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Maintenance of muscle stem-cell quiescence by microRNA-489


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.

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Figure 1: The miRNA pathway is essential for the maintenance of satellite-cell quiescence and survival of activated satellite cells.
Figure 2: miRNA expression in purified QSCs and ASCs.
Figure 3: miRNA-489 regulates satellite-cell quiescence.
Figure 4: Targeting of Dek mRNA by miR-489 and regulation of cell-fate decision of satellite-cell progeny by Dek.

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We thank the members of the Rando laboratory for comments and discussions. We thank B. Olwin for providing the syndecan 4 antibody. This work was supported by the Glenn Foundation for Medical Research and by grants from the National Institutes of Health (NIH) (P01 AG036695, R01 AG23806 (R37 MERIT Award), R01 AR062185 and DP1 OD000392 (an NIH Director's Pioneer Award)) and the Department of Veterans Affairs (Merit Review) to T.A.R.

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T.H.C. and T.A.R. conceived the study. T.H.C., N.L.Q., G.W.C., L.L. and T.A.R. designed the experiments. T.H.C., B.Y. and L.L. performed all FACS analyses. T.H.C., N.L.Q., G.W.C., L.P., A.E., B.Y. and P.H. performed the experiments and analysed the experimental data. T.H.C. and T.A.R. wrote the manuscript.

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Correspondence to Thomas A. Rando.

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The authors declare no competing financial interests.

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Cheung, T., Quach, N., Charville, G. et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524–528 (2012).

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