Regulation of Muscle Cell Determination and Migration

Our understanding of skeletal muscle lineage determination has enormously increased since the identification of the myogenic determination factor genes. The four members of this MyoD family, or basic helix-loop-helix (bHLH) transcription factor family, MyoD [3], Myf-5 [4], myogenin [5, 6] and MRF4 [7], also called myf-6 [8] or herculin [9], all have specific functions in muscle determination and differentiation (Figure 1) that became apparent after the introduction of null mutations in mice [10-16], as reviewed in [17-19]. MyoD and Myf-5 are responsible for commitment of mesenchymal precursor cells to the myogenic lineage. More specifically, MyoD is essential for migratory muscle cell lineages, whereas Myf-5 is necessary for determination of lineages that are derived from the myotomes [20, 21]. In mice lacking both genes, no muscle precursor cells are generated. In contrast, myogenin and MRF4 are not required for skeletal muscle lineage determination, but are active downstream of the other two members of the MyoD family: myogenin is responsible for fusion of muscle cells and the formation of myotubes, whereas MRF4 plays a role in the subsequent differentiation of myotubes into mature myofibers [ 12, 13, 15]. In adult muscle fibers, MRF4 is the predominant transcript [7]. Recent reviews on this topic, the regulation of expression of bHLH transcription factors and the role of integrins and cadherins in muscle development and migration, include references 22-25, all collected in a special issue of Cell and Tissue Research.

Figure 1. Functions of myogenic determination factors in muscle determination and differentiation. For more details see text.

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