Pulmonary hypoplasia in the myogenin null mouse embryo.

Although fetal breathing movements are required for normal lung development, there is uncertainty concerning the specific effect of absent fetal breathing movements on pulmonary cell maturation. We set out to evaluate pulmonary development in a genetically defined mouse model, the myogenin null mouse, in which there is a lack of normal skeletal muscle fibers and thus skeletal muscle movements are absent in utero. Significant decreases were observed in lung:body weight ratio and lung total DNA at embryonic days (E)14, E17, and E20. Reverse transcriptase/polymerase chain reaction, in situ immunofluorescence, and electron microscopy revealed early lung cell differentiation in both null and wild-type lungs as early as E14. However at E14, myogenin null lungs had decreased 5'-bromo-2-deoxyuridine incorporation compared with that of wild-type littermates, whereas at E17 and E20, increased Bax immunolabeling and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining were detected in the myogenin null mice but not in the wild-type littermates. These observations highlight the importance of skeletal muscle contractile activity in utero for normal lung organogenesis. Null mice lacking the muscle-specific transcription factor myogenin exhibit a secondary effect on lung development such that decreased lung cell proliferation and increased programmed cell death are associated with lung hypoplasia.

Human bHLH transcription factor gene myogenin (MYOG): genomic sequence and negative mutation analysis in patients with severe congenital myopathies.

The myogenin gene encodes an evolutionarily conserved basic helix-loop-helix transcription (bHLH) factor that is required for differentiation of skeletal muscle, and its homozygous deletion in mice results in perinatal death from respiratory failure due to the lack of muscle fibers. Since the histology of skeletal muscle in myogenin null mice is reminiscent of that found in severe congenital myopathy patients, many of whom also die of respiratory complications, we sought to test the hypothesis that an aberrant human myogenin (myf4) coding region could be associated with some congenital myopathy conditions. With PCR amplification, we found similarly sized PCR products for the three exons of the myogenin gene in DNA from 37 patient and 40 control individuals. In contrast to previously reported sequencing of human myogenin (myf4), we describe with automated sequencing several base differences in flanking and coding regions plus an additional 659 and 498 bp in the first and second introns, respectively, in all 37 patient and 40 control samples. We also find a variable length (CA)-dinucleotide repeat in the second intron, which may have utility as a marker for future linkage studies. In summary, no causative mutations were detected in the myogenin coding locus of genomic DNA from 37 patients with severe congenital myopathy.