title: Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction.
abstract: 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 alpha4, alpha5, and beta2 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 alpha5 and arrested in mutants lacking both alpha4 and alpha5. 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.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. hnishimune@kumc.edu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimune
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valdez
authors.forename: George
authors.initials: G
authors.lastname: Jarad
authors.forename: Casey L
authors.initials: CL
authors.lastname: Moulson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002478:Cells, Cultured; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009469:Neuromuscular Junction / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: C501370:Lama4 protein, mouse; D007797:Laminin; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; C097043:laminin alpha5; C058783:laminin beta2; D049030:Dystroglycans; D000110:Acetylcholinesterase
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