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

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 suffi...

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Bibliographic Details
Published in:Scientific reports 2015-12, Vol.5 (1), p.18240-18240, Article 18240
Main Authors: Chiavacci, Elena, D'Aurizio, Romina, Guzzolino, Elena, Russo, Francesco, Baumgart, Mario, Groth, Marco, Mariani, Laura, D'Onofrio, Mara, Arisi, Ivan, Pellegrini, Marco, Cellerino, Alessandro, Cremisi, Federico, Pitto, Letizia
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
Abnormalities, Multiple - therapy
Animal Fins - embryology
Animal Fins - pathology
Animals
Defects
Embryonic Development - genetics
Embryos
Gene expression
Gene Expression Regulation, Developmental
Genetic Therapy - methods
Genome-Wide Association Study
Genomics
Heart
Heart Defects, Congenital - genetics
Heart Defects, Congenital - pathology
Heart Defects, Congenital - therapy
Heart diseases
Heart Septal Defects, Atrial - genetics
Heart Septal Defects, Atrial - pathology
Heart Septal Defects, Atrial - therapy
Holt-Oram syndrome
Lower Extremity Deformities, Congenital - genetics
Lower Extremity Deformities, Congenital - pathology
Lower Extremity Deformities, Congenital - therapy
MicroRNAs - genetics
miRNA
Multigene Family
Phenotype
RNA Interference
T-Box Domain Proteins - genetics
TBX5 gene
Upper Extremity Deformities, Congenital - genetics
Upper Extremity Deformities, Congenital - pathology
Upper Extremity Deformities, Congenital - therapy
Zebrafish - embryology
Zebrafish - genetics
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep18240