Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse

The development of chemical synapses is regulated by interactions between p re- and postsynaptic cells. At the vertebrate skeletal neuromuscular juncti on, the organization of an acetylcholine receptor (AChR)-rich postsynaptic apparatus has been well studied. Much evidence suggests that the nerve-deri ved protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn. But how postsynapt ic differentiation is initiated, or why most synapses are restricted to an 'end-plate band' in the middle of the muscle remains unknown. Here we have used genetic methods to address these issues. We report that the initial st eps in postsynaptic differentiation and formation of an end-plate band requ ire MuSK and rapsyn, but are not dependent on agrin or the presence of moto r axons. In contrast, the subsequent stages of synaptic growth and maintena nce require nerve-derived agrin, and a second nerve-derived signal that dis perses ectopic postsynaptic apparatus.