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) genes in myofiber nuclei near the synaptic site, and signals associated with myofiber electrical activity inactivate AChR gene expression throughout 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 activity-dependent gene expression are mediated by the same DNA sequence and that activation and repression are determined by differential regulation of the same DNA binding protein. We produced transgenic mice carrying AChR delta subunit-hGH gene fusions, and we show here that a binding site (E-box) for myogenic basic helix-loop-helix proteins is required for electrical activity-dependent but not for synapse-specific gene 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 synapse-specific and electrical activity-dependent gene expression require different DNA sequences. Moreover, we show here that the cis-acting elements for both aspects of innervation-dependent gene regulation are contained in 181 bp of 5' flanking DNA from the AChR delta subunit gene.