Skeletal Myogenesis: Evidence for a Programmed Cell Lineage
Skeletal muscle fibers arise by the fusion of mononucleated precursor cells called myoblasts (Dienstman and Holtzer 1975). Although, for a long while, it was thought that myofibrils and their constituent, muscle-specific proteins were to be found only in multinucleated myotubes or muscle fibers, it is now clear that these structures can be found in certain mononucleated myoblasts (Holtzer et al. 1957; Keller and Nameroff 1974; Chi et al. 1975; Moss and Strohman 1976; Trotter and Nameroff 1976; Vertel and Fischman 1976; Turner 1978). These cells are post-mitotic (Holtzer et al. 1957; Nameroff et al. 1973; Turner 1978) and are capable of fusing with each other to form myotubes. Thus, it appears that fusion is not a prerequisite for either cessation of cell division or for the initiation of muscle-specific protein synthesis in myogenesis. Fusion seems to be only one property of mono-nucleated, post-mitotic myoblasts. It therefore follows that, in order to understand more about the control of skeletal muscle differentiation, we need to focus, not upon the formation of multinucleated myotubes through fusion (as interesting as this process is), but rather upon how individual myoblasts are generated from their precursor cells. Both Konigsberg (1977) and Lavie and Yaffe (1976) have attempted to examine this issue by studying the progeny of single myogenic cells in culture. Konigsberg reported that, after a mitosis, either one or both of the resulting daughter cells could fuse. In many cases, he stated that one daughter cell divided while the other fused. Lavie and Yaffe reported that cells which would have fused were induced to divide in culture medium that promoted mitosis. Both of these investigations relied upon fusion as an assay for terminal myogenic differentiation. That it is often impossible to determine with the light microscope that cells are, in fact, fused and not merely closely apposed to each other, has been reported by several laboratories (Fear 1977; Kligman and Nameroff 1980 b). Thus, an assay for differentiation based on fusion as the sole criterion is both inaccurate and imprecise. We therefore chose to examine the differentiation of daughter cells of individual mitoses by means of an assay which is independent of fusion. Using an antibody directed against the muscle-specific protein, MM-creatine phosphokinase (Puri and Turner 1978), we found, in immunocytofluorescence studies (Kligman and Nameroff 1980 a; Kligman and Nameroff 1980 b), evidence that post-mitotic myoblasts are generated from their precursors in what has been termed a “unipotent” lineage (Holtzer 1978) (Fig. 1).
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