INDUCTION BY AGRIN OF ECTOPIC AND FUNCTIONAL POSTSYNAPTIC-LIKE MEMBRANE IN INNERVATED MUSCLE

Two factors secreted from the nerve terminal, agrin and neuregulin, ha ve been postulated to induce localization of the acetylcholine recepto rs (AChRs) to the subsynaptic membrane in skeletal muscle fibers, The principal function ascribed to neuregulin is induction of AChR subunit gene expression and to agrin is the aggregation of AChRs, Here we rep ort that when myoblasts engineered to secrete an agrin fragment were p laced into the nerve-free region of denervated rodent muscle, the host muscle fibers expressed AChR epsilon-subunit gene transcripts, charac teristic of the neuromuscular synapse in adult muscle. Transcripts wer e colocalized with agrin deposits and AChR clusters that were resistan t to electrical muscle activity, More directly, single innervated musc le fibers injected intracellularly with agrin expression plasmids in t heir extrasynaptic region developed a functional ectopic postsynaptic membrane with clusters of adult-type AChR channels and acetylcholinest erase and accumulation of myonuclei, The results demonstrate that agri n is the principal neural signal that induces the formation of the sub synaptic apparatus in the muscle fiber and controls locally, either in directly or directly, the transcription of AChR subunit genes and the aggregation of AChRs.