SPATIAL RESTRICTION OF ACHR GENE-EXPRESSION TO SUBSYNAPTIC NUCLEI

Acetylcholine receptors (AChRs) and the mRNAs encoding the four AChR s ubunits are highly concentrated in the synaptic region of skeletal myo fibers. The initial localization of AChRs to synaptic sites is trigger ed by the nerve and is caused, in part, by post-translational mechanis ms that involve a redistribution of AChR protein in the myotube membra ne. We have used transgenic mice that harbor a gene fusion between the murine AChR delta subunit gene and the human growth hormone gene to s how that innervation also activates two independent transcriptional pa thways that are important for establishing and maintaining this non-un iform distribution of AChR mRNA and protein. One pathway is triggered by signal(s) that are associated with myofiber depolarization, and the se signals act to repress delta subunit gene expression in nuclei thro ughout the myofiber. Denervation of muscle removes this repression and causes activation of delta subunit gene expression in nuclei in non-s ynaptic regions of the myofiber. A second pathway is triggered by an u nknown signal that is associated with the synaptic site, and this sign al acts locally to activate delta subunit gene expression only in nucl ei within the synaptic region. Synapse-specific expression, however, d oes not depend upon the continuous presence of the nerve, since transc riptional activation of the delta subunit gene in subsynaptic nuclei p ersists after denervation. Thus, the nuclei in the synaptic region of multinucleated skeletal myofibers are transcriptionally distinct from nuclei elsewhere in the myofiber, and this spatially restricted transc ription pattern is presumably imposed initially by the nerve.