Abstract
Muscle precursor cells known as myoblasts are essential for muscle development and regeneration. Notch signaling is an ancient intercellular communication mechanism that plays prominent roles in controlling the myogenic program of myoblasts. Currently whether and how the myogenic cues feedback to refine Notch activities in these cells are largely unknown. Here, by mouse and human gene gain/loss-of-function studies, we report that MyoD directly turns on the expression of Notch-ligand gene Dll1 which activates Notch pathway to prevent precautious differentiation in neighboring myoblasts, while autonomously inhibits Notch to facilitate a myogenic program in Dll1 expressing cells. Mechanistically, we studied cis-regulatory DNA motifs underlying the MyoD–Dll1–Notch axis in vivo by characterizing myogenesis of a novel E-box deficient mouse model, as well as in human cells through CRISPR-mediated interference. These results uncovered the crucial transcriptional mechanism that mediates the reciprocal controls of Notch and myogenesis.
Highlights
Skeletal muscle accounts for around 40% of adult human body weight
Notch intracellular domain (NICD) translocates to nucleus where it binds with Rbpj and recruits a transcriptional complex to activate the expression of downstream target including Hairy/enhancer of split (Hes) and Hes-related with YRPW motif (Hey) family genes [24]
To understand which Notch ligand(s) may participate the human myogenic program, we performed gene expression analyses in low-passage human myoblasts that were derived from a healthy donor as described previously [48, 49]
Summary
Skeletal muscle accounts for around 40% of adult human body weight. Myogenesis involves a series of events that begins with the specification of muscle lineage by master transcriptional regulators, including Pax and Muscular Regulatory Factor (MRF), followed by the expression of a vast number of genes that establish muscle structure and function [1,2,3,4,5,6]. Notch signaling is an ancient intercellular communication mechanism that determines the cell-fate for various tissue types in metazoan [12,13,14,15]. Alterations of this pathway underline a spectrum of disease and cancer [16,17,18,19,20]. Endocytosis of Notch-bound ligand generates a mechanical pulling force that drives conformational change of the Notch receptor [22]. This facilitates subsequent proteolytic cleavage of Notch receptor and produces Notch intracellular domain (NICD) [23]. This is in part due to versatile ligand-utilizations for signaling in various biological processes [25, 26]
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