Wnt Signaling in Neuromuscular Junction Development

Koles, Kate; Budnik, Vivian

doi:10.1101/cshperspect.a008045

Cited by 94 publications

(108 citation statements)

References 139 publications

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“…Autoantibodies to this first Ig-like domain disrupt binding between Lrp4 and MuSK and cause autoimmune MuSK myasthenia gravis (Huijbers et al 2013;Koneczny et al 2013). Because Fz receptors bind Wnts, the presence of a Fz-like domain in MuSK raised the possibility that Wnts may bind to the MuSK Fz-like domain and function as alternative ligands for MuSK (Koles and Budnik 2012). Several findings are consistent with the idea that Wnts promote one or more steps in synapse formation.…”

supporting

confidence: 66%

“…As such, the first Ig-like domain plays an essential role in stimulation of MuSK by Agrin, which is crucial for synapse formation. The presence of a Fz-like domain in MuSK led to speculation that Wnts may bind to MuSK and regulate MuSK activity at one or more stages during synapse formation (Masiakowski and Yancopoulos 1998; Xu and Nusse 1998; Koles and Budnik 2012;Barik et al 2014). Consistent with this idea, the MuSK Fz-like domain as well as Wnt4 and Wnt11r play important roles in muscle prepatterning in zebrafish (Jing et al 2009).…”

Section: Discussionmentioning

confidence: 52%

“…Third, prepatterning of AChRs in zebrafish is dependent on the MuSK Fz-like domain as well as two Wnts, Wnt11r and Wnt4a, which are expressed by muscle (Jing et al 2009;Gordon et al 2012). Fourth, the development of neuromuscular synapses in Drosophila requires Wnt/Fz signaling and Neto (neuropilin and tolloid-like), an auxiliary subunit of glutamate receptors (Koles and Budnik 2012;Kim and Serpe 2013).…”

mentioning

confidence: 99%

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Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution

et al. 2016

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Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice.

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supporting

confidence: 66%

Section: Discussionmentioning

confidence: 52%

mentioning

confidence: 99%

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Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution

et al. 2016

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“…There are several divergent pathways that can be activated downstream of Wnt ligands, including a canonical pathway that results in nuclear import of b-catenin and transcriptional regulation. The role of these various pathways at neuromuscular junctions has been thoroughly reviewed elsewhere (Koles and Budnik 2012b). At the fly NMJ, Wnt signaling is bidirectional and activates different downstream cascades in the pre-and postsynaptic cells.…”

Section: Mechanisms Regulating Growth and Plasticitymentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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“…These results indicate that the two proteins are in close proximity to each other and are likely forming a complex in this region. Another synaptic protein we tested for Pak complex binding was Wingless (Wg), the Drosophila Wnt ligand, which plays numerous roles at the NMJ 22 . In wild-type, Wg is enriched at the presynaptic and postsynaptic sides of type I boutons, but is also present as puncta throughout the muscle cytoplasm (Figure 4C') …”

confidence: 99%

Detection of <em>In Situ</em> Protein-protein Complexes at the <em>Drosophila</em> Larval Neuromuscular Junction Using Proximity Ligation Assay

Wang¹,

Yoo²,

Kim³

et al. 2015

JoVE

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Discs large (Dlg) is a conserved member of the membrane-associated guanylate kinase family, and serves as a major scaffolding protein at the larval neuromuscular junction (NMJ) in Drosophila. Previous studies have shown that the postsynaptic distribution of Dlg at the larval NMJ overlaps with that of Hu-li tai shao (Hts), a homologue to the mammalian adducins. In addition, Dlg and Hts are observed to form a complex with each other based on co-immunoprecipitation experiments involving whole adult fly lysates. Due to the nature of these experiments, however, it was unknown whether this complex exists specifically at the NMJ during larval development.Proximity Ligation Assay (PLA) is a recently developed technique used mostly in cell and tissue culture that can detect protein-protein interactions in situ. In this assay, samples are incubated with primary antibodies against the two proteins of interest using standard immunohistochemical procedures. The primary antibodies are then detected with a specially designed pair of oligonucleotide-conjugated secondary antibodies, termed PLA probes, which can be used to generate a signal only when the two probes have bound in close proximity to each other. Thus, proteins that are in a complex can be visualized. Here, it is demonstrated how PLA can be used to detect in situ protein-protein interactions at the Drosophila larval NMJ. The technique is performed on larval body wall muscle preparations to show that a complex between Dlg and Hts does indeed exist at the postsynaptic region of NMJs. Video LinkThe video component of this article can be found at

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Wnt Signaling in Neuromuscular Junction Development

Cited by 94 publications

References 139 publications

Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution

Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution

Transmission, Development, and Plasticity of Synapses

Detection of <em>In Situ</em> Protein-protein Complexes at the <em>Drosophila</em> Larval Neuromuscular Junction Using Proximity Ligation Assay

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