Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin.
Wnt proteins regulate the formation of central synapses by stimulating synaptic assembly, but their role at the vertebrate neuromuscular junction (NMJ) is unclear. Wnt3 is expressed by lateral motoneurons of the spinal cord during the period of motoneuron-muscle innervation. Using gain- and loss-of-function studies in the chick wing, we demonstrate that Wnt signaling is necessary for the formation of acetylcholine receptor (AChR) clusters without affecting muscle growth. Similarly, diaphragms from Dishevelled-1 mutant mice with deficiency in Wnt signaling exhibit defects in cluster distribution. In cultured myotubes, Wnt3 increases the number and size of AChR clusters induced by agrin, a nerve-derived signal critical for NMJ development. Wnt3 does not signal through the canonical Wnt pathway to induce cluster formation. Instead, Wnt3 induces the rapid formation of unstable AChR micro-clusters through activation of Rac1, which aggregate into large clusters only in the presence of agrin. Our data reveal a role for Wnts in post-synaptic assembly at the vertebrate NMJ by enhancing agrin function through Rac1 activation.
Henriquez
Juan P
JP
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
Webb
Anna
A
Bence
Matthew
M
Bildsoe
Heidi
H
Sahores
Macarena
M
Hughes
Simon M
SM
Salinas
Patricia C
PC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D000072261:Dishevelled Proteins; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009469:Neuromuscular Junction / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018171:Agrin; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D010750:Phosphoproteins; D011950:Receptors, Cholinergic; D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D020830:rac1 GTP-Binding Protein