SEPARATE PATHWAYS FOR SYNAPSE-SPECIFIC AND ELECTRICAL ACTIVITY-DEPENDENT GENE-EXPRESSION IN SKELETAL-MUSCLE

Signaling between nerve and muscle is mediated by multiple mechanisms, including two transcriptional pathways. Signals provided by the nerve terminal activate transcription of acetylcholine receptor (AChR) gene s in myofiber nuclei near the synaptic site, and signals associated wi th myofiber electrical activity inactivate AChR gene expression throug hout the myofiber. These opposing effects of innervation are conferred by 1.8 kb of 5' flanking DNA from the AChR delta subunit gene. These results raise the possibility that synapse-specific and electrical act ivity-dependent gene expression are mediated by the same DNA sequence and that activation and repression are determined by differential regu lation of the same DNA binding protein. We produced transgenic mice ca rrying AChR delta subunit-hGH gene fusions, and we show here that a bi nding site (E-box) for myogenic basic helix-loop-helix proteins is req uired for electrical activity-dependent but not for synapse-specific g ene expression of the delta subunit gene. These results indicate that a change in the expression or activity of an E-box binding protein(s) mediates electrical activity-dependent gene regulation and that synaps e-specific and electrical activity-dependent gene expression require d ifferent DNA sequences. Moreover, we show here that the cis-acting ele ments for both aspects of innervation-dependent gene regulation are co ntained in 181 bp of 5' flanking DNA from the AChR delta subunit gene.