Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction

A prominent feature of synaptic maturation at the neuromuscular junction (NMJ) is the topological transformation of the acetylcholine receptor (AChR)-rich postsynaptic membrane from an ovoid plaque into a complex array of branches. We show here that laminins play an autocrine role in promoting this...

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Bibliographic Details
Published in:The Journal of cell biology 2008-09, Vol.182 (6), p.1201-1215
Main Authors: Nishimune, Hiroshi, Valdez, Gregorio, Jarad, George, Moulson, Casey L, Müller, Ulrich, Miner, Jeffrey H, Sanes, Joshua R
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Animals
Autocrine Communication - physiology
Cells
Cells, Cultured
Dystroglycans
Dystroglycans - genetics
Dystroglycans - metabolism
Humans
Integrins
Laminin - genetics
Laminin - metabolism
Membranes
Mice
Mice, Knockout
Mice, Transgenic
Muscle fibers
Muscle Fibers, Skeletal - cytology
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - cytology
Muscle, Skeletal - metabolism
Muscles
Mutation
Nerve of a covering
Neuromuscular Junction - physiology
Neurons
Receptors
Receptors, Cholinergic - genetics
Receptors, Cholinergic - metabolism
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Rodents
Schwann cells
Synapses
Topology
Transgenes
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Summary:A prominent feature of synaptic maturation at the neuromuscular junction (NMJ) is the topological transformation of the acetylcholine receptor (AChR)-rich postsynaptic membrane from an ovoid plaque into a complex array of branches. We show here that laminins play an autocrine role in promoting this transformation. Laminins containing the α4, α5, and β2 subunits are synthesized by muscle fibers and concentrated in the small portion of the basal lamina that passes through the synaptic cleft at the NMJ. Topological maturation of AChR clusters was delayed in targeted mutant mice lacking laminin α5 and arrested in mutants lacking both α4 and α5. Analysis of chimeric laminins in vivo and of mutant myotubes cultured aneurally demonstrated that the laminins act directly on muscle cells to promote postsynaptic maturation. Immunohistochemical studies in vivo and in vitro along with analysis of targeted mutants provide evidence that laminin-dependent aggregation of dystroglycan in the postsynaptic membrane is a key step in synaptic maturation. Another synaptically concentrated laminin receptor, Bcam, is dispensable. Together with previous studies implicating laminins as organizers of presynaptic differentiation, these results show that laminins coordinate post- with presynaptic maturation.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200805095