Presynaptic differentiation at the neuromuscular junction : regulation by a novel bFGF-p120 catenin signaling pathway

Abstract

The neuromuscular junction (NMJ) is widely used as a model for elucidating the molecular basis of synaptogenesis. At the developing NMJ, a nerve-derived factor, agrin, and its functional receptor MuSK (muscle-specific tyrosine kinase) orchestrate postsynaptic differentiation, but it is less clear how other aspects of NMJ development, such as early nerve-muscle interaction and presynaptic specialization, are regulated. We recently reported that in Xenopus nerve-muscle co-cultures, nerve-induced filopodia in muscle (myopodia) facilitated interactions between the synaptic partners and promoted NMJ formation, and that myopodial assembly was triggered by agrin signaling through the cadherin complex protein p120 catenin (p120ctn), a potent regulator of Rho family GTPases. Because nerve-muscle interaction is also mediated by filopodia along the approaching axon and p120ctn is expressed in neurons, here we examined p120ctn's role in neuritic filopodial formation. Overexpressing this catenin in Xenopus spinal neurons increased the formation of filopodia and also enhanced SV clustering along the neurite. On the other hand, expressing a deletion mutant of p120ctn that poorly regulates Rho GTPases suppressed the assembly of these specializations. Interestingly, neuritic filopodia preferentially developed along the side facing muscle cells in nerve-muscle co-cultures, suggesting that muscle-derived factors induce and/or stabilize neuritic filopodia. Based on our previous work showing that focally presented basic fibroblast growth factor (bFGF) promotes presynaptic differentiation in motor axons, we tested the effect of bath-applied bFGF on nerve cultures and found that it promoted the formation of both filopodia and SV clusters. Significantly, this bFGF-dependent assembly of filopodia was suppressed by expressing the deletion-mutant p120ctn in neurons. Collectively, our results suggest that a novel FGF-p120ctn signaling cascade in motor neurons promotes presynaptic differentiation at developing NMJs.

Date of Award	2007
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology