Differential requirement for MuSK and dystroglycan in generating patterns of neuromuscular innervation

Vertebrates display diverse patterns of neuromuscular innervation, but little is known about how such diversity is generated. In mammals, neuromuscular junctions form predominantly at equatorial locations, giving rise to a focal innervation pattern along a central endplate band. In addition, vertebrate striated muscles exhibit two nonfocal neuromuscular patterns, myoseptal and distributed innervation. Although agrin-MuSK-rapsyn signaling is essential for the focal innervation pattern, it is unknown whether the same genetic program also controls synaptogenesis at nonfocal innervation sites. Here we show that one of three transcripts generated by the zebrafish unplugged locus, unplugged FL, encodes the zebrafish MuSK ortholog. We demonstrate that UnpFL/MuSK is critical for the assembly of focal synapses in zebrafish and that it cooperates with dystroglycan in the formation of nonfocal myoseptal and distributed synapses. Our results provide the first genetic evidence that neuromuscular synapse formation can occur in the absence of MuSK and that the combinatorial function of UnpFL/MuSK and dystroglycan generates diverse patterns of vertebrate neuromuscular innervation.