microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart.
MicroRNAs (miRNAs) modulate gene expression by inhibiting mRNA translation and promoting mRNA degradation, but little is known of their potential roles in organ formation or function. miR-133a-1 and miR-133a-2 are identical, muscle-specific miRNAs that are regulated during muscle development by the SRF transcription factor. We show that mice lacking either miR-133a-1 or miR-133a-2 are normal, whereas deletion of both miRNAs causes lethal ventricular-septal defects in approximately half of double-mutant embryos or neonates; miR-133a double-mutant mice that survive to adulthood succumb to dilated cardiomyopathy and heart failure. The absence of miR-133a expression results in ectopic expression of smooth muscle genes in the heart and aberrant cardiomyocyte proliferation. These abnormalities can be attributed, at least in part, to elevated expression of SRF and cyclin D2, which are targets for repression by miR-133a. These findings reveal essential and redundant roles for miR-133a-1 and miR-133a-2 in orchestrating cardiac development, gene expression, and function and point to these miRNAs as critical components of an SRF-dependent myogenic transcriptional circuit.
Liu
Ning
N
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Bezprozvannaya
Svetlana
S
Williams
Andrew H
AH
Qi
Xiaoxia
X
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D005786:Gene Expression Regulation; D018816:Genes, cdc; D006330:Heart Defects, Congenital / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology*
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse