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The Journal of Neuroscience, February 15, 1998, 18(4):1250-1260

Laminin and -Dystroglycan Mediate Acetylcholine Receptor Aggregation via a MuSK-Independent Pathway

Federica Montanaro¹, Stephen H. Gee², Christian Jacobson¹, Michael H. Lindenbaum¹, Stanley C. Froehner² and Salvatore Carbonetto¹

¹ Centre for Research in Neuroscience, McGill University, Montreal General Hospital Research Institute, Montreal, Canada H3G 1A4, and ² Department of Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7545

Specific isoforms of laminin (LN) are concentrated at neuromuscular junctions (NMJs) where they may participate in synaptic organization or function. In myotubes from C2 cells, LN is concentrated within the majority of spontaneous acetylcholine receptor (AChR) aggregates. Neural agrin substantially increases this colocalization, suggesting that agrin can recruit LN into AChR aggregates. Addition of LN to C2 myotubes induces a more than twofold increase in the number of AChR aggregates. These aggregates have a larger size and are more dense than are those induced by agrin, suggesting that LN is involved in the growth and/or stabilization of AChR aggregates. Consistent with this hypothesis, an antiserum to LN reduces the size of individual AChR aggregates but increases their number. In C2 myotubes, extracellular matrix receptors containing the integrin 1 subunit are poorly colocalized with AChR aggregates, suggesting that integrins may not be involved in LN-induced aggregation. In contrast, almost all AChR aggregates are associated with dystroglycan immunoreactivity, and monoclonal antibody (mAb) IIH6 against -dystroglycan (-DG), a LN and agrin receptor, causes a concentration-dependent inhibition of LN-induced aggregation. Moreover, S27 cells, which lack a functional -DG, and two C2-derived cell lines expressing antisense DG mRNA fail to aggregate AChRs in response to LN. Finally, LN-induced AChR aggregation does not involve the phosphorylation of the muscle-specific tyrosine kinase receptor (MuSK) or the AChR  subunit. We hypothesize that the interaction of LN with -DG contributes to the growth and/or stabilization of AChR microaggregates into macroaggregates at the developing NMJ via a MuSK-independent mechanism.

Key words: laminin; -dystroglycan; acetylcholine receptor aggregation; neuromuscular synapse; agrin; MuSK

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1841250-11$05.00/0

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