Staufen1 inhibits MyoD translation to actively maintain muscle stem cell quiescence

Tissue regeneration depends on the timely activation of adult stem cells. In skeletal muscle, the adult stem cells maintain a quiescent state and proliferate upon injury. We show that muscle stem cells (MuSCs) use direct translational repression to maintain the quiescent state. High-resolution singl...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 43; pp. E8996 - E9005
Main Authors:	de Morrée, Antoine, van Velthoven, Cindy T. J., Gan, Qiang, Salvi, Jayesh S., Klein, Julian D. D., Akimenko, Igor, Quarta, Marco, Biressi, Stefano, Rando, Thomas A.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 24-10-2017
Series:	PNAS Plus
Subjects:	3' Untranslated regions Activation Animals Biological Sciences Cell Differentiation Gene Expression Regulation - physiology Localization Mice mRNA stability Muscle Cells - physiology Muscles MyoD protein MyoD Protein - genetics MyoD Protein - metabolism PNAS Plus Protein expression Regeneration Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Skeletal muscle Stem cell transplantation Stem cells Stem Cells - physiology Tissue engineering Transcription Translation quiescence satellite cell Staufen1 MyoD muscle stem cell
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Summary:	Tissue regeneration depends on the timely activation of adult stem cells. In skeletal muscle, the adult stem cells maintain a quiescent state and proliferate upon injury. We show that muscle stem cells (MuSCs) use direct translational repression to maintain the quiescent state. High-resolution single-molecule and single-cell analyses demonstrate that quiescent MuSCs express high levels of Myogenic Differentiation 1 (MyoD) transcript in vivo, whereas MyoD protein is absent. RNA pulldowns and costainings show that MyoD mRNA interacts with Staufen1, a potent regulator of mRNA localization, translation, and stability. Staufen1 prevents MyoD translation through its interaction with the MyoD 3′-UTR. MuSCs from Staufen1 heterozygous (Staufen1+/−) mice have increased MyoD protein expression, exit quiescence, and begin proliferating. Conversely, blocking MyoD translation maintains the quiescent phenotype. Collectively, our data show that MuSCs express MyoD mRNA and actively repress its translation to remain quiescent yet primed for activation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved September 8, 2017 (received for review May 26, 2017) 1A.d.M. and C.T.J.v.V. contributed equally to this work. Author contributions: A.d.M., C.T.J.v.V., and T.A.R. designed research; A.d.M., C.T.J.v.V., Q.G., J.S.S., J.D.D.K., I.A., M.Q., and S.B. performed research; A.d.M., C.T.J.v.V., Q.G., J.S.S., J.D.D.K., I.A., M.Q., and S.B. analyzed data; and A.d.M., C.T.J.v.V., and T.A.R. wrote the paper. 2Present address: Dulbecco Telethon Institute and Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1708725114