Editorial for “Regulatory RNAs in the nervous system”
Alessandro Cellerino
Laure Bally-Cuif
Tommaso Pizzorusso- 1Scuola Normale Superiore, Pisa, Italy
- 2Biology of Aging, Fritz Lipmann Institute for Age Research-Leibniz Institute, Jena, Germany
- 3Institute of Neurobiology A. Fessard, CNRS UPR3294, Gif-sur-Yvette, France
- 4Department of Neuroscience, Psychology, Drug Research and Child Health Neurofarba, University of Florence, Florence, Italy
- 5Pisa Unit, Institute of Neuroscience, National Research Council, Pisa, Italy
Until about a decade ago, the non-coding part of the genome was considered without function. The development of high-throughput RNA sequencing techniques (next-generation sequencing) revealed the existence of many transcripts that do not code for proteins in addition to the RNA components needed for mRNA translation: rRNAs and tRNAs. The aim of this issue was to put together reports on the role of non-coding RNAs in the nervous system, an emerging field not covered so far in a systematic manner.
Non-coding transcripts can be divided into three broad classes: (i) short RNAs (sRNAs), (ii) RNAs transcribed from the opposite strand of a protein-coding locus that contain sequences antisense with respect to the protein-coding transcript, (OS-RNAs) and (iii) long intergenic non-coding RNAs (lincRNAs). Many of these non-coding RNAs (nc-RNAs) can regulate the transcription or the translation of protein-coding genes. Almost on weekly basis, new findings reveal the regulatory role that nc-RNAs exert in many biological processes. Overall, these studies are making increasingly clear that, both in model organisms and in humans, complexity is not a function of the number of protein-coding genes, but results from the possibility of using combinations of genetic programs and controlling their spatial and temporal regulation during development, senescence and in disease by regulatory RNAs. This has generated a novel picture of gene regulatory networks where regulatory nc-RNAs represent novel layers of regulation. Publications reporting novel non-coding RNAs found using sequencing appears almost monthly, therefore dedicated bioinformatics techniques to analyze the result of this analysis are under development (Guffanti et al., 2014).
Particularly well-characterized is the role of microRNAs (miRNAs) in the post-transcriptional regulation of gene expression. MicroRNAs are short(~21 nt) nc-RNAs that arise from processing of a long primary transcript via a complex and well-described biosynthetic process. MicroRNAs bind to mRNAs (usually in the 3′untranslated region) and regulate gene expression by repressing mRNA translation and/or inducing degradation of the target mRNA. Up to now, several thousands of miRNAs have been predicted and identified in animals, plants and viruses (www.mirbase.org) and some microRNAs are highly conserved, facilitating the analysis of microRNA in non-model species. A feature of miRNAs is their combinatorial regulation: a given miRNA can target a multitude of different mRNAs and a given target might similarly be targeted by multiple miRNAs; for this reason, they frequently represent the central nodes of several regulatory networks and may act as rheostat to provide stability and fine-tuning to gene expression networks (Osella et al., 2011; Siciliano et al., 2013). MicroRNAs are also relatively easy to study experimentally and novel methods to study their function are continually coming out (Chaudhuri et al., 2013; Knauss et al., 2013). They can be transfected in cells, microinjected in embryos or delivered in vivo to neurons and their function can be blocked, in vitro and in vivo, by modified antisense oligonucleotides (antagomiRs). For all these reasons, the majority of contributions to this e-book relate to miRNAs. In the nervous system, miRNAs have been involved in the regulation of cellular pathways controlling fundamental functions during development (Benchoua and Peschanski, 2013; Coolen et al., 2013; Cremisi, 2013; Hong et al., 2013; Iyengar et al., 2014; Iyer et al., 2014; Terzibasi Tozzini et al., 