Myf-5(m1)/Myf-6(m1) compound heterozygous mouse mutants down-regulate Myf-5 expression and exert rib defects: evidence for long-range cis effects on Myf-5 transcription.

Myf-6 and Myf-5, two members of the family of muscle-specific regulatory genes, are located less than 10 kb apart in the mouse and human genomes. We have shown recently that homozygous mutant mice carrying a pgk-neo-cassette in the first exon of the Myf-6 gene display minor alterations of skeletal musculature but develop a severe rib defect, most likely due to a drastic down-regulation of Myf-5 expression. The mechanism by which the Myf-6 mutation affects the Myf-5 gene is unknown. In order to determine whether Myf-5 transcription is inhibited by the Myf-6 mutation in cis or in trans, we generated compound heterozygous mice carrying inactivated Myf-5 and Myf-6 alleles on different chromosomes. Here, we demonstrate that double-heterozygous mutants exhibit truncated ribs and severe depression of Myf-5 transcription, a phenotype similar to the previously described homozygous Myf-6 mutant mice. These results indicate that the Myf-6 mutation inhibits Myf-5 gene expression by a long-range cis effect.