MYF-5(M1) MYF-6(M1) COMPOUND HETEROZYGOUS MOUSE MUTANTS DOWN-REGULATEMYF-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 regulato ry genes, are located less than 10 kb apart in the mouse and human gen omes. We have shown recently that homozygous mutant mice carrying a pg k-neo-cassette in the first exon of the Myf-6 gene display minor alter ations of skeletal musculature but develop a severe rib defect, most l ikely due to a drastic down-regulation of Myf-5 expression. The mechan ism 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 mic e carrying inactivated Myf-5 and Myf-6 alleles on different chromosome s. Here, we demonstrate that double-heterozygous mutants exhibit trunc ated ribs and severe depression of Myf-5 transcription, a phenotype si milar to the previously described homozygous Myf-6 mutant mice. These results indicate that the Myf-6 mutation inhibits Myf-5 gene expressio n by a long-range cis effect. (C) 1996 Academic Press, Inc.