LAMININ-INDUCED ACETYLCHOLINE-RECEPTOR CLUSTERING - AN ALTERNATIVE PATHWAY

The induction of acetylcholine receptor (AChR) clustering by neurally released agrin is a critical, early step in the formation of the neuro muscular junction. Laminin, a component of the muscle fiber basal lami na, also induces AChR clustering. We find that induction of AChR clust ering in C2 myotubes is specific for laminin-1, neither laminin-2 (mer osin) nor laminin-11 (a synapse-specific isoform) are active. Moreover , laminin-1 induces AChR clustering by a pathway that is independent o f that used by neural agrin. The effects of laminin-1 and agrin are st rictly additive and occur with different time courses. Most importantl y, laminin 1-induced clustering does not require MuSK, a receptor tyro sine kinase that is part of the receptor complex for agrin. Laminin-1 does not cause tyrosine phosphorylation of MuSK in C2 myotubes and ind uces AChR clustering in myotubes from MuSK-/- mice that do not respond to agrin. In contrast to agrin, laminin-1 also does not induce tyrosi ne phosphorylation of the AChR, demonstrating that AChR tyrosine phosp horylation is not required for clustering in myotubes. Laminin-1 thus acts by a mechanism that is independent of that used by agrin and may provide a supplemental pathway for AChR clustering during synaptogenes is.