Résumé :
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Neuromuscular junction (NMJ) formation requires a highly coordinated communication via several reciprocal signaling processes between motoneurons and muscle targets. Identification of the local and early cues in target recognition at the NMJ is still poorly documented in mammals. Wnt signaling is one of the key pathways regulating synaptic connectivity. Here, we report that Wnt4 controls NMJ innervation in vivo. Results from a microarray screen and quantitative RT-PCR demonstrate that Wnt4 expression is regulated during muscle cell differentiation in vitro and muscle development in vivo, being highly expressed when the first synaptic contacts are formed and subsequently downregulated as muscle differentiation occurs. Analysis of the mouse Wnt4-/- NMJ phenotype reveals profound innervation defects with motor axons overgrowing and bypassing AChR aggregates and perturbation of AChR cluster distribution resulting in 30% of AChR clusters left unapposed by nerve terminals. Lack of Wnt4 function does not likely perturb muscle differentiation, prepatterning prior to innervation as well as the localization of several synaptic proteins including acetylcholinesterase, the muscle specific kinase MuSK and rapsyn. We show that Wnt4 is able to attract developing motor axons in vitro suggesting that Wnt4 acts as a guidance cue for motor neurons. Finally, we identify MuSK as a Wnt4 receptor: not only Wnt4 interacts with MuSK ectodomain but also mediates MuSK activation. Taken together these data demonstrate that Wnt4 through MuSK activation controls NMJ recognition by nerve terminals during mammalian NMJ formation.
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