miR-1/133a Clusters Cooperatively Specify the Cardiomyogenic Lineage by Adjustment of Myocardin Levels during Embryonic Heart Development

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. © 2013 wystub et al.