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MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome.
Sci Rep. 2015 Dec 14; 5:18240.SR

Abstract

Holt-Oram Syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene, a transcription factor capable of regulating hundreds of cardiac-specific genes through complex transcriptional networks. Here we show that, in zebrafish, modulation of a single miRNA is sufficient to rescue the morphogenetic defects generated by HOS. The analysis of miRNA-seq profiling revealed a decreased expression of miR-19a in Tbx5-depleted zebrafish embryos compared to the wild type. We revealed that the transcription of the miR-17-92 cluster, which harbors miR-19a, is induced by Tbx5 and that a defined dosage of miR-19a is essential for the correct development of the heart. Importantly, we highlighted that miR-19a replacement is able to rescue cardiac and pectoral fin defects and to increase the viability of HOS zebrafish embryos. We further observed that miR-19a replacement shifts the global gene expression profile of HOS-like zebrafish embryos towards the wild type condition, confirming the ability of miR-19a to rescue the Tbx5 phenotype. In conclusion our data demonstrate the importance of Tbx5/miR-19a regulatory circuit in heart development and provide a proof of principle that morphogenetic defects associated with HOS can be rescued by transient miRNA modulation.

Authors+Show Affiliations

Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics andTelematics (IIT) and Institute of Clinical Physiology (IFC), (CNR), Pisa, Italy.Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy.Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics andTelematics (IIT) and Institute of Clinical Physiology (IFC), (CNR), Pisa, Italy. Department of Computer Science, University of Pisa, Pisa, Italy.Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.Genomics Facility, European Brain Research Institute, Via del Fosso di Fiorano 64 00143 Roma, Italy.Genomics Facility, European Brain Research Institute, Via del Fosso di Fiorano 64 00143 Roma, Italy.Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics andTelematics (IIT) and Institute of Clinical Physiology (IFC), (CNR), Pisa, Italy.Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy.Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy.Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26657204

Citation

Chiavacci, Elena, et al. "MicroRNA 19a Replacement Partially Rescues Fin and Cardiac Defects in Zebrafish Model of Holt Oram Syndrome." Scientific Reports, vol. 5, 2015, p. 18240.
Chiavacci E, D'Aurizio R, Guzzolino E, et al. MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome. Sci Rep. 2015;5:18240.
Chiavacci, E., D'Aurizio, R., Guzzolino, E., Russo, F., Baumgart, M., Groth, M., Mariani, L., D'Onofrio, M., Arisi, I., Pellegrini, M., Cellerino, A., Cremisi, F., & Pitto, L. (2015). MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome. Scientific Reports, 5, 18240. https://doi.org/10.1038/srep18240
Chiavacci E, et al. MicroRNA 19a Replacement Partially Rescues Fin and Cardiac Defects in Zebrafish Model of Holt Oram Syndrome. Sci Rep. 2015 Dec 14;5:18240. PubMed PMID: 26657204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome. AU - Chiavacci,Elena, AU - D'Aurizio,Romina, AU - Guzzolino,Elena, AU - Russo,Francesco, AU - Baumgart,Mario, AU - Groth,Marco, AU - Mariani,Laura, AU - D'Onofrio,Mara, AU - Arisi,Ivan, AU - Pellegrini,Marco, AU - Cellerino,Alessandro, AU - Cremisi,Federico, AU - Pitto,Letizia, Y1 - 2015/12/14/ PY - 2015/07/03/received PY - 2015/11/06/accepted PY - 2015/12/15/entrez PY - 2015/12/15/pubmed PY - 2016/10/14/medline SP - 18240 EP - 18240 JF - Scientific reports JO - Sci Rep VL - 5 N2 - Holt-Oram Syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene, a transcription factor capable of regulating hundreds of cardiac-specific genes through complex transcriptional networks. Here we show that, in zebrafish, modulation of a single miRNA is sufficient to rescue the morphogenetic defects generated by HOS. The analysis of miRNA-seq profiling revealed a decreased expression of miR-19a in Tbx5-depleted zebrafish embryos compared to the wild type. We revealed that the transcription of the miR-17-92 cluster, which harbors miR-19a, is induced by Tbx5 and that a defined dosage of miR-19a is essential for the correct development of the heart. Importantly, we highlighted that miR-19a replacement is able to rescue cardiac and pectoral fin defects and to increase the viability of HOS zebrafish embryos. We further observed that miR-19a replacement shifts the global gene expression profile of HOS-like zebrafish embryos towards the wild type condition, confirming the ability of miR-19a to rescue the Tbx5 phenotype. In conclusion our data demonstrate the importance of Tbx5/miR-19a regulatory circuit in heart development and provide a proof of principle that morphogenetic defects associated with HOS can be rescued by transient miRNA modulation. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26657204/MicroRNA_19a_replacement_partially_rescues_fin_and_cardiac_defects_in_zebrafish_model_of_Holt_Oram_syndrome_ L2 - http://dx.doi.org/10.1038/srep18240 DB - PRIME DP - Unbound Medicine ER -