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The Journal of Neuroscience, May 1, 2001, 21(9):3151-3160
Src, Fyn, and Yes Are Not Required for Neuromuscular Synapse
Formation But Are Necessary for Stabilization of Agrin-Induced Clusters
of Acetylcholine Receptors
Cynthia L.
Smith1,
Peggy
Mittaud2,
Elizabeth
D.
Prescott1,
Christian
Fuhrer2, and
Steven J.
Burden1
1 Molecular Neurobiology Program, Skirball Institute
for Biomolecular Medicine, New York University Medical School, New
York, New York 10016, and 2 Brain Research Institute,
University of Zürich-Irchel, CH-8057 Zürich, Switzerland
Mice deficient in src and fyn or
src and yes move and breathe poorly and
die perinatally, consistent with defects in neuromuscular function. Src
and Fyn are associated with acetylcholine receptors (AChRs) in
muscle cells, and Src and Yes can act downstream of ErbB2,
suggesting roles for Src family kinases in signaling pathways regulating neuromuscular synapse formation. We studied neuromuscular synapses in src /;
fyn/ and
src/; yes/
mutant mice and found that muscle development, motor axon pathfinding, clustering of postsynaptic proteins, and synapse-specific transcription are normal in these double mutants, showing that these pairs of kinases
are not required for early steps in synapse formation. We generated
muscle cell lines lacking src and fyn and
found that neural agrin and laminin-1 induced normal clustering of
AChRs and that agrin induced normal tyrosine phosphorylation of the AChR  subunit in the absence of Src and Fyn. Another Src family member, most likely Yes, was associated with AChRs and phosphorylated by agrin in myotubes lacking Src and Fyn, indicating that Yes may
compensate for the loss of Src and Fyn. Nevertheless, PP1 and
PP2, inhibitors of Src-class kinases, did not inhibit agrin signaling,
suggesting that Src class kinase activity is dispensable for
agrin-induced clustering and tyrosine phosphorylation of AChRs. AChR
clusters, however, were less stable in myotubes lacking Src and Fyn but
not in PP1- or PP2-treated wild-type cells. These data show that the
stabilization of agrin-induced AChR clusters requires Src and Fyn and
suggest that the adaptor activities, rather than the kinase activities,
of these kinases are essential for this stabilization.
Key words:
AChR; Src; Yes; cytoskeleton; agrin; neuromuscular
synapse
Copyright © 2001 Society for Neuroscience 0270-6474/01/2193151-10$05.00/0
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