Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells
- Ines Lahmann1,11,
- Dominique Bröhl1,11,
- Tatiana Zyrianova1,
- Akihiro Isomura2,
- Maciej T. Czajkowski1,
- Varun Kapoor3,
- Joscha Griger1,
- Pierre-Louis Ruffault1,
- Despoina Mademtzoglou4,
- Peter S. Zammit5,
- Thomas Wunderlich6,
- Simone Spuler7,
- Ralf Kühn8,9,
- Stephan Preibisch3,
- Jana Wolf10,
- Ryoichiro Kageyama2 and
- Carmen Birchmeier1
- 1Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
- 2Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan;
- 3Microscopy/Image Analysis, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
- 4IMRB U955-E10, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Medicine, Université Paris Est, 94000 Creteil, France;
- 5Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom;
- 6Max Planck Institute for Metabolism Research, 50931 Cologne, Germany;
- 7Muscle Research Unit, Experimental and Clinical Research Center, Max-Delbrück-Center, Charité Medical Faculty, 13125 Berlin, Germany;
- 8Transgenic Core Facility, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
- 9Berlin Institute of Health, 10178 Berlin, Germany;
- 10Mathematical Modelling, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- Corresponding authors: cbirch{at}mdc-berlin.de, ines.lahmann{at}mdc-berlin.de
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↵11 These authors contributed equally to this work.
Abstract
The balance between proliferation and differentiation of muscle stem cells is tightly controlled, ensuring the maintenance of a cellular pool needed for muscle growth and repair. We demonstrate here that the transcriptional regulator Hes1 controls the balance between proliferation and differentiation of activated muscle stem cells in both developing and regenerating muscle. We observed that Hes1 is expressed in an oscillatory manner in activated stem cells where it drives the oscillatory expression of MyoD. MyoD expression oscillates in activated muscle stem cells from postnatal and adult muscle under various conditions: when the stem cells are dispersed in culture, when they remain associated with single muscle fibers, or when they reside in muscle biopsies. Unstable MyoD oscillations and long periods of sustained MyoD expression are observed in differentiating cells. Ablation of the Hes1 oscillator in stem cells interfered with stable MyoD oscillations and led to prolonged periods of sustained MyoD expression, resulting in increased differentiation propensity. This interfered with the maintenance of activated muscle stem cells, and impaired muscle growth and repair. We conclude that oscillatory MyoD expression allows the cells to remain in an undifferentiated and proliferative state and is required for amplification of the activated stem cell pool.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.322818.118.
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Freely available online through the Genes & Development Open Access option.
- Received November 20, 2018.
- Accepted February 19, 2019.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
