title: microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart.
abstract: microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle-enriched miRNA. Most mammalian genomes contain two copies of miR-1, and in mice, deletion of a single locus, miR-1-2, causes incompletely penetrant lethality and subtle cardiac defects. Here, we report that deletion of miR-1-1 resulted in a phenotype similar to that of the miR-1-2 mutant. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth muscle gene expression network. DOI: http://dx.doi.org/10.7554/eLife.01323.001.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Heidersbach
authors.forename: Chris
authors.initials: C
authors.lastname: Saxby
authors.forename: Karen
authors.initials: K
authors.lastname: Carver-Moore
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Yen-Sin
authors.initials: YS
authors.lastname: Ang
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Ivey
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D012518:Sarcomeres
chemical_list: C544547:MIRN1 microRNA, human; D035683:MicroRNAs
keywords: Myocardin; Telokin; cardiac; microRNA-1; sarcomere; smooth muscle gene expression