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

Year: 2020

Authors: Guzzolino E., Pellegrino M., Ahuja N., Garrity D., D’Aurizio R., Groth M., Baumgart M., Hatcher C.J., Mercatanti A., Evangelista M., Ippolito C., Tognoni E., Fukuda R., Lionetti V., Pellegrini M., Cremisi F., Pitto L.

Autors Affiliation: CNR, Inst Clin Physiol, IFC Via Moruzzi 1, I-56124 Pisa, Italy; Scuola Super Sant Anna, Inst Life Sci, Pisa, Italy; CNR, Natl Inst Opt, Pisa, Italy; Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA; CNR, Inst Informat & Telemat, Pisa, Italy; FLI, Leibniz Inst Aging, Jena, Germany; Philadelphia Coll Osteopath Med, Dept Biomed Sci, Philadelphia, PA USA; Univ Pisa, Dept Clin & Expt Med, I-56126 Pisa, Italy; Max Planck Inst Heart & Lung Res, Dept Dev Genet, Bad Nauheim, Germany; Fdn Toscana G Monasterio, UOS Anesthesiol, Pisa, Italy; Scuola Normale Super Pisa, Pisa, Italy.

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.

Journal/Review: CELLULAR AND MOLECULAR LIFE SCIENCES

Volume: 77 (16)      Pages from: 3215  to: 3229

More Information: 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.
KeyWords: microRNAs; Holt-Oram syndrome; Zebrafish; Cardiac development
DOI: 10.1007/s00018-019-03343-7

Citations: 12
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