Oscillations of Delta-like1 regulate the balance between differentiation and maintenance of muscle stem cells

Yao Zhang (), Ines Lahmann, Katharina Baum, Hiromi Shimojo, Philippos Mourikis, Jana Wolf, Ryoichiro Kageyama and Carmen Birchmeier ()
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Yao Zhang: Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine
Ines Lahmann: Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine
Katharina Baum: Mathematical Modelling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine
Hiromi Shimojo: Institute for Frontier Life and Medical Sciences, Kyoto University
Philippos Mourikis: Univ Paris Est Creteil, INSERM, IMRB
Jana Wolf: Mathematical Modelling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine
Ryoichiro Kageyama: Institute for Frontier Life and Medical Sciences, Kyoto University
Carmen Birchmeier: Developmental Biology/Signal Transduction, Max-Delbrück-Center for Molecular Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Cell-cell interactions mediated by Notch are critical for the maintenance of skeletal muscle stem cells. However, dynamics, cellular source and identity of functional Notch ligands during expansion of the stem cell pool in muscle growth and regeneration remain poorly characterized. Here we demonstrate that oscillating Delta-like 1 (Dll1) produced by myogenic cells is an indispensable Notch ligand for self-renewal of muscle stem cells in mice. Dll1 expression is controlled by the Notch target Hes1 and the muscle regulatory factor MyoD. Consistent with our mathematical model, our experimental analyses show that Hes1 acts as the oscillatory pacemaker, whereas MyoD regulates robust Dll1 expression. Interfering with Dll1 oscillations without changing its overall expression level impairs self-renewal, resulting in premature differentiation of muscle stem cells during muscle growth and regeneration. We conclude that the oscillatory Dll1 input into Notch signaling ensures the equilibrium between self-renewal and differentiation in myogenic cell communities.

Date: 2021
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DOI: 10.1038/s41467-021-21631-4

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