Thoracic skeletal defects in myogenin- and MRF4-deficient mice correlate with early defects in myotome and intercostal musculature

Myogenin and MRF4 are skeletal muscle-specific bHLH transcription factors c ritical for muscle development. In addition to a variety of skeletal muscle defects, embryos homozygous for mutations in myogenin or MRF4 display phen otypes in the thoracic skeleton, including rib fusions and sternal defects. These skeletal defects are likely to be secondary because myogenin and MRF 4 are not expressed in the rib cartilage or sternum. In this study, the req uirement for myogenin and MRF4 in thoracic skeletal development was further examined. When a hypomorphic allele of myogenin and an MRF4-null mutation were placed together, the severity of the thoracic skeletal defects was gre atly increased and included extensive rib cartilage fusion and fused sterne brae. Additionally, new rib defects were observed in myogenin/MRF4 compound mutants, including a failure of the rib cartilage to contact the sternum. These results suggested that myogenin and MRF4 share overlapping functions in thoracic skeletal formation. Spatial expression patterns of skeletal mus cle-specific markers in myogenin- and MRF4-mutant embryos revealed early sk eletal muscle defects not previously reported. MRF4-/- mice displayed abnor mal intercostal muscle morphology, including bifurcation and fusion of adja cent intercostals. myogenin/ MRF4-mutant combinations displayed ventral myo tome defects, including a failure to express normal levels of myf5. The res ults suggested that the early muscle defects observed in myogenin and MRF4 mutants may cause subsequent thoracic skeletal defects, and that myogenin a nd MRF4 have overlapping functions in ventral myotome differentiation and i ntercostal muscle morphogenesis. (C) 2000 Academic Press.