Regulation of Gene expression at the neuromuscular Junction.

Gene expression in skeletal muscle is profoundly changed upon innervation. 50 years of research on the neuromuscular system have greatly increased our understanding of the mechanisms underlying these changes. By controlling the expression and the activity of key transcription factors, nerve-evoked electrical activity in the muscle fiber positively and negatively regulates the expression of hundreds of genes. Innervation also compartmentalizes gene expression into synaptic and extra-synaptic regions of muscle fibers. In addition, electrically-evoked, release of several factors (e.g. Agrin, Neuregulin, Wnt ligands) induce the clustering of synaptic proteins and of a few muscle nuclei. The sub-synaptic nuclei acquire a particular chromatin organization and develop a specific gene expression program dedicated to building and maintaining a functional neuromuscular synapse. Deciphering synapse-specific, transcriptional regulation started with the identification of the N-box, a six base pair element present in the promoters of the acetylcholine δ and ε subunits. Most genes with synapse-specific expression turned out to contain at least one N-box in their promoters. The N-box is a response element for the synaptic signals Agrin and Neuregulins as well as a binding site for transcription factors of the Ets family. The Ets transcription factors GABP and Erm are implicated in the activation of post-synaptic genes via the N-box. In muscle fibers, Erm expression is restricted to the NMJ whereas GABP is expressed in all muscle nuclei but phosphorylated and activated by the JNK and ERK signaling pathways in response to Agrin and Neuregulins. Post-synaptic gene expression also correlates with chromatin modifications at the genomic level as evidenced by the strong enrichment of decondensed chromatin and acetylated histones in sub-synaptic nuclei. Here we discuss these transcriptional pathways for synaptic specialization at NMJs.