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Genes Dev. 2019 Mar 12. doi: 10.1101/gad.322818.118. [Epub ahead of print]

Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells.

Author information

1
Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
2
Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
3
Microscopy/Image Analysis, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
4
IMRB U955-E10, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Medicine, Université Paris Est, 94000 Creteil, France.
5
Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
6
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
7
Muscle Research Unit, Experimental and Clinical Research Center, Max-Delbrück-Center, Charité Medical Faculty, 13125 Berlin, Germany.
8
Transgenic Core Facility, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
9
Berlin Institute of Health, 10178 Berlin, Germany.
10
Mathematical Modelling, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
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Contributed equally

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.

KEYWORDS:

Hes1; MyoD; muscle stem cell; ultradian oscillation

PMID:
30862660
DOI:
10.1101/gad.322818.118
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