PUBLICATION
miR-182-5p is an evolutionarily conserved Tbx5 effector that impacts cardiac development and electrical activity in zebrafish
- 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.
- ID
- ZDB-PUB-191108-6
- Date
- 2019
- Source
- Cellular and molecular life sciences : CMLS 77(16): 3215-3229 (Journal)
- Registered Authors
- Garrity, Deborah
- Keywords
- Cardiac development, Holt–Oram syndrome, Zebrafish, microRNAs
- MeSH Terms
-
- Animals
- Animals, Genetically Modified/genetics
- Animals, Genetically Modified/metabolism
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/metabolism
- Calcium/metabolism
- Cell Line
- Down-Regulation/genetics
- Female
- Gene Expression Regulation/genetics
- Heart/growth & development*
- Mice
- Mice, Inbred C57BL
- MicroRNAs/genetics*
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/physiology
- Pregnancy
- T-Box Domain Proteins/genetics*
- T-Box Domain Proteins/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Up-Regulation/genetics
- Zebrafish/genetics*
- Zebrafish/metabolism
- PubMed
- 31686119 Full text @ Cell. Mol. Life Sci.
Citation
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. (2019) miR-182-5p is an evolutionarily conserved Tbx5 effector that impacts cardiac development and electrical activity in zebrafish. Cellular and molecular life sciences : CMLS. 77(16):3215-3229.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping