Fig. 2

The Notch signaling network in murine muscle stem cells. A In the proliferating cells, enhancer competition and negative autoregulation establish an oscillatory system (pendulum sign) comprising transcription factors and ligands that regulate each other. Competition is also occurring for the transcriptional co-activator Mastermind-like 1 between the NICD activating complex and the differentiation factor Mef2c, while Mef2c is under the control of the Notch-controlled Dusp1 kinase that targets p38. Notch signaling also safeguards cells from spontaneous fusing by repressing the expression of the membrane activator of myoblast fusion Myomaker (Mymk). Ligand presentation on the growing fibers is stimulated by extrinsic cues, including mechanical stress (fetal chick fibers) and circulating sex hormones (puberty and muscle regeneration). The factors that maintain quiescence (Fig. 2B) are reiterated for self-renewal. Double-headed arrow indicates protein interaction; pendulum sign indicates oscillation; dashed arrow line indicates self-renewal; *the YAP/Jag2 link has been demonstrated in chick embryos. B Notch signaling maintains both quiescent and activated MuSCs by engaging different targets and interactors. Quiescent MuSC express Notch-1, -2, and -3 and, in the mouse, the principal ligand is Dll4 from the myofibers. Diverse direct NICD/RBPJ transcriptional targets execute different functions: the Hes/Hey repressors prevent the expression of differentiation factors, collagen V chain encoding genes directly contribute to the build-up of the quiescent niche, and micro-RNA mir-708 anchors MuSCs by targeting molecules involved in cell migration