Abstract
miRNAs are master regulators of gene expression in diverse biological processes, including the modulation of neuronal cytoarchitecture. The identification of their physiological target genes remains one of the outstanding challenges. Recently, it has been demonstrated that the activation of serotonin receptor 7 (5-HT7R) plays a key role in regulating the neuronal structure, synaptogenesis, and synaptic plasticity during embryonic and early postnatal development of the central nervous system (CNS). In order to identify putative miRNAs targeting the 3′UTR of 5-HT7R mouse transcript, we used a computational prediction tool and detected the miR-29 family members as the only candidates. Thus, since miR-29a is more expressed than other members in the brain, we investigated its possible involvement in the regulation of neuronal morphology mediated by 5-HT7R. By luciferase assay, we show that miR-29a can act as a post-transcriptional regulator of 5-HT7R mRNA. Indeed, it downregulates 5-HT7R gene expression in cultured hippocampal neurons, while the expression of other serotonin receptors is not affected. From a functional point of view, miR-29a overexpression in hippocampal primary cultures impairs the 5HT7R-dependent neurite elongation and remodeling through the inhibition of the ERK intracellular signaling pathway. In vivo, the upregulation of miR-29a in the developing hippocampus parallels with the downregulation of 5-HT7R expression, supporting the hypothesis that this miRNA is a physiological modulator of 5-HT7R expression in the CNS.
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References
Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PP, Middlemiss DN, Mylecharane EJ, Richardson BP et al (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25(6):563–576
McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150:129–142. https://doi.org/10.1016/j.pharmthera.2015.01.009
Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annu Rev Med 60:355–366. https://doi.org/10.1146/annurev.med.60.042307.110802
Artigas F (2015) Developments in the field of antidepressants, where do we go now? Eur Neuropsychopharmacol 25(5):657–670. https://doi.org/10.1016/j.euroneuro.2013.04.013
Hoyer D, Hannon JP, Martin GR (2002) Molecular pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71(4):533–554
Leopoldo M, Lacivita E, Berardi F, Perrone R, Hedlund PB (2011) Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol Ther 129(2):120–148. https://doi.org/10.1016/j.pharmthera.2010.08.013
Adriani W, Travaglini D, Lacivita E, Saso L, Leopoldo M, Laviola G (2012) Modulatory effects of two novel agonists for serotonin receptor 7 on emotion, motivation and circadian rhythm profiles in mice. Neuropharmacology 62(2):833–842. https://doi.org/10.1016/j.neuropharm.2011.09.012
Monti JM, Leopoldo M, Jantos H (2014) Systemic administration and local microinjection into the central nervous system of the 5-HT(7) receptor agonist LP-211 modify the sleep-wake cycle in the rat. Behav Brain Res 259:321–329. https://doi.org/10.1016/j.bbr.2013.11.030
Romano E, Ruocco LA, Nativio P, Lacivita E, Ajmone-Cat MA, Boatto G, Nieddu M, Tino A et al (2014) Modulatory effects following subchronic stimulation of brain 5-HT7-R system in mice and rats. Rev Neurosci 25(3):383–400. https://doi.org/10.1515/revneuro-2014-0007
Roberts AJ, Hedlund PB (2012) The 5-HT(7) receptor in learning and memory. Hippocampus 22(4):762–771. https://doi.org/10.1002/hipo.20938
Freret T, Paizanis E, Beaudet G, Gusmao-Montaigne A, Nee G, Dauphin F, Bouet V, Boulouard M (2014) Modulation of 5-HT7 receptor: effect on object recognition performances in mice. Psychopharmacology 231(2):393–400. https://doi.org/10.1007/s00213-013-3247-x
Meneses A (2014) Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative. Rev Neurosci 25(3):325–356. https://doi.org/10.1515/revneuro-2014-0001
