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Review
. 2012 Jun;4(6):a008045.
doi: 10.1101/cshperspect.a008045.

Wnt signaling in neuromuscular junction development

Kate Koles  1 , Vivian Budnik
Affiliations
Review

Wnt signaling in neuromuscular junction development

Kate Koles et al. Cold Spring Harb Perspect Biol. 2012 Jun.

Abstract

Wnt proteins are best known for their profound roles in cell patterning, because they are required for the embryonic development of all animal species studied to date. Besides regulating cell fate, Wnt proteins are gaining increasing recognition for their roles in nervous system development and function. New studies indicate that multiple positive and negative Wnt signaling pathways take place simultaneously during the formation of vertebrate and invertebrate neuromuscular junctions. Although some Wnts are essential for the formation of NMJs, others appear to play a more modulatory role as part of multiple signaling pathways. Here we review the most recent findings regarding the function of Wnts at the NMJ from both vertebrate and invertebrate model systems.

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Figures

Figure 1.
Figure 1.
Overview of Wnt signaling pathways. Wnts signal through Frizzled receptors that can form a complex with Lrp-5/6 receptors. With the exception of the FNI pathway, these signaling pathways activate the scaffolding protein Dishevelled (Dvl). The different pathways diverge downstream from Dvl. (A) In the canonical pathway, Dvl disrupts the “destruction complex” composed of Axin, Adenomatous Polyposis Coli (APC), and Gsk3β. This prevents the phosphorylation of β-catenin by Gsk3β, which leads to its stabilization and subsequent nuclear import. In the nucleus, β-catenin associates with the transcription factor T-cell factor/lymphoid enhancer factor 1 (TCF/Lef1) and regulates gene expression. The secreted proteins Dickkopf1 (Dkk1) and secreted Frizzled-related protein (Sfrp) inhibit this pathway. (B) Following Wnt activation of the divergent canonical pathway, Dvl inhibits Gsk3β, which leads to the decreased phosphorylation of microtubule-associated proteins (MAPs), such as Tau, MAP-1B, MAP-2, or the related Drosophila protein Futsch. (C) In the planar cell polarity pathway, Dvl activates the small Rho GTPases RhoA and Rac1, and c-Jun–amino-terminal kinase (Jnk), which leads to the regulation of actin and microtubule cytoskeletons. (D) In the Wnt calcium pathway, Dvl activation leads to a rapid increase in intracellular calcium levels and subsequent activation of calcium-sensitive enzymes such as protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CaMKII) and the Ca2+-activated phosphatase calcineurin (Cn). Calcineurin directly binds to and dephosphorylates nuclear factor of activated T-cells (NFAT), which, in turn, allows their nuclear translocation where they regulate gene expression. (E) In the Frizzled nuclear import pathway (FNI), Wnt binding to Frizzled-2 (DFz2) leads to its endocytosis and Grip-dependent trafficking to the periphery of the nucleus. Here the carboxyl terminus of DFz2 is cleaved and imported. In Drosophila, DFz2-C organizes ribonucleoprotein (RNP) particles containing specific transcripts, which then egress from the nucleus and are likely translated in the cytoplasm. A similar nuclear import pathway has also been described for the atypical Ryk receptor during cortical neurogenesis (Lyu et al. 2008).
Figure 2.
Figure 2.
Wnt signaling at vertebrate neuromuscular junctions. (A) Mouse Wnt3 and zebrafish Wnt11r function during prepatterning. Wnt11r signaling through Unplugged/MuSK before innervation leads to aneural AChR clustering and also via a parallel signaling pathway to changes in extracellular matrix modifications (EMMs), possibly via chondroitin sulfate proteoglycans (CSPGs) that eventually influence incoming motor neuron axonal growth cone guidance. Wnt3 signaling leads to the rapid and transient activation of Rac1 and AChR microcluster formation, which (B) in the presence of neural agrin at the time of innervation are stabilized in exact opposition to the presynaptic terminal.
Figure 3.
Figure 3.
Negative regulation of AChR clustering by Wnt3a. Muscle Wnt3a initiates a Wnt signaling pathway in the muscle that leads to decreased Rapsyn levels. This is achieved through the β-catenin-mediated negative regulation of rapsyn gene expression, and decreased Rapsyn levels result in the destabilization and dispersal of AChR clusters. In addition, Wnt3a, via β-catenin, also triggers an unknown retrograde signal that affects presynaptic function and/or assembly.
Figure 4.
Figure 4.
Evi-mediated synaptic release of Drosophila Wg and regulation of ACR-16 receptor abundance in postsynaptic muscle membranes by CWN-2 in C. elegans. (A) Schematic representation of Evi-mediated Wg release at Drosophila larval NMJs. Wg carried by Evi-exosomes is sorted into multivesicular bodies in synaptic terminals that fuse with the synaptic membrane, releasing their content to the cisternae of underlying subsynaptic reticulum. Potential fates of postsynaptic exosomes are shown, such as fusion with the postsynaptic membrane and subsequent endocytosis. The endocytosed DFz2/Wg/Evi-containing vesicles can be either sorted and targeted to lysosomes or, via DFz2 binding to Grip, transported near the muscle nucleus (also see Fig. 1E). (B) In C. elegans, motor neurons release CWN-2, which binds to the heteromeric CAM-1/Lin-17 receptor and activates Dishevelled-1. Activated Dvl-1, in turn, leads to the mobilization and membrane delivery of subsynaptic ACR-16 receptor pools.
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References

    1. Anderson MJ, Cohen MW 1977. Nerve-induced and spontaneous redistribution of acetylcholine receptors on cultured muscle cells. J Physiol 268: 757–773 - PMC - PubMed
    1. Aoki K, Taketo MM 2007. Adenomatous polyposis coli (APC): A multi-functional tumor suppressor gene. J Cell Sci 120: 3327–3335 - PubMed
    1. Ataman B, Ashley J, Gorczyca D, Gorczyca M, Mathew D, Wichmann C, Sigrist SJ, Budnik V 2006. Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP. Proc Natl Acad Sci 103: 7841–7846 - PMC - PubMed
    1. Ataman B, Ashley J, Gorczyca M, Ramachandran P, Fouquet W, Sigrist SJ, Budnik V 2008. Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling. Neuron 57: 705–718 - PMC - PubMed
    1. Babu K, Hu Z, Chien SC, Garriga G, Kaplan JM 2011. The immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling. Neuron 71: 103–116 - PMC - PubMed

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