The molecular control of cardiogenesis is central to an understanding of both developmental defects of the heart as well as adaptive mechanisms in the adult heart. It has become clear that the dosage of major cardiac regulatory proteins is critical during discrete developmental windows and regulates the balance of proliferation, cell death and differentiation. While the transcriptional regulation of several such factors is becoming well understood, the translational control is relatively unexplored. MicroRNAs have recently emerged as an elegant and novel mechanism to titrate dosage of critical proteins by regulating the translation of mRNA transcripts. However, there are only a few known targets of microRNAs and the role of microRNAs in mammalian organogenesis is poorly understood. We have found that the closely related microRNAs, miR1-1 and miR1-2, are expressed specifically in the developing cardiac and skeletal muscle in a dynamic and chamber-specific manner during embryonic development. We found that miR1 overexpression in transgenic mice resulted in premature exit of cardiomyocytes from the cell cycle during cardiogenesis. We also developed a relatively specific in silico algorithm to predict mRNA targets of microRNAs that predicted Hand2, a major transcriptional regulator of ventricular development, as a miR1 target. Endogenous Hand2 was validated as a target both in vitro and in vivo at the protein level. These findings represent only the third validated microRNA target in mammals to date and the first role of microRNAs in the heart. In this proposal, we will build on the preliminary data regarding miR1 and explore the following specific aims: 1) Determine the mechanisms that establish the unique spatial and temporal domains of miR1-1 and miR1-2 activity; 2) Determine whether miR1-1 and miR1-2 are necessary for cardiac or skeletal muscle differentiation; and 3) Determine if and how miR1 might regulate the balance between myocyte differentiation and proliferation. This work promises to uncover a new area of molecular regulation in the heart and may provide mechanisms to finely regulate dosages of critical proteins in the prenatal or postnatal heart. ? ?
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