title: MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome.
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.affiliation: Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Chiavacci
authors.affiliation: Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics andTelematics (IIT) and Institute of Clinical Physiology (IFC), (CNR), Pisa, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: D'Aurizio
authors.affiliation: Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Guzzolino
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Russo
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Baumgart
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.affiliation: Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Genomics Facility, European Brain Research Institute, Via del Fosso di Fiorano 64 00143 Roma, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: D'Onofrio
authors.affiliation: Genomics Facility, European Brain Research Institute, Via del Fosso di Fiorano 64 00143 Roma, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Arisi
authors.affiliation: Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics andTelematics (IIT) and Institute of Clinical Physiology (IFC), (CNR), Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cellerino
authors.affiliation: Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cremisi
authors.affiliation: Institute of Clinical Physiology, National Research Council, via Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Pitto
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D058500:Animal Fins / Q000196:embryology / Q000473:pathology; D000818:Animals; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015316:Genetic Therapy / Q000379:methods; D055106:Genome-Wide Association Study; D023281:Genomics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D010641:Phenotype; D034622:RNA Interference; D020825:T-Box Domain Proteins / Q000235:genetics; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5