WNTs tune up the neuromuscular junction

Abstract

Although WNTs have been long thought of as regulators of cell fate, recent studies highlight their involvement in crucial aspects of synaptic development in the nervous system. Particularly compelling are recent studies of the neuromuscular junction in nematodes, insects, fish and mammals. These studies place WNTs as major determinants of synapse differentiation and neurotransmitter receptor clustering.

Figure 1. Role of WNTs in AChR clustering at the vertebrate neuromuscular junction

a ∣ WNT3 (in mice) and Wnt11r (in zebrafish) induce AChr (acetylcholine receptor) preclustering before innervation. b ∣ WNT3 has been implicated in AChr clustering after innervation. c ∣ ACh release and WNT3a mediate AChr declustering. A retrograde signal induced by muscle β-catenin, to regulate the development of the presynaptic motor endings, is also shown. APC, adenomatous polyposis coli; DVL, mammalian homologue of Drosophila Dishevelled; GSK3β, glycogen synthase kinase 3β; LRP, low density lipoprotein receptor-related protein; MUsK, muscle, skeletal, receptor tyrosine kinase; PAK1, protein (Cdc42/rac)-activated kinase 1.

Figure 2. Role of WNTs during Drosophila melanogaster larval neuromuscular junction development

Wingless secreted from presynaptic motor neuron endings, binds to Frizzled-2 and co-receptor Arrow, which are localized presynaptically and postsynaptically. In the presynaptic cell, Wingless activates a divergent canonical pathway, involving DVL (Dishevelled) activation, inhibition of GSK3β (glycogen synthase kinase 3β) activity and the regulation of the microtubule cytoskeleton through Futsch. In the postsynaptic cell, Wingless activates the Frizzled nuclear import pathway, which involves the cleavage and nuclear import of Frizzled-2. grIP (7-PDZ-domain glutamate-receptor binding protein) is required for the trafficking of receptors from the postsynaptic membrane towards the nucleus. WNT5 is also released from the presynaptic boutons and binds to its receptor Derailed (DrL) on the postsynaptic membrane to regulate synaptic bouton growth.

Figure 3. inhibitory role of WNT signalling at the neuromuscular junction of Caenorhabditis elegans

At the tail region of C. elegans, the axon from the DA9 motor neuron forms neuromuscular junctions (NMJs) with the body wall muscles. synaptic terminals do not form posteriorly as the axon receives the anti-synaptogenic WNT/LIN-44 signal. Inset: WNT/LIN-44 binds its receptor Frizzled/ LIN-17, which leads to activation of DVL-1 (Dishevelled 1). This signalling pathway prevents neuromuscular synapse formation. ACh, acetylcholine; AChr, ACh receptor.