Alternatively spliced isoforms of nerve- and muscle-derived agrin: Their roles at the neuromuscular junction

Agrin induces synaptic differentiation at the skeletal neuromuscular juncti on (NMJ); both pre- and postsynaptic differentiation are drastically impair ed in its absence. Multiple alternatively spliced forms of agrin that diffe r in binding characteristics and bioactivity are synthesized by nerve and m uscle cells. We used surgical chimeras, isoform-specific mutant mice, and n erve-muscle cocultures to determine the origins and nature of the agrin req uired for synaptogenesis. We show that agrin containing Z exons (Z(+)) is a critical nerve-derived inducer of postsynaptic differentiation, whereas ne ural isoforms containing a heparin binding site (Y+) and all muscle-derived isoforms are dispensable for major steps in synaptogenesis. Our results al so suggest that the requirement of agrin for presynaptic differentiation is mediated indirectly by its ability to promote postsynaptic production or l ocalization of appropriate retrograde signals.