miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development

• Published in: PLoS genetics Vol. 9; no. 9; p. e1003793
• Main Authors: Wystub, Katharina, Besser, Johannes, Bachmann, Angela, Boettger, Thomas, Braun, Thomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2013; Public Library of Science (PLoS)
• Subjects: Adjustment; Animals; Binding sites; Cardiomyocytes; Cell Lineage; Embryonic Development; Embryos; Gene expression; Gene Expression Regulation, Developmental; Genetic aspects; Genomes; Genotype & phenotype; Heart; Heart - embryology; Mice; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Muscle, Smooth - metabolism; Muscular system; Musculoskeletal system; Mutation; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Physiological aspects; Proteins; Regulation; RNA sequencing; Rodents; Smooth muscle; Trans-Activators - genetics; Trans-Activators - metabolism; Up-Regulation; Germany
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003793

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.