Garcia GG, Miranda HF, Noriega V, Sierralta F, Olavarría L, Zepeda RJ, Prieto JC (2011) Antinociception induced by atorvastatin in different pain models. Pharmacol Biochem Behav 100(1):125–129. https://doi.org/10.1016/j.pbb.2011.08.007
Errico M, Crozier RA, Plummer MR, Cowen DS (2001) 5-HT(7) receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons. Neuroscience 102(2):361–367
Volpicelli F, Speranza L, di Porzio U, Crispino M, Perrone-Capano C (2014) The serotonin receptor 7 and the structural plasticity of brain circuits. Front Behav Neurosci 8:318. https://doi.org/10.3389/fnbeh.2014.00318
Kvachnina E, Liu G, Dityatev A, Renner U, Dumuis A, Richter DW, Dityateva G, Schachner M et al (2005) 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci 25(34):7821–7830
Speranza L, Chambery A, Di Domenico M, Crispino M, Severino V, Volpicelli F, Leopoldo M, Bellenchi GC et al (2013) The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways. Neuropharmacology 67:155–167. https://doi.org/10.1016/j.neuropharm.2012.10.026
Speranza L, Giuliano T, Volpicelli F, De Stefano ME, Lombardi L, Chambery A, Lacivita E, Leopoldo M et al (2015) Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Front Behav Neurosci 9:62. https://doi.org/10.3389/fnbeh.2015.00062
Rojas PS, Neira D, Muñoz M, Lavandero S, Fiedler JL (2014) Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons. J Neurosci Res 92(8):1000–1009. https://doi.org/10.1002/jnr.23390
Kobe F, Guseva D, Jensen TP, Wirth A, Renner U, Hess D, Müller M, Medrihan L et al (2012) 5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner. J Neurosci 32(9):2915–2930. https://doi.org/10.1523/JNEUROSCI.2765-11.2012
Speranza L, Labus J, Volpicelli F, Guseva D, Lacivita E, Leopoldo M, Bellenchi GC, di Porzio U et al (2017) Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons. J Neurochem 141(5):647–661. https://doi.org/10.1111/jnc.13962
Matthys A, Haegeman G, Van Craenenbroeck K, Vanhoenacker P (2011) Role of the 5-HT7 receptor in the central nervous system: from current status to future perspectives. Mol Neurobiol 43(3):228–253. https://doi.org/10.1007/s12035-011-8175-3
Naumenko VS, Popova NK, Lacivita E, Leopoldo M, Ponimaskin EG (2014) Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci Ther 20(7):582–590. https://doi.org/10.1111/cns.12247
Morita T, McClain SP, Batia LM, Pellegrino M, Wilson SR, Kienzler MA, Lyman K, Olsen AS et al (2015) HTR7 mediates serotonergic acute and chronic itch. Neuron 87(1):124–138. https://doi.org/10.1016/j.neuron.2015.05.044
Santello M, Nevian T (2015) Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation. Neuron 86(1):233–246. https://doi.org/10.1016/j.neuron.2015.03.003
Nikiforuk A (2015) Targeting the serotonin 5-HT7 receptor in the search for treatments for CNS disorders: rationale and progress to date. CNS Drugs 29(4):265–275. https://doi.org/10.1007/s40263-015-0236-0
Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5(5):396–400
Winter J, Jung S, Keller S, Gregory RI, Diederichs S (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11(3):228–234. https://doi.org/10.1038/ncb0309-228
Chiu H, Alqadah A, Chang C (2014) The role of microRNAs in regulating neuronal connectivity. Front Cell Neurosci 7:283. https://doi.org/10.3389/fncel.2013.00283
Rajman M, Schratt G (2017) MicroRNAs in neural development: from master regulators to fine-tuners. Development 144(13):2310–2322. https://doi.org/10.1242/dev.144337
Ye Y, Xu H, Su X, He X (2016) Role of microRNA in governing synaptic plasticity. Neural Plast 2016(4959523):1–13. https://doi.org/10.1155/2016/4959523
Wei CW, Luo T, Zou SS, Wu AS (2017) Research progress on the roles of microRNAs in governing synaptic plasticity, learning and memory. Life Sci 188:118–122. https://doi.org/10.1016/j.lfs.2017.08.033
Wu YE, Parikshak NN, Belgard TG, Geschwind DH (2016) Genome-wide, integrative analysis implicates microRNA dysregulation in autism spectrum disorder. Nat Neurosci 19(11):1463–1476. https://doi.org/10.1038/nn.4373