2014), synaptic plasticity (Tognini and Pizzorusso, 2012; Chiu et al., 2014), and in neurodegenerative disease. Intriguingly, miRNAs show a double-sided relationship with neuronal activity: electrical activity (Eacker et al., 2013; Pai et al., 2014) regulates miRNAs at the level of transcription, biogenesis, stability and specific targeting to dendrites and also axons and presynaptic terminals (Kaplan et al., 2013) on one side, but miRNAs are also able to regulate membrane conductances altering neuronal biophysical properties (Gavazzo et al., 2013). Synaptic localization is particularly relevant in the context of local translational control (Heise et al., 2014), thereby providing a molecular substrate for synaptic plasticity. Deregulation of expression of miRNAs is proposed not only as potential disease biomarker (Sheinerman and Umansky, 2013; Maffioletti et al., 2014), but it has been implicated directly in the pathogenesis of complex neurological and neuropsychiatric disease (Dogini et al., 2013; Goodall et al., 2013; Maciotta et al., 2013; Serafini et al., 2013; Barbato et al., 2014; Della Ragione et al., 2014; Elramah et al., 2014; Fragkouli and Doxakis, 2014; Kye and Goncalves Ido, 2014; Nieto-Diaz et al., 2014). This so-called RNA revolution also lead to the exploitation of RNA interference and the development of related tools as potential treatment of a vast array of CNS disease that could benefit from regulation of disease-associated genes.
A second class of small RNAs are the piwi-interacting RNAs (piRNAs). These are slightly larger than miRNAs (24–32 nt) originate from intergenicrepetive sequences that are transcribed as a long RNA and processed and play an important role in gametogenesis and transposon silencing. PiRNAs are expressed at low level (if at all) in somatic tissues and their role in the nervous system is still ill-characterized.
Long non-coding RNAs are a heterogeneous population and are much less studied (see Ernst and Morton, 2013). They can be associated to chromatin and either interfere with transcription of the target gene(s) or induce epigenetic modifications. Long ncRNAs can indeed interact with chromatin remodellers such as Polycomb and target these to specific genomic regions. Opposite-strand RNAs can hybridize with their protein-coding complementary transcript and modulate splicing or induce RNA degradation. Finally, long ncRNAs derived from pseudogenes can act as competitive inhibitors for miRNAs thereby increasing the expression of their protein-coding paralog. Examples of these mechanisms relate to transcription of repetitive elements (Pascarella et al., 2014) or fine tuning of developmental patterning and positional information in the central nervous system mediated by regulation of the spatial pattern of expression of Hox genes in Drosophila (Gummalla et al., 2014).
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Barbato, C., Pezzola, S., Caggiano, C., Antonelli, M., Frisone, P., Ciotti, M. T., et al. (2014). A lentiviral sponge for miR-101 regulates RanBP9 expression and amyloid precursor protein metabolism in hippocampal neurons. Front. Cell. Neurosci. 8:37. doi: 10.3389/fncel.2014.00037
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Benchoua, A., and Peschanski, M. (2013). Pluripotent stem cells as a model to study non-coding RNAs function in human neurogenesis. Front. Cell. Neurosci. 7:140. doi: 10.3389/fncel.2013.00140
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Chaudhuri, A. D., Yelamanchili, S. V., and Fox, H. S. (2013). Combined fluorescent in situ hybridization for detection of microRNAs and immunofluorescent labeling for cell-type markers. Front. Cell. Neurosci. 7:160. doi: 10.3389/fncel.2013.00160
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Chiu, H., Alqadah, A., and Chang, C. (2014). The role of microRNAs in regulating neuronal connectivity. Front. Cell. Neurosci. 7:283. doi: 10.3389/fncel.2013.00283
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Coolen, M., Katz, S., and Bally-Cuif, L. (2013). miR-9: a versatile regulator of neurogenesis. Front. Cell. Neurosci. 7:220. doi: 10.3389/fncel.2013.00220
