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

Ines Lahmann, Dominique Bröhl, Tatiana Zyrianova, Akihiro Isomura, Maciej T. Czajkowski, Varun Kapoor, Joscha Griger, Pierre Louis Ruffault, Despoina Mademtzoglou, Peter S. Zammit, Thomas Wunderlich, Simone Spuler, Ralf Kühn, Stephan Preibisch, Jana Wolf, Ryoichiro Kageyama, Carmen Birchmeier

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)524-535
Number of pages12
JournalGenes & development
Volume33
Issue number9-10
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • Hes1
  • muscle stem cell
  • MyoD
  • ultradian oscillation

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