Critical roles of miRNA-mediated regulation of TGF? signalling during mouse cardiogenesis.

ABSTRACT:

Aims

MicroRNAs (miRNAs) play critical roles during the development of the cardiovascular system. Blocking miRNA biosynthesis in embryonic hearts through a conditional gene inactivation approach led to differential cardiac defects depending on the Cre drivers used in different studies. The goal of this study is to reveal the cardiogenic pathway that is regulated by the miRNA mechanism at midgestation, a stage that has not been evaluated in previous publications.

Methods and results

We specifically inactivated Dicer1, which is essential for generation of functional mature miRNAs, in the myocardium by crossing cTnt-Cre mice with Dicer1(loxP) mice. cTnt-Cre efficiently inactivates target genes in cardiomyocytes at midgestation. All mutants died between E14.5 and E16.5 with severe myocardial wall defects, including reduced cell proliferation, increased cell death, and spongy myocardial wall. Expression of TGF? type I receptor (Tgfbr1), which encodes the Type I receptor of TGF? ligands, was up-regulated in mutant hearts. As expected, TGF? activity was increased in Dicer1-inactivated hearts. Our further molecular analysis suggested that Tgfbr1 is a direct target of three miRNAs. Reducing TGF? activities using a pharmacological inhibitor on in vitro cultured hearts, or through an in vivo genetic approach, partially rescued the cardiac defects caused by Dicer1 inactivation.

Conclusions

We show for the first time that TGF? signalling is directly regulated by the miRNA mechanism during myocardial wall morphogenesis. Increased TGF? activity plays a major role in the cardiac defects caused by myocardial deletion of Dicer1. Thus, miRNA-mediated regulation of TGF? signalling is indispensable for normal cardiogenesis.

SUBMITTER: Peng Y 

PROVIDER: S-EPMC4110444 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature