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Published online 19 May 2003. doi:10.1083/jcb.200210156
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© The Rockefeller University Press, 0021-9525/2003/5/727 $5.00
The Journal of Cell Biology, Volume 161, Number 4, 727-736

Article

 A novel pathway for MuSK to induce key genes in neuromuscular synapse formation

Eric Lacazette, Sophie Le Calvez, Nadesan Gajendran and Hans Rudolf Brenner

Department of Physiology, University of Basel, CH-4056 Basel, Switzerland

Address correspondence to Hans Rudolf Brenner, Dept. of Physiology Biozentrum/Pharmazentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland. Tel.: 41-61-267-16-38. Fax: 41-61-267-16-28. E-mail: Hans-Rudolf.Brenner{at}unibas.ch

At the developing neuromuscular junction the Agrin receptor MuSK is the central organizer of subsynaptic differentiation induced by Agrin from the nerve. The expression of musk itself is also regulated by the nerve, but the mechanisms involved are not known. Here, we analyzed the activation of a musk promoter reporter construct in muscle fibers in vivo and in cultured myotubes, using transfection of multiple combinations of expression vectors for potential signaling components. We show that neuronal Agrin by activating MuSK regulates the expression of musk via two pathways: the Agrin-induced assembly of muscle-derived neuregulin (NRG)-1/ErbB, the pathway thought to regulate acetylcholine receptor (AChR) expression at the synapse, and via a direct shunt involving Agrin-induced activation of Rac. Both pathways converge onto the same regulatory element in the musk promoter that is also thought to confer synapse-specific expression to AChR subunit genes. In this way, a positive feedback signaling loop is established that maintains musk expression at the synapse when impulse transmission becomes functional. The same pathways are used to regulate synaptic expression of AChR{varepsilon} . We propose that the novel pathway stabilizes the synapse early in development, whereas the NRG/ErbB pathway supports maintenance of the mature synapse.

Key Words: Agrin; MuSK; synapse formation; skeletal muscle; neuromuscular junction

N. Gajendran's present address is Max-Planck-Institut für Infektionsbiologie, Abt. Immunologie, Schumannstrasse 21/22, D-10117 Berlin, Germany.

* Abbreviations used in this paper: AChE, acetylcholinesterase; AChR, acetylcholine receptor; ß-Gal, ß-galactosidase; ERK, extracellular signal–regulated kinase; JNK, c-Jun NH2-terminal kinase; NRG, neuregulin.


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