Hedgehog signaling regulates the amount of hypaxial muscle development during Xenopus myogenesis.

Hedgehog (Hh) signaling is proposed to have different roles on differentiation of hypaxial myoblasts of amniotes. Within the somitic environment, Hh signals restrict hypaxial development and promote epaxial muscle formation. On the other hand, in the limb bud, Hh signaling represses hypaxial myoblast differentiation. This poses the question of whether differences in response to Hh signaling are due to variations in local environment or are intrinsic differences between pre- and post-migratory hypaxial myoblasts. We have approached this question by examining the role of Hh signaling on myoblast development in Xenopus laevis, which, due to its unique mode of hypaxial muscle development, allows us to examine myoblast development in vivo in the absence of the limb environment. Cyclopamine and sonic hedgehog (shh) mRNA overexpression were used to inhibit or activate the Hh pathway, respectively. We find that hypaxial myoblasts respond similarly to Hh manipulations regardless of their location, and that this response is the same for epaxial myoblasts. Overexpression of shh mRNA causes a premature differentiation of the dermomyotome, subsequently inhibiting all further growth of the epaxial and hypaxial myotome. Cyclopamine treatment has the opposite effect, causing an increase in dermomyotome and a shift in myoblast fate from epaxial to hypaxial, eventually leading to an excess of hypaxial body wall muscle. Cyclopamine treatment before stage 20 can rescue the effects of shh overexpression, indicating that early Hh signaling plays an essential role in maintaining the balance between epaxial and hypaxial muscle mass. After stage 20, the premature differentiation of the dermomyotome caused by shh overexpression cannot be rescued by cyclopamine, and no further embryonic muscle growth occurs.