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T. Braun, M.A. Rudnicki, H.H. Arnold, R. Jaenisch, "Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death," Cell, 71:369-82, 1992. M.A. Rudnicki, T. Braun, S. Hinuma, R. Jaenisch, "Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development," Cell, 71:383-90, 1992. M.A. Rudnicki, P.N.J. Schnegelaberg, R.H. Stead, T. Braun, H.H. Arnold, R. Jaenisch, "MyoD or Myf-5 is required for the formation of skeletal muscle," Cell, 75:1351-9, 1993. Michael A. Rudnicki (Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada): "Gene targeting has allowed the genetic dissection of the roles played by the myogenic regulatory factors (MRFs) in the development of skeletal muscle. The introduction of null [loss-of-function] mutations in Myf-5, MyoD, and myogenin into the germline of mice has revealed insights into the hierarchical relationships existing among the MRFs and established that functional redundancy is a feature of the MRF regulatory network. "Mice lacking a functional MyoD gene were found to have no overt abnormalities in skeletal muscle and are altogether viable and fertile (M.A. Rudnicki et al., Cell, 71:383-90, 1992). RNA and histological analysis could not detect any difference between wild type and mutant MyoD mice. The amount of Myf-5 mRNA is increased in mutant MyoD mice, which suggests that Myf-5 may substitute for the absence of MyoD in the development of skeletal muscle. RAs with MyoD mutant mice, histological and northern-blot analyses of newborn Myf-5-deficient animals did not reveal any abnormalities in skeletal muscle. Muscle development is delayed until the MyoD is expressed. As an indirect consequence of this delayed development, Myf-5 mutant mice have rib abnormalities that prevent normal respiration (T. Braun et al., Cell, 71:369-82, 1992) and therefore die soon after birth. The onset of MyoD expression, however, occurs normally, followed by the expression of myogenin and other differentiation-specific markers (T. Braun et al., Development, in press). These results suggest that the activation of MyoD occurs independently of Myf-5 and that MyoD can substitute for the absence of Myf-5 in the development of skeletal muscle. "The potential ability of Myf-5 and MyoD to substitute for one another led to the hypothesis that Myf-5 and MyoD have, at least to some degree, functionally redundant roles in the development of skeletal muscle (M.A. Rudnicki et al., Cell, 71:383-90, 1992). To test this hypothesis, Myf-5 and MyoD mutant mice were interbred. Newborn mice deficient for the two MRFs are totally devoid of skeletal myoblasts as well as muscle (M.A. Rudnicki et al., Cell, 75:1351-9, 1993). Mutant pups are born alive but are immobile and die within minutes. The spaces normally occupied by muscle are filled with amorphous connective and adipose tissues, and desmin- containing myoblast cells are absent. "Other investigators have targeted the remaining MRF genes. Mice lacking a functional myogenin gene are immobile and die perinatally owing to deficits in skeletal muscle differentiation (P. Hasty et al., Nature, 364:501-6, 1993; Y. Nabeshima et al., Nature, 364:532-5, 1993). The skeletal muscle in mice lacking myogenin display a marked reduction in myofibers. However, myoblasts are present, and these are organized in groups similar to wild-type skeletal muscle, suggesting myogenin is not involved in patterning. Myogenin- deficient mice also display a relatively mild rib deformity. These results indicate an essential in vivo role for myogenin in terminal differentiation of myoblasts into myotubes. "The absence of myoblasts in mice lacking both Myf-5 and MyoD places these two factors upstream of myogenin in the regulatory pathway. Moreover, this result suggests that Myf- 5 and MyoD are involved in the determination of myoblasts, as these cells are absent when these factors are missing. However, it is important to note that these results do not preclude a role for Myf-5 and MyoD as differentiation factors. For example, while myoblasts lacking myogenin fail to differentiate efficiently in vivo, they form normal multinucleated myotubes in vitro (Y. Nabeshima et al., Nature, 364:532-35, 1993). This suggests that in arrested myoblasts in vitro MyoD can substitute for the role myogenin plays in differentiation. The fourth myogenic factor MRF4 may function late in the myogenic pathway, as has been implied by its expression pattern in cultured cells. Alternatively, MRF4 may have a vital role early in the development of the dorsal subdomain of the dermamyotome, as suggested by its expression in vivo (T.H. Smith et al., Journal of Cell Biology, in press). "The ability to target specific genes for inactivation in the mouse has proved to be an extremely powerful tool to genetically dissect complex biological phenomena. In the near future, targeted inactivation of other important players involved in skeletal myogenesis will certainly provide much information as well as a few surprises."

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