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 critical for muscle development. In addition to a variety of skeletal muscle defects, embryos homozygous for mutations in myogenin or MRF4 display phenotypes in the thoracic skeleton, including rib fusions and sternal defects. These skeletal defects are likely to be secondary because myogenin and MRF4 are not expressed in the rib cartilage or sternum. In this study, the requirement 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 greatly increased and included extensive rib cartilage fusion and fused sternebrae. 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 muscle-specific markers in myogenin- and MRF4-mutant embryos revealed early skeletal muscle defects not previously reported. MRF4-/- mice displayed abnormal intercostal muscle morphology, including bifurcation and fusion of adjacent intercostals. myogenin/MRF4-mutant combinations displayed ventral myotome defects, including a failure to express normal levels of myf5. The results suggested that the early muscle defects observed in myogenin and MRF4 mutants may cause subsequent thoracic skeletal defects, and that myogenin and MRF4 have overlapping functions in ventral myotome differentiation and intercostal muscle morphogenesis.
Vivian
J L
JL
Department of Biochemistry and Molecular Biology and Graduate Program in Genes & Development, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77050, USA.
Olson
E N
EN
Klein
W H
WH
D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D003893:Desmin / Q000378:metabolism; D017403:In Situ Hybridization; D007366:Intercostal Muscles / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D018008:Myogenin / Q000235:genetics* / Q000378:metabolism; D012272:Ribs / Q000002:abnormalities / Q000196:embryology; D019170:Somites / Q000378:metabolism*; D013249:Sternum / Q000002:abnormalities / Q000196:embryology; D013909:Thorax / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism
D003893:Desmin; C503801:Myog protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; C063403:myogenic factor 6