P481Regulation of regulators: Tbx5 impacts cardiac expression through miR-218 modulation in zebrafish

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Abstract

Background

Tbx5, a member of the T-box gene family, is one of the key transcription factor of vertebrate heart development Minor alterations in its dosage cause Holt-Oram syndrome (HOS) an autosomal dominant disease characterized upper limb malformation and congenital heart defects of variable severity. In mouse model of HOS gene expression profiling revealed that TBX5 regulate a complextranscriptional network probably acting directely on gene expression or indirectely by " regulating regulators" such as TF and miRNAs. The integration of miRNAs and TFs into the genetic cardiac circuitry provides a rich and robust array of regulatory interactions to control cardiac gene expression. Looking for TBX5/miRNA regulatory circuit we identified miR-218 which, together with its host gene, Slit2, has been already shown to be involved in heart development.

Purpose

the goal of our project is to demonstrate the existence of a regulatory circuit involving Tbx5/slit2/miR-218 and its importance in cardiac development.

Methods

For in vitro studies P19CL6, a murine cell line able to differentiate cardiomyocites were utilized. For in vivo functional studies, gain and loss of function experiments of both, Tbx5 and

Results

in cardiomyocyte differentiation of mouse P19CL6 cell culture, we confirmed a correlation between Tbx5 and miR-218 expression. Using zebrafish model, we showed that alterations of miR-218 expression have a deep impact on heart development. Interestingly, down-regulation of miR-218 was able to almost rescue defects generated by Tbx5 over-expression, confirming a functional relation between these two regulators.

Conclusions

these data demonstrate that TBX5 directly and indirectly controls TF/miRNA regulatory circuitries and support the importance of miRNA regulationin HOS.

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