., Brar, G. A., Rouskin, S., McGeachy, A. M., & Weissman, J. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.086 · Cited by 1,240 · see citing works
Homer: a protein that selectively binds metabotropic glutamate receptors
Brakeman, P., Lanahan, A. A., O’Brien, R., Roche, K. W., Barnes, C. A., Huganir, R. L., & Worley, P. F. (1997) · Nature · doi:10.1038/386284a0 · Cited by 1,115 · see citing works
Westholm, J. O., Miura, P., Olson, S., Shenker, S., Joseph, B. J., Sanfilippo, P., Celniker, S., Graveley, B. R., & Lai, E. C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.062 · Cited by 1,001 · see citing works
Identification of novel transcripts in annotated genomes using RNA-Seq
Roberts, A., Pimentel, H., Trapnell, C., & Pachter, L. S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr355 · Cited by 963 · see citing works
Carlin, R. K., Grab, D. J., Cohen, R. S., & Siekevitz, P. (1980) · The Journal of Cell Biology · doi:10.1083/jcb.86.3.831 · Cited by 788 · see citing works
Circular RNA Is Expressed across the Eukaryotic Tree of Life
Wang, P. L., Bao, Y., Yee, M., Barrett, S. P., Hogan, G. J., Olsen, M. N., Dinneny, J. R., Brown, P. O., & Salzman, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090859 · Cited by 754 · see citing works
Cajigas, I. J., Tushev, G., Will, T. J., tom Dieck, S., Fuerst, N., & Schuman, E. M. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.036 · Cited by 709 · see citing works
Self-citationRBPDB: a database of RNA-binding specificities
Cook, K. B., Kazan, H., Zuberi, K., Morris, Q., & Hughes, T. R. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq1069 · Cited by 638 · see citing works
Dynamic visualization of local protein synthesis in hippocampal neurons
Aakalu, G., Smith, W. B., Nguyen, N., Jiang, C., & Schuman, E. M. (2001) · Neuron · doi:10.1016/s0896-6273(01)00295-1 · Cited by 611 · see citing works
Self-citationTranscriptome-wide discovery of circular RNAs in Archaea
Danan, M., Schwartz, S., Edelheit, S., & Sorek, R. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1009 · Cited by 560 · see citing works
Circular RNAs: splicing’s enigma variations
Hentze, M. W., & Preiss, T. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.53 · Cited by 455 · see citing works
The Long Noncoding RNA RMST Interacts with SOX2 to Regulate Neurogenesis
Ng, S., Bogu, G. K., Soh, B.-S., & Stanton, L. W. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.017 · Cited by 413 · see citing works
A rapid Percoll gradient procedure for preparation of synaptosomes
Dunkley, P. R., Jarvie, P. E., & Robinson, P. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.171 · Cited by 410 · see citing works
A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages
Yu, Y., Fuscoe, J. C., Zhao, C., Guo, C., Jia, M., Qing, T., Bannon, D. I., Lancashire, L., Bao, W., Du, T., et al. (2014) · Nature Communications · doi:10.1038/ncomms4230 · Cited by 395 · see citing works
Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation
Mercer, T. R., Qureshi, I., Gökhan, Ş., Dinger, M. E., Li, G., Mattick, J. S., & Mehler, M. F. (2010) · BMC Neuroscience · doi:10.1186/1471-2202-11-14 · Cited by 390 · see citing works
Subcellular Profiling Reveals Distinct and Developmentally Regulated Repertoire of Growth Cone mRNAs
Zivraj, K. H., Tung, Y. C. L., Piper, M., Gumy, L., Fawcett, J. W., Yeo, G. S. H., & Holt, C. E. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1800-10.2010 · Cited by 315 · see citing works
Homeostatic Scaling Requires Group I mGluR Activation Mediated by Homer1a
Hu, J.-H., Park, J. M., Park, S. J., Xiao, B., Dehoff, M. H., Kim, S., Hayashi, T., Schwarz, M. K., Huganir, R. L., Seeburg, P. H., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.008 · Cited by 263 · see citing works
Bottai, D., Guzowski, J. F., Schwarz, M. K., Kang, S. H., Xiao, B., Lanahan, A. A., Worley, P. F., & Seeburg, P. H. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-01-00167.2002 · Cited by 217 · see citing works
Proteostasis in complex dendrites
Hanus, C., & Schuman, E. M. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3546 · Cited by 130 · see citing works
Self-citationSun, W., You, X. A., Gogol‐Döring, A., He, H., Kise, Y., Sohn, M., Chen, T., Klebes, A., Schmucker, D., & Chen, W. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.144 · Cited by 71 · see citing works
Self-citationMicroRNA: microRNAs reach out into dendrites
Tai, H.-C., & Schuman, E. M. (2006) · Current Biology · doi:10.1016/j.cub.2006.02.006 · Cited by 21 · see citing works
Self-citationStimfit: A Fast Visualization and Analysis Environment for Cellular Neurophysiology
Schlögl, A., Jónás, P., Schmidt‐Hieber, C., et al. (2013) · Biomedizinische Technik/Biomedical Engineering · doi:10.1515/bmt-2013-4181 · Cited by 8 · see citing works
A Simple and Rapid Method of Dissociating Hepatocytes from Fixed Liver of the Mouse
Yamashita, K., Kusakabe, M., & Sano, M. (1981) · Stain Technology · doi:10.3109/10520298109067271 · Cited by 3 · see citing works
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- Authors
- You, X., Vlatkovic, I., Babic, A., Will, T., Epstein, I., Tushev, G., Akbalik, G., Wang, M., Glock, C., Quedenau, C., Wang, X., Hou, J., Liu, H., Sun, W., Sambandan, S., Chen, T., Schuman, E. M., & Chen, W.
- Affiliations
- Max Delbrück Center (DE)
- Max Planck Institute for Brain Research (DE)
- Corresponding author
- Schuman, Erin M
- Chen, Wei
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-02-25
- Volume
- 18
- Issue
- 4
- Pages
- 603-610
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4376664
- OpenAlex
- W1967791012
- Cited by
- 1,149
- References
- 42
- Citations by year
- 2026: 38 · 2025: 78 · 2024: 79 · 2023: 101 · 2022: 116 · 2021: 167 · 2020: 162 · 2019: 138 · 2018: 112 · 2017: 75 · 2016: 53 · 2015: 26 · 2014: 1
- FWCI
- 38.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- circular RNA, synaptic genes, synaptogenesis, homeostatic plasticity, neuropil, dendrites, brain transcriptome
- MeSH terms
- RNA, Circular, Animals, Brain, Dendrites, Female, Hippocampus, Male, Mice, Inbred C57BL, Neuronal Plasticity, RNA, Synapses, Rats, Sprague-Dawley, In Situ Hybridization, Sequence Analysis, RNA, Patch-Clamp Techniques, Neuropil, Reverse Transcriptase Polymerase Chain Reaction, Mice, Rats
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