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Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse

Abstract

The development of chemical synapses is regulated by interactions between pre- and postsynaptic cells. At the vertebrate skeletal neuromuscular junction, the organization of an acetylcholine receptor (AChR)-rich postsynaptic apparatus has been well studied. Much evidence suggests that the nerve-derived protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn. But how postsynaptic differentiation is initiated, or why most synapses are restricted to an ‘end-plate band’ in the middle of the muscle remains unknown. Here we have used genetic methods to address these issues. We report that the initial steps in postsynaptic differentiation and formation of an end-plate band require MuSK and rapsyn, but are not dependent on agrin or the presence of motor axons. In contrast, the subsequent stages of synaptic growth and maintenance require nerve-derived agrin, and a second nerve-derived signal that disperses ectopic postsynaptic apparatus.

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Figure 1: Aneural AChR clusters at initial stage of synaptogenesis.
Figure 2: Distinct roles of agrin and MuSK in initiating AChR clustering.
Figure 3: Clustering of AChRs in the absence of the motor nerve.
Figure 4: Localization of AChRα mRNA and AChE in the presumptive end-plate band of aneural muscle.
Figure 5: MuSK is required for AChR clustering in aneural muscle.
Figure 6: Multiple steps in postsynaptic differentiation in the neuromuscular junction.

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Acknowledgements

We thank J. Kehrl for HB9 mutant mice, and G. Yancopoulos, D. Glass and T. DeChiara for MuSK mutant mice. We thank S. Anant, C. Kintner, F. Gage and S. Heinemann for comments on the manuscript. This work was supported by grants from the NIH (J.R.S., S.L.P. and K.F.L.), the Leducq Foundation and NIH training grant (W.L.) and an NIH postdoctoral fellowship (R.W.B). S.L.P. and K.F.L are Pew Scholars.

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Correspondence to Kuo-Fen Lee.

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Lin, W., Burgess, R., Dominguez, B. et al. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 1057–1064 (2001). https://doi.org/10.1038/35074025

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