What controls the position, number, size, and distribution of neuromuscular junctions on rat muscle fibers?

This review focuses on mechanisms that determine the position, number, size, and distribution of neuromuscular junctions (NMJs) on skeletal muscle fibers. Most of the data reviewed derive from studies of ectopic NMJ formation on soleus (SOL) muscle fibers in adult rats, which recapitulates essential aspects of NMJ formation in normal development. Transplanted axons induce acetylcholine receptor (AChR) aggregates, which are multiple and irregularly distributed initially but subsequently undergo massive reorganization such that one or a few winners survive and reach a certain size while the rest are eliminated (the losers). Results obtained by blocking nerve activity early and stimulating the SOL electrically show that evoked muscle impulse activity is responsible for the growth of winners to a given size and the creation of refractory zones, about 0.75 long, on each side of the winners, in which the elimination of losers occurs. Consequently, when two or more aggregates or NMJs survive on one fiber, they are, on average, at least 1.5 mm apart. Locally applied neural agrin induces comparable aggregation of AChRs and other postsynaptic proteins on denervated SOL fibers and such aggregates undergo similar activity-dependent selection for survival or elimination in refractory zones. In a dose-dependent way, neural agrin alone also induces expression of epsilon-AChR subunits and stabilizes AChRs to a half-life of 10 days, as found at normal NMJs. It is argued that signs of prepatterning of innervation sites by intrinsic muscle mechanisms may refer to epiphenomena that play no important role in NMJ formation. The conclusion is that neural agrin initiates and then maintains NMJs where motor axons happen to contact receptive muscle fibers and that evoked muscle impulse activity then ensures that the NMJs reach their appropriate size, efficiency and spatial distribution along each fiber.