LOCAL TRANSCRIPTIONAL CONTROL OF UTROPHIN EXPRESSION AT THE NEUROMUSCULAR SYNAPSE

Recently, the use of a transgenic mouse model system for Duchenne musc ular dystrophy has demonstrated the ability of utrophin to functionall y replace dystrophin and alleviate the muscle pathology (see Tinsley, J. M., Potter, A. C., Phelps, S. R., Fisher, R., Trickett, J. I., and Davies, K. E. (1996) Nature 384, 349-353). However, there is currently a clear lack of information concerning the regulatory mechanisms pres iding over utrophin expression during normal myogenesis and synaptogen esis. Using in situ hybridization, we show that utrophin mRNAs selecti vely accumulate within the postsynaptic sarcoplasm of adult muscle fib ers. In addition, we demonstrate that a 1.3-kilobase fragment of the h uman utrophin promoter is sufficient to confer synapse-specific expres sion to a reporter gene. Deletion of 800 base pairs from this promoter fragment reduces the overall expression of the reporter gene and abol ishes its synapse-specific expression. Finally, we also show that utro phin is present at the postsynaptic membrane of ectopic synapses induc ed to form at sites distant from the original neuromuscular junctions. Taken together, these results indicate that nerve-derived factors reg ulate locally the transcriptional activation of the utrophin gene in s keletal muscle fibers and that myonuclei located in extrasynaptic regi ons are capable of expressing utrophin upon receiving appropriate neur onal cues.