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 approximately 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.
Zhu
Z
Z
Neuromuscular Laboratory, Massachusetts General Hospital, Charlestown 02129, USA.
Miller
J B
JB
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009132:Muscles / Q000196:embryology*; D017570:MyoD Protein / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D018008:Myogenin / Q000502:physiology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011950:Receptors, Cholinergic / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D019076:Transgenes
D017570:MyoD Protein; C503801:Myog protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D011950:Receptors, Cholinergic; D014157:Transcription Factors; C063403:myogenic factor 6