A hypomorphic myogenin allele reveals distinct myogenin expression levels required for viability, skeletal muscle...

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 nothing is known about the quantitative requirements for myogenin in these processes. Here, we describe the generation of mice carrying a hypomorphic allele of myogenin, which expresses myogenin transcripts at approximately one-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 from homozygous wild type to homozygous null were analyzed for their viability, ability to form normal ribs and sternum, and extent of skeletal muscle differentiation. Embryos carrying the hypomorphic myogenin allele over a wild-type allele were normal. In embryos bearing homozygous hypomorphic alleles, the sternum developed normally and extensive skeletal muscle differentiation 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 allele, the resulting embryos had sternum defects resembling homozygous myogenin-null embryos, and there was severe muscle hypoplasia. Our results demonstrate that skeletal muscle formation is highly sensitive to the absolute levels of myogenin and that correct sternum formation, skeletal muscle differentiation, and viability each require distinct threshold levels of myogenin.