Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost

Studies of the vertebrate skeletal neuromuscular junction led to an influential model of how neurotransmitter receptors accumulate in the postsynaptic membrane. In this model, motor axons organize postsynaptic development by secreting neuregulin to induce acetylcholine receptor gene transcription in specialized subsynaptic nuclei, agrin to cluster diffuse receptors in the postsynaptic membrane, and acetylcholine to evoke electrical activity that promotes synaptic maturation. However, new studies in this area have first, demonstrated that axons sometimes innervate pre-existing receptor clusters; second, recast the roles of agrin and neuregulin; third, revealed early effects of neurotransmission; fourth, questioned the role of subsynaptic myonuclei; fifth, shown that elaborately-branched postsynaptic structures can form aneurally; and sixth, raised the possibility that neurotransmitter affects receptor type as well as distribution. These recent studies challenge the widely-held paradigms, although not the results that led to them, and suggest a new model for neuromuscular synaptogenesis.