Stage-specific and cell-autonomous functions of Delta-like 1 in skeletal muscle stem cells and myogenesis

NOTCH signaling plays multiple roles in muscle satellite cells (MuSCs), but the regulation of NOTCH signaling in MuSCs is poorly defined. Using conditional knockout (cKO) mice, here we explore the role of Delta-Like 1 (DLL1), a ligand of NOTCH receptors, in MuSCs and myogenesis. Dll1-cKO in embryonic myoblasts, but not post-differentiation myocytes, diminishes myogenic progenitors and myogenesis. Dll1-cKO in MuSCs of adult mice disrupts MuSCs homeostasis in non-injured muscles, leading to precocious differentiation, self-renewal deficiency, and regenerative failure upon injuries. These defects of Dll1-cKO myoblasts are cell intrinsic, as they cannot be rescued by cocultured wild-type myoblasts. Overexpression of full-length Dll1 leads to a truncated intracellular domain (DLL1ICD), which promotes differentiation and fusion of myoblasts. Thus, besides its widely accepted role in transactivating NOTCH in a neighboring cell, DLL1ICD also plays a cell-autonomous role in the Dll1-expressing cell. These cell-autonomous and non-autonomous roles together are essential for embryonic myogenesis and postnatal regeneration.