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miR-182-5p is an evolutionarily conserved Tbx5 effector that impacts cardiac development and electrical activity in zebrafish

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Abstract

To dissect the TBX5 regulatory circuit, we focused on microRNAs (miRNAs) that collectively contribute to make TBX5 a pivotal cardiac regulator. We profiled miRNAs in hearts isolated from wild-type, CRE, Tbx5lox/+and Tbx5del/+ mice using a Next Generation Sequencing (NGS) approach. TBX5 deficiency in cardiomyocytes increased the expression of the miR-183 cluster family that is controlled by Kruppel-like factor 4, a transcription factor repressed by TBX5. MiR-182-5p, the most highly expressed miRNA of this family, was functionally analyzed in zebrafish. Transient overexpression of miR-182-5p affected heart morphology, calcium handling and the onset of arrhythmias as detected by ECG tracings. Accordingly, several calcium channel proteins identified as putative miR-182-5p targets were downregulated in miR-182-5p overexpressing hearts. In stable zebrafish transgenic lines, we demonstrated that selective miRNA-182-5p upregulation contributes to arrhythmias. Moreover, cardiac-specific down-regulation of miR-182-5p rescued cardiac defects in a zebrafish model of Holt–Oram syndrome. In conclusion, miR-182-5p exerts an evolutionarily conserved role as a TBX5 effector in the onset of cardiac propensity for arrhythmia, and constitutes a relevant target for mediating the relationship between TBX5, arrhythmia and heart development.

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Acknowledgements

We are grateful to Dr.Elena Chiavacci (International Centre for Genetic Engineering and Biotechnology,Trieste, Italy) for experimental assistance, Dr. Marnie Halpern (Carnegie Institution Baltimore, Maryland) for kindly providing the pME-Galff-2a-mCherry and 4XNR UAS GFP plasmids, Dr. Héctor Sanchez Iranzo (Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid,Spain) for kindly providing pDestCrysGFP plasmid and Prof.Sheng-Ping L. Hwang (Institute of Cellular and Organismic Biology Academia Sinica Taiwan) for the kind gift of the T7TS-klf4a plasmid for dre klf4 overexpression in zebrafish embryos. RF thanks Didier Stainier (Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany) for support.

Funding

The project was supported by grants from the American Heart Association (17AIREA33660773) and PCOM Center for Chronic Disorders of Aging to C.J. Hatcher and by the American Heart Association 17GRNT33460256 to D.Garrity.

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Authors and Affiliations

  1. Institute of Clinical Physiology, National Research Council, IFC via Moruzzi 1, 56124, Pisa, Italy

    Elena Guzzolino, Alberto Mercatanti, Monica Evangelista & Letizia Pitto

  2. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy

    Elena Guzzolino & Vincenzo Lionetti

  3. National Institute of Optics, CNR, Pisa, Italy

    Mario Pellegrino & Elisabetta Tognoni

  4. Department of Biology, Colorado State University (CSU), Fort Collins, CO, USA

    Neha Ahuja & Deborah Garrity

  5. Institute of Informatics and Telematics, CNR, Pisa, Italy

    Romina D’Aurizio & Marco Pellegrini

  6. The Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany

    Marco Groth & Mario Baumgart

  7. Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

    Cathy J. Hatcher

  8. Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy

    Chiara Ippolito

  9. Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

    Ryuichi Fukuda

  10. UOS Anesthesiology, Fondazione Toscana “G.Monasterio”, Pisa, Italy

    Vincenzo Lionetti

  11. Scuola Normale Superiore, Pisa, Italy

    Federico Cremisi

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  1. Elena Guzzolino
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Guzzolino, E., Pellegrino, M., Ahuja, N. et al. miR-182-5p is an evolutionarily conserved Tbx5 effector that impacts cardiac development and electrical activity in zebrafish. Cell. Mol. Life Sci. 77, 3215–3229 (2020). https://doi.org/10.1007/s00018-019-03343-7

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