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

  • Elena Guzzolino
  • Mario Pellegrino
  • Neha Ahuja
  • Deborah Garrity
  • Romina D’Aurizio
  • Marco Groth
  • Mario Baumgart
  • Cathy J. Hatcher
  • Alberto Mercatanti
  • Monica Evangelista
  • Chiara Ippolito
  • Elisabetta Tognoni
  • Ryuichi Fukuda
  • Vincenzo Lionetti
  • Marco Pellegrini
  • Federico Cremisi
  • Letizia PittoEmail author
Original Article

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.

Keywords

microRNAs Holt–Oram syndrome Zebrafish Cardiac development 

Notes

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.

Supplementary material

18_2019_3343_MOESM1_ESM.xlsx (75 kb)
Supplementary material 1 (XLSX 75 kb)
18_2019_3343_MOESM2_ESM.pdf (2.5 mb)
Supplementary material 2 (PDF 2591 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Elena Guzzolino
    • 1
    • 2
  • Mario Pellegrino
    • 3
  • Neha Ahuja
    • 4
  • Deborah Garrity
    • 4
  • Romina D’Aurizio
    • 5
  • Marco Groth
    • 6
  • Mario Baumgart
    • 6
  • Cathy J. Hatcher
    • 7
  • Alberto Mercatanti
    • 1
  • Monica Evangelista
    • 1
  • Chiara Ippolito
    • 8
  • Elisabetta Tognoni
    • 3
  • Ryuichi Fukuda
    • 9
  • Vincenzo Lionetti
    • 2
    • 10
  • Marco Pellegrini
    • 5
  • Federico Cremisi
    • 11
  • Letizia Pitto
    • 1
    Email author
  1. 1.Institute of Clinical PhysiologyNational Research CouncilPisaItaly
  2. 2.Institute of Life SciencesScuola Superiore Sant’AnnaPisaItaly
  3. 3.National Institute of Optics, CNRPisaItaly
  4. 4.Department of BiologyColorado State University (CSU)Fort CollinsUSA
  5. 5.Institute of Informatics and Telematics, CNRPisaItaly
  6. 6.The Leibniz Institute on AgingFritz Lipmann Institute (FLI)JenaGermany
  7. 7.Department of Bio-Medical SciencesPhiladelphia College of Osteopathic MedicinePhiladelphiaUSA
  8. 8.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  9. 9.Department of Developmental GeneticsMax Planck Institute for Heart and Lung ResearchBad NauheimGermany
  10. 10.UOS Anesthesiology, Fondazione Toscana “G.Monasterio”PisaItaly
  11. 11.Scuola Normale SuperiorePisaItaly

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