Editors' ChoiceDevelopment

Dispersing Extrasynaptic Clusters

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Science's STKE  24 May 2005:
Vol. 2005, Issue 285, pp. tw195
DOI: 10.1126/stke.2852005tw195

Prior to formation of the neuromuscular junction, clusters of acetylcholine receptors (AChRs) form a band in the central region of the muscle fiber; with innervation, nascent AChRs become stabilized in the muscle membrane underlying the nerve terminal but disperse elsewhere. Agrin, a protein released from motor neurons, is involved in promoting and maintaining postsynaptic AChR clusters, but the signals that promote dispersal of AChRs in extrasynaptic regions of the muscle have remained unclear (see Xiong and Mei). Lin et al. found that cyclin-dependent kinase 5 (Cdk5) mutant mouse embryos showed more AChR clusters in diaphragm muscle than wild-type embryos. Moreover, at a stage at which agrin mutant mouse embryos show few AChR clusters in diaphragm muscle, pharmacological blockade of cdk5 activity in in utero agrin mutants inhibited dispersal so that many clusters were apparent, as did inactivation of the gene encoding Cdk5. The cholinergic agonist carbachol activated Cdk5 in mouse C2C12 myotube cultures and caused dispersal of AChR clusters induced by prior treatment with agrin. Both pharmacologic and genetic analysis indicated that Cdk5 was required for carbachol-induced AChR dispersal. Moreover, AChR clusters were maintained in E17.5 mice that were deficient in the acetylcholine synthetic enzyme choline acetyltransferase as well as in agrin. Thus, the authors concluded that acetylcholine, which likely diffuses further than agrin, plays a role in dispersal of extrasynaptic AChR clusters and negatively regulates formation of the neuromuscular synapse.

W. Lin, B. Dominguez, J. Yang, P. Aryal, E. P. Brandon, F. H. Gage, K.-F. Lee, Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46, 569-579 (2005).[Online Journal]

W. C. Xiong, L. Mei, An unconventional role of neurotransmission in synapse formation. Neuron 46, 521-523 (2005). [Online Journal]

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