The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane

The dystrophin-associated protein (DAP) complex spans the sarcolemmal membr ane linking the cytoskeleton to the basement membrane surrounding each myof iber. Defects in the DAP complex have been linked previously to a variety o f muscular dystrophies, Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiate d from dystroglycan(-/-) embryonic stem cells are responsive to agrin, but produce acetyl choline receptor (AChR) clusters which are two to three time s larger in area, about half as dense, and significantly less stable than t hose on dystroglycan+/+ myotubes, AChRs at neuromuscular junctions are simi larly affected in dystroglycan-deficient chimeric mice and there is a coord inate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR cluster s of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes, These results suggest that dystro glycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan, In addition. th ey suggest that dystroglycan functions in the organization and stabilizatio n of AChR clusters, which appear to be mediated through its binding of lami nin.