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.
Max-Planck-Institut für Herz- und Lungenforschung, Department of Cardiac Development and Remodelling, Bad Nauheim, Germany.
Katharina
K
Wystub
Johannes
J
Besser
Angela
A
Bachmann
Thomas
T
Boettger
Thomas
T
Braun
D000818:Animals; D019070:Cell Lineage; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099251:Myocardin
D035683:MicroRNAs; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin; C548234:MIRN133 microRNA, human