15 The formation of skeletal muscle: from somite to hand

Skeletal muscle in the embryonic limb is formed by cells which migrate out from the somites, segments of paraxial mesoderm which form progressively along the anterior-posterior axis of the vertebrate embryo as development proceeds. This migration depends on the transcription factor Pax3 manipulation of the gene in mice we have examined the behaviour of Pax3 at sites of myogenesis, and shown that it functions as a transcriptional activator with cofactors. We also show that the c-met receptor, required for migration, is not the only target of Pax3. Once the muscle progenitor cells reach the limb they activate the muscle determination factor genes encoding Myf5 and MyoD. Distinct regulatory sequences situated in an enhancer upstream of Myf5 direct expression of the gene in the limb; this appears to depend on 2 regulatory elements differentially affecting the fore and hind limbs. A number of potential regulatory factors, such as Msx1, are differentially expressed in limb muscle precursors and mutation of genes such as Lbx2 or Mox2 has revealed unexpected heterogeneity between limb muscle masses. In adult muscle this is also evident. Pax7, the orthologue of Pax3, essential for the specification of adult muscle precursors and hence for regeneration, is expressed by these so-called satellite cells in most, but not all, limb muscles. We show that Pax3 is also present and probably confers the potential for muscle identity to the Pax7 negative satellite cells. The origin of peri- and post-natal muscle precursor cells appears to differ from that of the earier somite derived cells which form the embryonic musculature. A retrospective clonal analysis of muscles at later developmental stages, points to an oligoclonal origin of muscle masses including those of the limb, which is difficult to explain on the basis of a muscle cell population derived exclusively from the embryonic somites.