Regulation of a muscle-specific transgene by persistent expression of Hox genes in postnatal murine limb muscle

Homeobox genes are necessary for the generation of the embryonic body plan in both invertebrate and vertebrate organisms. To investigate the potential function of homeodomain proteins in normal and regenerating skeletal muscl e, we analyzed patterns of clustered homeobox gene expression in neonatal a nd adult muscle tissue. Transcripts encoding 5' genes in the HoxA cluster w ere detected in muscles from both the fore- and hindlimbs of neonatal and a dult mice, whereas expression of HoxC gene transcripts was generally restri cted to the muscles of the hindlimb. In contrast, transcripts encoding gene s of the HoxB or HoxD clusters were not detected in muscles from either for e- or hindlimbs, Although ectopic expression of select HOX proteins in musc le cell cultures had modest effects upon the activity of a co-transfected m yosin light chain (MLC) enhancer, mutation of a Hox binding site in this en hancer elicited increased linked reporter gene expression. Induction of mus cle damage and regeneration was accompanied by the down-regulation of at le ast one Hox gene, concurrent with the activation of the regenerative progra m. Moreover, targeted ablation of the Hoxc-8 gene, normally expressed in ma ture fore- and hindlimb muscles, resulted in reduced expression of an MLC e nhancer-driven transgene only in specific leg muscles. These results indica te that members of the HoxA and C clusters may, in combination, mediate var ious aspects of differentiation and patterning in adult musculature, (C) 19 99 Wiley-Liss, Inc.