title: MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development.
abstract: tbx5, a member of the T-box gene family, encodes one of the key transcription factors mediating vertebrate heart development. Tbx5 function in heart development appears to be exquisitely sensitive to gene dosage, since both haploinsufficiency and gene duplication generate the cardiac abnormalities associated with Holt-Oram syndrome (HOS), a highly penetrant autosomal dominant disease characterized by congenital heart defects of varying severity and upper limb malformation. It is suggested that tight integration of microRNAs and transcription factors into the cardiac genetic circuitry provides a rich and robust array of regulatory interactions to control cardiac gene expression. Based on these considerations, we performed an in silico screening to identify microRNAs embedded in genes highly sensitive to Tbx5 dosage. Among the identified microRNAs, we focused our attention on miR-218-1 that, together with its host gene, slit2, is involved in heart development. We found correlated expression of tbx5 and miR-218 during cardiomyocyte differentiation of mouse P19CL6 cells. In zebrafish embryos, we show that both Tbx5 and miR-218 dysregulation have a severe impact on heart development, affecting early heart morphogenesis. Interestingly, down-regulation of miR-218 is able to rescue the heart defects generated by tbx5 over-expression supporting the notion that miR-218 is a crucial mediator of Tbx5 in heart development and suggesting its possible involvement in the onset of heart malformations.
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Chiavacci
authors.forename: Luca
authors.initials: L
authors.lastname: Dolfi
authors.forename: Lorena
authors.initials: L
authors.lastname: Verduci
authors.forename: Francesco
authors.initials: F
authors.lastname: Meghini
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.forename: Alberto Mercatanti Monica
authors.initials: AM
authors.lastname: Evangelista
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.forename: Federico
authors.initials: F
authors.lastname: Cremisi
authors.forename: Letizia
authors.initials: L
authors.lastname: Pitto
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression; D006321:Heart / Q000254:growth & development*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D020825:T-Box Domain Proteins / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development*
chemical_list: C547684:MIRN218 microRNA, mouse; D035683:MicroRNAs; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5