MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome

TY - JOUR

T1 - MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome

AU - Chiavacci, Elena

AU - Daurizio, Romina

AU - Guzzolino, Elena

AU - Russo, Francesco

AU - Baumgart, Mario

AU - Groth, Marco

AU - Mariani, Laura

AU - Donofrio, Mara

AU - Arisi, Ivan

AU - Pellegrini, Marco

AU - Cellerino, Alessandro

AU - Cremisi, Federico

AU - Pitto, Letizia

PY - 2015/12/14

Y1 - 2015/12/14

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84950113441&partnerID=8YFLogxK

U2 - 10.1038/srep18240

DO - 10.1038/srep18240

M3 - Journal article

C2 - 26657204

AN - SCOPUS:84950113441

SN - 2045-2322

VL - 5

JO - Scientific Reports

JF - Scientific Reports

M1 - 18240

ER -