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

TY - JOUR

T1 - Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells

AU - Lahmann, Ines

AU - Bröhl, Dominique

AU - Zyrianova, Tatiana

AU - Isomura, Akihiro

AU - Czajkowski, Maciej T.

AU - Kapoor, Varun

AU - Griger, Joscha

AU - Ruffault, Pierre Louis

AU - Mademtzoglou, Despoina

AU - Zammit, Peter S.

AU - Wunderlich, Thomas

AU - Spuler, Simone

AU - Kühn, Ralf

AU - Preibisch, Stephan

AU - Wolf, Jana

AU - Kageyama, Ryoichiro

AU - Birchmeier, Carmen

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

KW - Hes1

KW - muscle stem cell

KW - MyoD

KW - ultradian oscillation

UR - http://www.scopus.com/inward/record.url?scp=85065540687&partnerID=8YFLogxK

U2 - 10.1101/gad.322818.118

DO - 10.1101/gad.322818.118

M3 - Article

C2 - 30862660

AN - SCOPUS:85065540687

SN - 0890-9369

VL - 33

SP - 524

EP - 535

JO - Genes & development

JF - Genes & development

IS - 9-10

ER -