Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act in cis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, and axon terminal development. LRP4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of cocultured neurons, suggesting a synaptogenic function. Analysis of LRP4 muscle and motoneuron double mutants and mechanistic studies suggest that NMJ formation may also be regulated by LRP4 in motoneurons, which could serve as agrin's receptor in trans to induce AChR clusters. These observations uncovered distinct roles of LRP4 in motoneurons and muscles in NMJ development. ► Muscle LRP4 is critical for presynaptic differentiation at the NMJ ► Muscle LRP4 directs the location and maturation of NMJs ► LPR4 appears to have synaptogenic activity ► Motoneuron LRP4 is able to form immature NMJs in the absence of muscle LRP4 LRP4 is an obligated receptor of agrin for AChR clustering. Wu et al. find that muscle LRP4 is critical for presynaptic differentiation. NMJ formation is also regulated by LRP4 in motoneurons, suggesting that LRP4 may also be capable of serving as an agrin receptor in trans.