A hypomorphic myogenin allele reveals distinct myogenin expression levels required for viability, skeletal muscle development, and sternum formation

The myogenic basic helix-loop-helix transcription factor myogenin plays an essential role in the differentiation of skeletal muscle and, secondarily, in rib and sternum formation during mouse development. However, virtually n othing is known about the quantitative requirements for myogenin in these p rocesses. Here, we describe the generation of mice carrying a hypomorphic a llele of myogenin, which expresses myogenin transcripts at approximately on e-fourth the level of the wild-type myogenin allele. The hypomorphic allele in combination with wild-type and myogenin-null alleles was used to create an allelic series. Embryos representing the complete range of genotypes fr om homozygous wild type to homozygous null were analyzed for their viabilit y, ability to form normal ribs and sternum, and extent of skeletal muscle d ifferentiation. Embryos carrying the hypomorphic myogenin allele over a wil d-type allele were normal. In embryos bearing homozygous hypomorphic allele s, the sternum developed normally and extensive skeletal muscle differentia tion occurred. However, muscle hypoplasia and reduced muscle-specific gene expression were apparent in these embryos, and the mice were not viable as neonates. When the hypomorphic allele was placed over a myogenin-null allel e, the resulting embryos had sternum defects resembling homozygous myogenin -null embryos, and there was severe muscle hypoplasia. Our results demonstr ate that skeletal muscle formation is highly sensitive to the absolute leve ls of myogenin and that correct sternum formation, skeletal muscle differen tiation, and viability each require distinct threshold levels of myogenin. (C) 1999 Academic Press.