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The microRNA-29a Modulates Serotonin 5-HT7 Receptor Expression and Its Effects on Hippocampal Neuronal Morphology

Molecular Neurobiology volume 56, pages 8617–8627 (2019)Cite this article

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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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).

Author information

Author notes

  1. L. Speranza & C. De Sanctis

    Present address: Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, 10461, USA

  2. S. Pulcrano

    Present address: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy

  3. R. De Gregorio

    Present address: Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY, 10461, USA

Affiliations

  1. Department of Pharmacy, University of Naples Federico II, Naples, Italy

    Floriana Volpicelli, S. Pulcrano & C. Perrone-Capano

  2. Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, Naples, Italy

    Floriana Volpicelli, L. Speranza, S. Pulcrano, R. De Gregorio, C. De Sanctis, U. di Porzio, G. C. Bellenchi & C. Perrone-Capano

  3. Department of Biology, University of Naples Federico II, Naples, Italy

    M. Crispino

  4. Department of Pharmacy – Drug Science, University of Bari Aldo Moro, Bari, Italy

    M. Leopoldo & E. Lacivita

  5. Department of Systems Medicine, University of Rome ‘Tor Vergata’, 00133, Rome, Italy

    G. C. Bellenchi

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  1. Floriana Volpicelli
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Correspondence to Floriana Volpicelli.

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Supplementary Fig. 1
figure 6

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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Keywords

  • 5-HT7R
  • Hippocampus
  • miR-29a
  • Neurite outgrowth
  • Neuronal primary cultures
  • Neuronal structural plasticity