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© The Rockefeller University Press, 0021-9525/2001//435 $5.00
The Journal of Cell Biology, Volume 152, Number 3, , 2001 435-450

The Dystroglycan Complex Is Necessary for Stabilization of Acetylcholine Receptor Clusters at Neuromuscular Junctions and Formation of the Synaptic Basement Membrane

^a Department of Biology, McGill University/Center for Neuroscience Research, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada
^b Department Neurology and Neurosurgery, McGill University/Center for Neuroscience Research, Montréal General Hospital Research Institute, Montréal, Québec H3G 1A4, Canada
^c Department of Cell Biology and Anatomy and Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33136
Center for Research in Neuroscience, McGill University, Montréal General Hospital Research Institute, 1650 Cedar Ave., Montréal, Québec H3G 1A4, Canada.(514) 937-6011 ext

The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve–muscle synapses. We show that myotubes differentiated from dystroglycan^–/– embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters 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 dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

Key Words: synapse formation • acetylcholinesterase • acetylcholine receptors • dystroglycan • dystrophin-associated proteins

© 2001 The Rockefeller University Press

Abbreviations used in this paper: -Btx, -bungarotoxin; AChE, acetylcholinesterase; AChR, acetylcholine receptor; ANOVA, analysis of variance; DAP, dystrophin-associated protein; EHS, Engelbreth-Holm-Swarm; ES, embryonic stem; fas-2, fasciculin 2; HS, horse serum; MASC, myotube-associated specificity component; MuSK, muscle-specific tyrosine kinase; NMJ, neuromuscular junction.

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