Im HI, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35(5):325–334. https://doi.org/10.1016/j.tins.2012.01.004
Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA (2013) Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 152(1–2):262–275. https://doi.org/10.1016/j.cell.2012.11.052
Lippi G, Fernandes CC, Ewell LA, John D, Romoli B, Curia G, Taylor SR, Frady EP et al (2016) MicroRNA-101 regulates multiple developmental programs to constrain excitation in adult neural networks. Neuron 92(6):1337–1351. https://doi.org/10.1016/j.neuron.2016.11.017
Li H, Mao S, Wang H, Zen K, Zhang C, Li L (2014) MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons. Protein Cell 5(2):160–169. https://doi.org/10.1007/s13238-014-0022-7
De Gregorio R, Pulcrano S, De Sanctis C, Volpicelli F, Guatteo E, von Oerthel L, Latagliata EC, Esposito R et al (2018) miR-34b/c regulates Wnt1 and enhances mesencephalic dopaminergic neuron differentiation. Stem Cell Rep 10(4):1237–1250. https://doi.org/10.1016/j.stemcr.2018.02.006
Caiazzo M, Dell’Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A et al (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476(7359):224–227. https://doi.org/10.1038/nature10284
Livak KJ, Schmittgen TD (2001) Analyzing of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408
Hwang HW, Wentzel EA, Mendell JT (2007) A hexanucleotide element directs microRNA nuclear import. Science 315(5808):97–100
Colucci-D’Amato L, Perrone-Capano C, di Porzio U (2003) Chronic activation of ERK and neurodegenerative diseases. Bioessays. 25(11):1085–1095
Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP (2010) Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology. Mol Syst Biol 6:391. https://doi.org/10.1038/msb.2010.52
Volpicelli F, Caiazzo M, Moncharmont B, di Porzio U, Colucci-D’Amato L (2014) Neuronal differentiation dictates estrogen-dependent survival and ERK1/2 kinetic by means of caveolin-1. PLoS One 9(10):e109671. https://doi.org/10.1371/journal.pone.0109671
Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH, Wilson SW (2007) MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol 8(8):R173
McNeill E, Van Vactor D (2012) MicroRNAs shape the neuronal landscape. Neuron 75(3):363–379. https://doi.org/10.1016/j.neuron.2012.07.005
Smith ACW, Kenny PJ (2018) MicroRNAs regulate synaptic plasticity underlying drug addiction. Genes Brain Behav 17(3):e12424. https://doi.org/10.1111/gbb.12424
Crispino M, Chun JT, Cefaliello C, Perrone Capano C, Giuditta A (2014) Local gene expression in nerve endings. Dev Neurobiol 74(3):279–291. https://doi.org/10.1002/dneu.22109
Wirth A, Holst K, Ponimaskin E (2017) How serotonin receptors regulate morphogenic signalling in neurons. Prog Neurobiol 151:35–56. https://doi.org/10.1016/j.pneurobio.2016.03.007
Papadopoulou AS, Serneels L, Achsel T, Mandemakers W, Callaerts-Vegh Z, Dooley J, Lau P, Ayoubi T et al (2015) Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice. Neurobiol Dis 73:275–288. https://doi.org/10.1016/j.nbd.2014.10.006
Costa L, Sardone LM, Bonaccorso CM, D’Antoni S, Spatuzza M, Gulisano W, Tropea MR, Puzzo D et al (2018) Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome. Front Mol Neurosci 11:353. https://doi.org/10.3389/fnmol.2018.00353
Pillai RS, Bhattacharyya SN, Filipowicz W (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 17(3):118–126
Broderick JA, Zamore PD (2011) MicroRNA therapeutics. Gene Ther 18(12):1104–1110. https://doi.org/10.1038/gt.2011.50
Nolan K, Mitchem MR, Jimenez-Mateos EM, Henshall DC, Concannon CG, Prehn JH (2014) Increased expression of microRNA-29a in ALS mice: functional analysis of its inhibition. J Mol Neurosci 53(2):231–241. https://doi.org/10.1007/s12031-014-0290-y
Sun E, Shi Y (2015) MicroRNAs: small molecules with big roles in neurodevelopment and diseases. Exp Neurol 268:46–53. https://doi.org/10.1016/j.expneurol.2014.08.005
