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