miR-182-5p is an Evolutionarily Conserved Tbx5 Effector that Impacts Cardiac Development and Electrical Activity in Zebrafish
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.
Cellular and Molecular Life Sciences
Guzzolino, Elena; Pellegrino, Mario; Ahuja, Neha; Garrity, Deborah; D'Aurizio, Romina; Groth, Marco; Baumgart, Mario; Hatcher, Cathy J.; Mercatanti, Alberto; Evangelista, Monica; Ippolito, Chiara; Tognoni, Elisabetta; Fukuda, Ryuichi; Lionetti, Vincenzo; Pellegrini, Marco; Cremisi, Federico; and Pitto, Letizia, "miR-182-5p is an Evolutionarily Conserved Tbx5 Effector that Impacts Cardiac Development and Electrical Activity in Zebrafish" (2019). PCOM Scholarly Papers. 2028.