WILD-TYPE MYOBLASTS RESCUE THE ABILITY OF MYOGENIN-NULL MYOBLASTS TO FUSE IN-VIVO

Skeletal muscle is formed via a complex series of events during embryo genesis. These events include commitment of mesodermal precursor cells , cell migration, cell-cell recognition, fusion of myoblasts, activati on of structural genes, and maturation. In mice lacking the bHLH trans cription factor myogenin, myoblasts are specified and positioned corre ctly, but few fuse to form multinucleated fibers. This indicates that myogenin is critical for the fusion process and subsequent differentia tion events of myogenesis. To further define the nature of the myogeni c defects in myogenin-null mice, we investigated whether myogenin-null myoblasts are capable of fusing with wild-type myoblasts in vivo usin g chimeric mice containing mixtures of myogenin-null and wild-type cel ls. Chimeric embryos demonstrated that myogenin-null myoblasts readily fused in the presence of wild-type myoblasts. However, chimeric myofi bers did not express wild-type levels of muscle-specific gene products , and myofibers with a high percentage of mutant nuclei appeared abnor mal, suggesting that the wild-type nuclei could not fully rescue mutan t nuclei in the myofibers. These data demonstrate that myoblast fusion can be uncoupled from complete myogenic differentiation and that myog enin regulates a specific subset of genes with diverse function. Thus, myogenin appears to control not only transcription of muscle structur al genes but also the extracellular environment in which myoblast fusi on takes place. We propose that myogenin regulates the expression of o ne or more extracellular or cell surface proteins required to initiate the muscle differentiation program. (C) 1997 Academic Press.