Transcriptional networks that regulate muscle stem cell function

(a) Model for the mechanisms regulating satellite cell behavior. Damage to muscle fibers stimulates the production of nitric oxide which, in turn, triggers a release of hepatocyte growth factor (HGF) from the extracellular matrix (b). These signals activate nearby satellite cells that reenter the cell cycle. Following activation, they undergo many rounds of proliferation producing myoblasts, most of which will acquire MyoD expression, differentiate, and fuse to repair or form new myotubes at sites of injury. Satellite cells are a heterogeneous population comprising Pax7 + Myf5‐ and Pax7 + Myf5+ expressing cells (a). Myf5‐ satellite cells are thought to represent self‐renewing “stem” cells that replenish the satellite cell niche and can give rise to both Myf5‐ and Myf5+ satellite cells. Conversely, Myf5+ cells preferentially commit to myogenic differentiation. While committed cells typically downregulate Pax7 and express myogenin121 (b), some committed cells may instead lose MyoD expression and return to quiescence.88 Notch3 is asymmetrically expressed by Myf5‐ cells, while the Notch‐activating ligand Delta‐1 is highly expressed by Myf5+ cells (a), forming a potential regulatory network which may direct self‐renewal versus differentiation fate decisions in Myf5‐/Myf5+ daughter cell pairs. Additionally, Notch signaling prevents early activation of MyoD and thereby positively regulates proliferative expansion of myoblast progeny. A transition from Notch to canonical Wnt signaling acts as a switch to halt proliferation and initiate terminal differentiation in myoblasts120 (b).

Transcriptional networks of embryonic myogenesis. Somites on either side of the neural tube give rise to muscle progenitor cells. Cellular migration within the somites gives rise to the myotome (epaxial muscles) and the dermamyotome (hypaxial muscles). Survival of myogenic cells within the hypaxial dermamyotome requires Pax3 whose expression is dependent on Six1 or Six4 (pannel 1)39, 134 Pax3, in turn, regulates the expression of c‐met and Lbx1. Delamination and migration of myogenic cells from the hypaxial dermamyotome to limb buds is dependent on the expression of c‐met, a tyrosine kinase receptor, and its ligand hepatocyte growth factor (HGF). Lbx1 is required for proper movement along migratory routes. Within the myotome, Pax3 can activate the expression of Myf5 (pannel 2). Differentiation proceeds in the absence of MyoD expression, however, MRF4 expression is dependent on Six1 or Six4.39 Myf5 expression is stimulated by Sonic hedgehog (Shh) signals produced by the notochord and floor plate and by Wnt1 signals produced by the neural tube. In limb buds, Six1 can activate Pax3 and Myf5, and Pax3 can drive the expression of MyoD and Myf5 (pannel 3). The expression of either Myf5 or MyoD is sufficient to initiate the myogenesis. MyoD expression is tightly regulated by Wnt and BMP pathways. Wnt7a, produced by the dorsal ectoderm, activates MyoD in hypaxial cells, while BMP4, produced by the lateral plate mesoderm, inhibits the expression of MyoD. Noggin expression at the dorsal medial lip of the hypaxial dermamyotome blocks BMP signaling facilitating the fine control of MyoD expression in specific domains.