Maintenance of muscle stem-cell quiescence by microRNA-489

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Abstract
Adult muscle stem cells are used as a model system to show that the microRNA pathway, and specifically miR-489, is essential for the maintenance of the quiescent state of an adult stem-cell population by suppressing a key proliferation factor, Dek. Little is known about the molecular pathways that maintain stem-cell quiescence. The microRNA (miRNA) pathway is known to be essential for stem-cell pluripotency, proliferation and differentiation, and here Thomas Rando and colleagues show that the miRNA pathway actively maintains the quiescent state of an adult stem-cell population. Using adult-mouse muscle stem cells as a model system, they found that miR-489 is expressed in stem cells, and that the knockdown of miR-489 is sufficient to induce a quiescent muscle stem cell to break quiescence and enter the cell cycle. The oncogene Dek was identified as a key target of miR-489, providing an indication of the kinds of transcriptional programs involved in maintaining and breaking quiescence. Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time1,2. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.