DEFECTIVE NEUROMUSCULAR SYNAPTOGENESIS IN AGRIN-DEFICIENT MUTANT MICE

During neuromuscular synapse formation, motor axons induce clustering of acetylcholine receptors (AChRs) in the muscle fiber membrane. The p rotein agrin, originally isolated from the basal lamina of the synapti c cleft, is synthesized and secreted by motoneurons and triggers forma tion of AChR clusters on cultured myotubes. We show here that postsyna ptic AChR aggregates are markedly reduced in number, size, and density in muscles of agrin-deficient mutant mice. These results support the hypothesis that agrin is a critical organizer of postsynaptic differen tiation. However, some postsynaptic differentiation does occur in the mutant, suggesting the existence of a second nerve-derived synaptic or ganizing signal. In addition, we show that intramuscular nerve branchi ng and presynaptic differentiation are abnormal in the mutant, phenoty pes which may reflect either a distinct effect of agrin or impaired re trograde signaling from a defective postsynaptic apparatus.