Agrin-induced clustering of acetylcholine receptors: a cytoskeletal link

F ORMATION of synaptic connections involves the localized differentiation of preand postsynaptic cells as the result of a bidirectional exchange of information molecules during development. At a well-studied synapse, the neuromuscular junction (NMJ)', agrin is thought to play an important role in the synaptic differentiation of the muscle induced by the motorneuron. Agrin is an extracellular matrix protein synthesized by motorneurons at the time of synapse formation, which can induce the clustering of synaptic molecules on the surface of culture muscle cells (for review see McMahan, 1990). Molecular analysis has shown that agrin is a family of proteins of '~ 220 kD that are produced by alternative splicing and that contain a number of structural motifs known from other extracellular proteins (Fig. 1; Rupp et al., 1991; Tsim et al., 1992). Full-length recombinant agrin, as well as truncated soluble forms, induce the clustering of nicotinic acetylcholine receptors (AChR) (Campanelli et al., 1991; Ruegg et al., 1992; Ferns et al., 1992, 1993). AChR clusters also form spontaneously on cultured myotubes, suggesting that the machinery for clustering is contributed by muscle. Although both motorneurons and muscles synthesize agrin, antibody inhibition experiments showed that motorneuron-derived agrin, but not the muscle-derived form, is required for synapse formation in culture (Reist et al., 1992). Here, we review the role of agrin in synaptogenesis, focusing on the structural requirements for agrin activity and implications of the recently described agrin-dystroglycan interaction for models of the mechanism of agrin-induced AChR clustering.