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

¹ Department of Molecular and Cellular Biology and ² Center for Brain Science, Harvard University, Cambridge, MA 02138
³ Department of Anatomy and Cell Biology and ⁴ Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical School, Kansas City, KS 66160
⁵ Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
⁶ Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037

Correspondence to H. Nishimune: hnishimune{at}kumc.edu; or J.R. Sanes: sanesj{at}mcb.harvard.edu

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 4, 5, 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 5 and arrested in mutants lacking both 4 and 5. 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.

Abbreviations used in this paper: AChR, acetylcholine receptor; Bcam, basal cell adhesion molecule/Lutheran blood group antigen; BTX, -bungarotoxin; LG, laminin globular; MuSK, muscle-specific kinase; NMJ, neuromuscular junction.

© 2008 Nishimune et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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