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Cremisi, F. (2013). MicroRNAs and cell fate in cortical and retinal development. Front. Cell. Neurosci. 7:141. doi: 10.3389/fncel.2013.00141
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Della Ragione, F., Gagliardi, M., D'Esposito, M., and Matarazzo, M. R. (2014). Non-coding RNAs in chromatin disease involving neurological defects. Front. Cell. Neurosci. 8:54. doi: 10.3389/fncel.2014.00054
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Dogini, D. B., Avansini, S. H., Vieira, A. S., and Lopes-Cendes, I. (2013). MicroRNA regulation and dysregulation in epilepsy. Front. Cell. Neurosci. 7:172. doi: 10.3389/fncel.2013.00172
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Eacker, S. M., Dawson, T. M., and Dawson, V. L. (2013). The interplay of microRNA and neuronal activity in health and disease. Front. Cell. Neurosci. 7:136. doi: 10.3389/fncel.2013.00136
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Elramah, S., Landry, M., and Favereaux, A. (2014). MicroRNAs regulate neuronal plasticity and are involved in pain mechanisms. Front. Cell. Neurosci. 8:31. doi: 10.3389/fncel.2014.00031
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Ernst, C., and Morton, C. C. (2013). Identification and function of long non-coding RNA. Front. Cell. Neurosci. 7:168. doi: 10.3389/fncel.2013.00168
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Fragkouli, A., and Doxakis, E. (2014). miR-7 and miR-153 protect neurons against MPP(+)-induced cell death via upregulation of mTOR pathway. Front. Cell. Neurosci. 8:182. doi: 10.3389/fncel.2014.00182
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Gavazzo, P., Vassalli, M., Costa, D., and Pagano, A. (2013). Novel ncRNAs transcribed by Pol III and elucidation of their functional relevance by biophysical approaches. Front. Cell. Neurosci. 7:203. doi: 10.3389/fncel.2013.00203
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Goodall, E. F., Heath, P. R., Bandmann, O., Kirby, J., and Shaw, P. J. (2013). Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front. Cell. Neurosci. 7:178. doi: 10.3389/fncel.2013.00178
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Guffanti, A., Simchovitz, A., and Soreq, H. (2014). Emerging bioinformatics approaches for analysis of NGS-derived coding and non-coding RNAs in neurodegenerative diseases. Front. Cell. Neurosci. 8:89. doi: 10.3389/fncel.2014.00089
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Gummalla, M., Galetti, S., Maeda, R. K., and Karch, F. (2014). Hox gene regulation in the central nervous system of Drosophila. Front. Cell. Neurosci. 8:96. doi: 10.3389/fncel.2014.00096
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Heise, C., Gardoni, F., Culotta, L., di Luca, M., Verpelli, C., and Sala, C. (2014). Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. Front. Cell. Neurosci. 8:35. doi: 10.3389/fncel.2014.00035
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Hong, J., Zhang, H., Kawase-Koga, Y., and Sun, T. (2013). MicroRNA function is required for neurite outgrowth of mature neurons in the mouse postnatal cerebral cortex. Front. Cell. Neurosci. 7:151. doi: 10.3389/fncel.2013.00151
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Iyengar, B. R., Choudhary, A., Sarangdhar, M. A., Venkatesh, K. V., Gadgil, C. J., and Pillai, B. (2014). Non-coding RNA interact to regulate neuronal development and function. Front. Cell. Neurosci. 8:47. doi: 10.3389/fncel.2014.00047
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Iyer, A. N., Bellon, A., and Baudet, M. L. (2014). microRNAs in axon guidance. Front. Cell. Neurosci. 8:78. doi: 10.3389/fncel.2014.00078
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Kaplan, B. B., Kar, A. N., Gioio, A. E., and Aschrafi, A. (2013). MicroRNAs in the axon and presynaptic nerve terminal. Front. Cell. Neurosci. 7:126. doi: 10.3389/fncel.2013.00126
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Knauss, J. L., Bian, S., and Sun, T. (2013). Plasmid-based target protectors allow specific blockade of miRNA silencing activity in mammalian developmental systems. Front. Cell. Neurosci. 7:163. doi: 10.3389/fncel.2013.00163
