1. Department of Pediatrics (Cardiology) and
2. Molecular Biology, University of Texas Southwestern Medical Center and Children's Medical Center Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA
3. †Present address: Gladstone Institute of Cardiovascular Disease and Department of Pediatrics, University of California San Francisco, 1650 Owens Street, San Francisco, California 94158, USA

Correspondence to: Deepak Srivastava^1,2,3 Correspondence and requests for materials should be addressed to D.S. (Email: dsrivastava@gladstone.ucsf.edu).

Abstract

Gradients of signalling and transcription factors govern many aspects of embryogenesis, highlighting the need for spatiotemporal control of regulatory protein levels. MicroRNAs are phylogenetically conserved small RNAs that regulate the translation of target messenger RNAs, providing a mechanism for protein dose regulation. Here we show that microRNA-1-1 (miR-1-1) and miR-1-2 are specifically expressed in cardiac and skeletal muscle precursor cells. We found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2. Correspondingly, excess miR-1 in the developing heart leads to a decreased pool of proliferating ventricular cardiomyocytes. Using a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility, we show that Hand2, a transcription factor that promotes ventricular cardiomyocyte expansion, is a target of miR-1. This work suggests that miR-1 genes titrate the effects of critical cardiac regulatory proteins to control the balance between differentiation and proliferation during cardiogenesis.

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