Cushing L, Costinean S, Xu W, Jiang Z, Madden L, Kuang P, Huang J, Weisman A et al (2015) Disruption of miR-29 leads to aberrant differentiation of smooth muscle cells selectively associated with distal lung vasculature. PLoS Genet 11(5):e1005238. https://doi.org/10.1371/journal.pgen.1005238
Roshan R, Shridhar S, Sarangdhar MA, Banik A, Chawla M, Garg M, Singh VP, Pillai B (2014) Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA 20(8):1287–1297. https://doi.org/10.1261/rna.044008.113
Lippiello P, Hoxha E, Speranza L, Volpicelli F, Ferraro A, Leopoldo M, Lacivita E, Perrone-Capano C et al (2016) The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK. Neuropharmacology 101:426–438. https://doi.org/10.1016/j.neuropharm.2015.10.019
Camkurt MA, Güneş S, Coşkun S, Fındıklı E (2017) Peripheral signatures of psychiatric disorders: MicroRNAs. Clin Psychopharmacol Neurosci 15(4):313–319. https://doi.org/10.9758/cpn.2017.15.4.313
Dean B, Pavey G, Thomas D, Scarr E (2006) Cortical serotonin7, 1D and 1F receptors: effects of schizophrenia, suicide and antipsychotic drug treatment. Schizophr Res 88(1–3):265–274
Huang W (2017) MicroRNAs: biomarkers, diagnostics, and therapeutics. Methods Mol Biol 1617:57–67. https://doi.org/10.1007/978-1-4939-7046-9_4
Nijhuis A, Biancheri P, Lewis A, Bishop CL, Giuffrida P, Chan C, Feakins R, Poulsom R et al (2014) In Crohn’s disease fibrosis-reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts. Clin Sci (Lond) 127(5):341–350. https://doi.org/10.1042/CS20140048
Guseva D, Holst K, Kaune B, Meier M, Keubler L, Glage S, Buettner M, Bleich A et al (2014) Serotonin 5-HT7 Receptor Is Critically Involved in Acute and Chronic Inflammation of the Gastrointestinal Tract. Inflamm Bowel Dis 20(9):1516–1529. https://doi.org/10.1097/MIB.0000000000000150
Shajib MS, Baranov A, Khan WI (2017) Diverse effects of gut-derived serotonin in intestinal inflammation. ACS Chem Neurosci 8(5):920–931. https://doi.org/10.1021/acschemneuro.6b00414
Zhu H, Xiao X, Chai Y, Li D, Yan X, Tang H (2019) MiRNA-29a modulates visceral hyperalgesia in irritable bowel syndrome by targeting HTR7. Biochem Biophys Res Commun 511(3):671–678. https://doi.org/10.1016/j.bbrc.2019.02.126
Acknowledgments
We are grateful to the Integrated Microscopy Facility of the Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, Naples, IT. We thank Massimiliano Caiazzo who provided the pRev, pVSVG, and pMDL plasmids, and Sara Mancinelli for the Tet-O-FUW-Ires-GFP empty vector.
Funding
This work was supported by “Finanziamento Ricerca di Ateneo” from University of Naples Federico II, and by “POR Campania FESR 2014/2020” from Regione Campania (Project N. B61G18000470007).
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GCB is currently seconded at the ERCEA (European Research Council Executive Agency), Bruxelles, Belgium. The views expressed here are purely those of the writer and may not in any circumstances be regarded as stating an official position of the European Commission.
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Supplementary Fig. 1
LP-211 treatment does not affect the levels of 5-HT7R protein and miR-29a transcript. P0-P1 mouse hippocampal neuronal cultures were treated at DIV 14 for 2 h with the 5-HT7R agonist LP (100 nM). a The diagram (mean ± SEM, n=3) shows the level of 5-HT7R normalized with that of ß-actin. The image shows a representative Western blot using 5-HT7R and ß-actin antibodies. The protein molecular weight is shown on the left in kilodalton (kDa). b. The diagram shows the relative quantitation of miR-29a (mean ± SEM, n=3) normalized to the reference gene sno202 (2-dCTmethod). (PNG 61.7 kb)
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Volpicelli, F., Speranza, L., Pulcrano, S. et al. The microRNA-29a Modulates Serotonin 5-HT7 Receptor Expression and Its Effects on Hippocampal Neuronal Morphology. Mol Neurobiol 56, 8617–8627 (2019). https://doi.org/10.1007/s12035-019-01690-x
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DOI: https://doi.org/10.1007/s12035-019-01690-x