Synapse formation molecules in muscle and autonomic ganglia: the dual constraint hypothesis

In 1970 it was thought that if the motor-nerve supply to a muscle was interrupted and then allowed to regenerate into the muscle, motor-synaptic terminals most often formed presynaptic specializations at random positions over the surface of the constituent muscle fibres, so that the original spatial pattern of synapses was not restored. However, in the early 1970s a systematic series of experiments were carried out showing that if injury to muscles was avoided then either reinnervation or cross-reinnervation reconstituted the pattern of synapses on the muscle fibres according to an analysis using the combined techniques of electrophysiology, electronmicroscopy and histology on the muscles. It was thus shown that motor-synaptic terminals are uniquely restored to their original synaptic positions. This led to the concept of the synaptic site, defined as that region on a muscle fibre that contains molecules for triggering synaptic terminal formation. However, nerves in developing muscles were found to form connections at random positions on the surface of the very short muscle cells, indicating that these molecules are not generated by the muscle but imprinted by the nerves themselves; growth in length of the cells on either side of the imprint creates the mature synaptic site in the approximate middle of the muscle fibres. This process is accompanied at first by the differentiation of an excess number of terminals at the synaptic site, and then the elimination of all but one of the terminals. In the succeeding 25 years, identification of the synaptic site molecules has been a major task of molecular neurobiology. This review presents an historical account of the developments this century of the idea that synaptic-site formation molecules exist in muscle. The properties that these molecules must possess if they are to guide the differentiation and elimination of synaptic terminals is considered in the context of a quantitative model of this process termed the dual-constraint hypothesis. It is suggested that the molecules agrin, ARIA, MuSK and S-laminin have suitable properties according to the dual-constraint hypothesis to subserve this purpose. The extent to which there is evidence for similar molecules at neuronal synapses such as those in autonomic ganglia is also considered.