MRF4 can substitute for myogenin during early stages of myogenesis

MRF4, myogenin, MyoD, and Myf‐5 are the four members of the basic helix‐loop‐helix family of muscle‐specific regulatory factors (MRFs). We examined whether MRF4 could substitute for myogenin in vivo by determining if the myofiber‐ and MRF4‐deficient phenotype of myogenin (−/−) mice could be rescued by a myogenin promoter‐MRF4 transgene. When the transgene was expressed at a physiological level in myogenin‐deficient fetuses, we found that expression of the endogenous MRF4 gene was restored to normal levels, whereas MyoD levels were unchanged. Thus, MRF4 can participate in a positive autoregulatory loop and can substitute for myogenin to activate its own promoter. Myogenin‐deficient fetuses that expressed the transgene also had more myosin, more and larger myofibers, and a more normal ribcage morphology than myogenin‐deficient littermates without the transgene. The transgene failed, however, to restore normal numbers of myofibers or viability to myogenin‐deficient mice, because the ≈1.6 kb myogenin promoter fragment was not expressed in most late‐forming myofibers. These results demonstrate that MRF4 is able to substitute for myogenin to activate MRF4 expression and promote myofiber formation during the early stages of myogenesis. Dev. Dyn. 209:233–241, 1997. © 1997 Wiley‐Liss Inc.