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Kye, M. J., and Goncalves Ido, C. (2014). The role of miRNA in motor neuron disease. Front. Cell. Neurosci. 8:15. doi: 10.3389/fncel.2014.00015
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Maciotta, S., Meregalli, M., and Torrente, Y. (2013). The involvement of microRNAs in neurodegenerative diseases. Front. Cell. Neurosci. 7:265. doi: 10.3389/fncel.2013.00265
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Maffioletti, E., Tardito, D., Gennarelli, M., and Bocchio-Chiavetto, L. (2014). Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front. Cell. Neurosci. 8:75. doi: 10.3389/fncel.2014.00075
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Nieto-Diaz, M., Esteban, F. J., Reigada, D., Munoz-Galdeano, T., Yunta, M., Caballero-Lopez, M., et al. (2014). MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front. Cell. Neurosci. 8:53. doi: 10.3389/fncel.2014.00053
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Osella, M., Bosia, C., Cora, D., and Caselle, M. (2011). The role of incoherent microRNA-mediated feedforward loops in noise buffering. PLoS Comput. Biol. 7:e1001101. doi: 10.1371/journal.pcbi.1001101
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Pai, B., Siripornmongcolchai, T., Berentsen, B., Pakzad, A., Vieuille, C., Pallesen, S., et al. (2014). NMDA receptor-dependent regulation of miRNA expression and association with Argonaute during LTP in vivo. Front. Cell. Neurosci. 7:285. doi: 10.3389/fncel.2013.00285
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Pascarella, G., Lazarevic, D., Plessy, C., Bertin, N., Akalin, A., Vlachouli, C., et al. (2014). NanoCAGE analysis of the mouse olfactory epithelium identifies the expression of vomeronasal receptors and of proximal LINE elements. Front. Cell. Neurosci. 8:41. doi: 10.3389/fncel.2014.00041
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Serafini, G., Pompili, M., Hansen, K. F., Obrietan, K., Dwivedi, Y., Amore, M., et al. (2013). MicroRNAs: fundamental regulators of gene expression in major affective disorders and suicidal behavior? Front. Cell. Neurosci. 7:208. doi: 10.3389/fncel.2013.00208
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Sheinerman, K. S., and Umansky, S. R. (2013). Circulating cell-free microRNA as biomarkers for screening, diagnosis and monitoring of neurodegenerative diseases and other neurologic pathologies. Front. Cell. Neurosci. 7:150. doi: 10.3389/fncel.2013.00150
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Siciliano, V., Garzilli, I., Fracassi, C., Criscuolo, S., Ventre, S., and di Bernardo, D. (2013). MiRNAs confer phenotypic robustness to gene networks by suppressing biological noise. Nat. Commun. 4:2364. doi: 10.1038/ncomms3364
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Terzibasi Tozzini, E., Savino, A., Ripa, R., Battistoni, G., Baumgart, M., and Cellerino, A. (2014). Regulation of microRNA expression in the neuronal stem cell niches during aging of the short-lived annual fish Nothobranchius furzeri. Front. Cell. Neurosci. 8:51. doi: 10.3389/fncel.2014.00051
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tognini, P., and Pizzorusso, T. (2012). MicroRNA212/132 family: molecular transducer of neuronal function and plasticity. Int. J. Biochem. Cell Biol. 44, 6–10. doi: 10.1016/j.biocel.2011.10.015
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Keywords: microRNA, non-coding RNA, neuronal development, neuronal plasticity, aging
Citation: Cellerino A, Bally-Cuif L and Pizzorusso T (2015) Editorial for “Regulatory RNAs in the nervous system”. Front. Cell. Neurosci. 9:38. doi: 10.3389/fncel.2015.00038
Received: 19 January 2015; Accepted: 22 January 2015;
Published online: 10 February 2015.
Edited and reviewed by: Christian Hansel, Erasmus Medical Center, Netherlands
Copyright © 2015 Cellerino, Bally-Cuif and Pizzorusso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: tommaso.pizzorusso@in.cnr.it