SYNAPTOGENESIS Abl-ity to Form Synapses

Synaptogenesis, the process whereby the specialized junction between a neuron and its target cell develops, depends on an intricate interplay of signals between the presynaptic and postsynaptic cells. At the neuromuscular junction (NMJ), agrin, which is secreted by the presynaptic neuron, acts through muscle-specific receptor tyrosine kinase (MuSK) to stimulate clustering of muscle acetylcholine receptors (AChRs). AChR clustering involves activation of an unknown downstream tyrosine kinase and reorganization of the actin cytoskeleton. Finn et al. identified the Abl nonreceptor tyrosine kinases 1 and 2 (Abls 1 and 2), which have actin-bundling ability and have been implicated in the formation of cell-to-cell junctions (as well as in the pathogenesis of some leukemias), as critical components of the signaling cascade downstream of agrin and MuSK. The authors used Western analysis to identify Abls 1 and 2 in mouse muscle and immunohistochemistry to localize them to the postsynaptic NMJ. Pharmacologic analysis in C2C12, a murine myoblast cell line, as well as expression of Abl mutants, indicated that Abl activity was involved in both MuSK phosphorylation and in AChR clustering downstream of agrin and MuSK. Coexpression experiments in HEK cells indicated that MuSK and Abl1 phosphorylated each other. Western analysis of immunoprecipitates indicated that Abl formed a complex with MuSK; agrin treatment promoted formation of this complex. The authors propose a model in which Abl kinases promote AChR clustering through both phosphorylation and induction of a postsynaptic actin scaffold.

A. I. Finn, G. Feng, A. M. Pendergast, Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction. Nat. Neurosci. 6, 717-723 (2003). [Online Journal]