Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2
Yong Zhao1, 2, 3, 8, Joshua F. Ransom1, 2, 3, 8, Ankang Li6, 7, Vasanth Vedantham1, 4, Morgan von Drehle1, Alecia N. Muth1, Takatoshi Tsuchihashi1, 2, 3 Michael T. McManus5, Robert J. Schwartz6 and Deepak Srivastava1, 2, 3
1Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
2Department of Pediatrics (Cardiology), University of California, San Francisco, San Francisco, CA 94143, US
. 3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
4Department of Internal Medicine (Cardiology), University of California, San Francisco, San Francisco, CA 94143, USA
5Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
6Institute of Biosciences and Technology, Texas A & M Health Science Center, Baylor College of Medicine, Houston, TX 77030, USA
7Graduate Program in Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA
Cell, Volume 129, Issue 2, 20 April 2007, Pages 303-317





Brief Summary:
  • > MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 “seed matches” and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.

    NOTE: Transthoracic echocardiography was used for noninvasive serial assessment of cardiac function in mice using a Vevo 770 ultrasound machine (VisualSonics).