Abstract
miRNAs are small RNAs directing many developmental processes by posttranscriptional regulation of protein-coding genes. We uncovered a new role for miR-1-1/133a-2 and miR-1-2/133a-1 clusters in the specification of embryonic cardiomyocytes allowing transition from an immature state characterized by expression of smooth muscle (SM) genes to a more mature fetal phenotype. Concomitant knockout of miR-1-1/133a-2 and miR-1-2/133a-1 released suppression of the transcriptional co-activator myocardin, a major regulator of SM gene expression, but not of its binding partner SRF. Overexpression of myocardin in the embryonic heart essentially recapitulated the miR-1/133a mutant phenotype at the molecular level, arresting embryonic cardiomyocytes in an immature state. Interestingly, the majority of postulated miR-1/133a targets was not altered in double mutant mice, indicating that the ability of miR-1/133a to suppress target molecules strongly depends on the cellular context. Finally, we show that myocardin positively regulates expression of miR-1/133a, thus constituting a negative feedback loop that is essential for early cardiac development.
Highlights
IntroductionVentricular contractions continuously provide blood supply to the developing embryo despite major morphological and functional reorganization of the heart during embryogenesis [1]
The mammalian heart is the earliest functional organ of the embryo
We have generated compound mutant mice of both miR-1/ 133a gene clusters resulting in early arrest of heart development while single cluster mutants showed normal morphology but reacted differently to pressure overload
Summary
Ventricular contractions continuously provide blood supply to the developing embryo despite major morphological and functional reorganization of the heart during embryogenesis [1]. Coordination of this complex task is accomplished by a tightly regulated concert of cellular and molecular interactions. Relatively little is known about regulatory mechanisms controlling the transition between immature and mature cardiomyocytes that express smooth muscle genes only under stress conditions or during dedifferentiation [5]. Diseases of the heart go along with changes of miR-1/133a expression similar to intronic myomirs, it is often not clear whether such changes are due to an increase of non-cardiomyocytes in diseased hearts [10]
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