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MuSK controls where motor axons grow and form synapses

Nature Neuroscience volume 11, pages 19–27 (2008)Cite this article

An Erratum to this article was published on 01 February 2008

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Abstract

Motor axons approach muscles that are regionally prespecialized, as acetylcholine receptors are clustered in the central region of muscle before and independently of innervation. This muscle prepattern requires MuSK, a receptor tyrosine kinase that is essential for synapse formation. It is not known how muscle prepatterning is established, and whether motor axons recognize this prepattern. Here we show that expression of Musk is prepatterned in muscle and that early Musk expression in developing myotubes is sufficient to establish muscle prepatterning. We further show that ectopic Musk expression promotes ectopic synapse formation, indicating that muscle prepatterning normally has an instructive role in directing where synapses will form. In addition, ectopic Musk expression stimulates synapse formation in the absence of Agrin and rescues the lethality of Agrn mutant mice, demonstrating that the postsynaptic cell, and MuSK in particular, has a potent role in regulating the formation of synapses.

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Figure 1: Endogenous Musk expression is patterned independent of innervations, whereas HSA::Musk is expressed uniformly in skeletal muscle.
Figure 2: High ectopic Musk expression induces ectopic AChR clusters and disrupts AChR prepatterning.
Figure 3: High ectopic Musk expression promotes motor axon outgrowth.
Figure 4: Ectopic Musk induces ectopic synapses that arise from axon collateral branching.
Figure 5: Synaptic AChR clusters mature, whereas ectopic non-innervated AChR clusters remain simplified and are not extinguished in Musk-H mice.
Figure 6: The Musk-L transgene is sufficient to initiate but not to maintain muscle prepatterning.
Figure 7: Ectopic MuSK promotes synapse formation and stabilization in the absence of Agrin.

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Change history

  • 11 January 2008

    In the version of this article initially published online, several items were omitted from the text. On page 20, left column, the sentence “To determine whether this restricted pattern…regulatory region of the human skeletal α-actin (HAS; Fig. 1e)” should read “To determine whether this restricted pattern…regulatory region of the human skeletal α-actin gene (HAS; Fig. 1e)”. On page 25, left column, the sentence “Muscle is pre-specialized in the central, prospective synaptic region before and independently of innervation, and have led to a revised model of the steps and mechanisms that regulate neuromuscular synapse formation” should read “Muscle is pre-specialized in the central, prospective synaptic region before and independently of innervation, and these findings have led to a revised model of the steps and mechanisms that regulate neuromuscular synapse formation.” Finally, on page 19, left column, the sentence “This organizational feature of neurons is essential for forming synapses on appropriate target cells and establishing functional neuronal circuits” should read “This organizational feature of neurons is critical for forming synapses on appropriate target cells and establishing functional neuronal circuits.” These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T. Jessell for antibodies to Isl1/Isl2, and HB9cre and Isl2DTA mice, J. Sanes for AgrnΔZ and Agrn-null mice, E. Hardeman for pHSA2000CAT, J. Fan for technical assistance, and M. Raff, J. Dasen, W. Gan, R. Lehmann and D. Littman for comments on the manuscript. This work was supported with funds from the US National Institutes of Health (NS36193) and the Robert Packard Center for ALS Research.

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  1. Molecular Neurobiology Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, 540 First Avenue, New York, 10016, New York, USA

    Natalie Kim & Steven J Burden

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Correspondence to Steven J Burden.

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Kim, N., Burden, S. MuSK controls where motor axons grow and form synapses. Nat Neurosci 11, 19–27 (2008). https://doi.org/10.1038/nn2026

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