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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.

MicroRNA 218 Mediates the Effects of Tbx5a Over-Expression on Zebrafish Heart Development