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Nerve-independent formation of a topologically complex postsynaptic apparatus

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Joshua R. Sanes, Dept. of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: (314) 362-2507. Fax: (314) 747-1150. email: sanesj{at}pcg.wustl.edu

As the mammalian neuromuscular junction matures, its acetylcholine receptor (AChR)–rich postsynaptic apparatus is transformed from an oval plaque into a pretzel-shaped array of branches that precisely mirrors the branching pattern of the motor nerve terminal. Although the nerve has been believed to direct postsynaptic maturation, we report here that myotubes cultured aneurally on matrix-coated substrates form elaborately branched AChR-rich domains remarkably similar to those seen in vivo. These domains share several characteristics with the mature postsynaptic apparatus, including colocalization of multiple postsynaptic markers, clustering of subjacent myonuclei, and dependence on the muscle-specific kinase and rapsyn for their formation. Time-lapse imaging showed that branched structures arise from plaques by formation and fusion of AChR-poor perforations through a series of steps mirroring that seen in vivo. Multiple fluorophore imaging showed that growth occurs by circumferential, asymmetric addition of AChRs. Analysis in vivo revealed similar patterns of AChR addition during normal development. These results reveal the sequence of steps by which a topologically complex domain forms on a cell and suggest an unexpected nerve-independent role for the postsynaptic cell in generating this topological complexity.

Key Words: acetylcholine receptor; laminin; muscle; neuromuscular junction; synapse formation

Abbreviations used in this paper: AChR, acetylcholine receptor; Btx, -bungarotoxin; MuSK, muscle-specific kinase; NMJ, neuromuscular junction.

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