Crosstalk between <scp>Agrin</scp> and <scp>Wnt</scp> signaling pathways in development of vertebrate neuromuscular junction

Barik, Arnab; Zhang, Bin; Sohal, G.S.; Xiong, Wen Cheng; Mei, Lin

doi:10.1002/dneu.22190

Cited by 61 publications

(61 citation statements)

References 81 publications

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“…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: 49%

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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Section: Discussionmentioning

confidence: 49%

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

et al. 2016

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“…Their function during the formation of the NMJ has been best described in invertebrates (Drosophila melanogaster and Caenorhabditis elegans), and involvement of Wnt signaling at the vertebrate NMJ has also been revealed (reviewed in Refs. 24,232). Wnts in mammals signal through 11 different Frizzled (Fzd) receptors to regulate, via at least five different transduction pathways involving Dishevelled (Dvl), various cellular processes (FIGURE 3C).…”

Section: Wntsmentioning

confidence: 99%

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

Tintignac

Brenner

Rüegg

2015

Physiological Reviews

314

341

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The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia.

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“…However, this does not preclude the compensatory secretion of Wnts by other cells. Moreover, several groups have shown that, in addition to Wnt4 and Wnt11, other Wnt proteins are able to stimulate AChR clustering in the absence (Wnt9a, 9b, 10b and 16) or presence (Wnt3) of exogenous neuronal agrin in vitro (Barik et al, 2014;Henriquez et al, 2008), suggesting that NMJ formation is likely to require the coordinated function of multiple pro-synaptogenic Wnts and that Wnt functional redundancy and/or compensatory mechanisms that are dependent on the genetic background might also in part explain why single or double Wnt deletion in mice can induce distinct NMJ phenotypes. GOF, gain of function; Sfrp4 and Dkk1 refer to direct injections of protein.…”

Section: Coordinated Roles Of Wnt4 and Wnt11 In Achr Clusteringmentioning

confidence: 99%

“…Among the 19 Wnts currently identified in mammals, Wnt2, 3a, 4, 6, 7b, 9a and 11 directly interact with MuSK but only Wnt4, 9a and 11 enhance AChR clustering in muscle cells (Barik et al, 2014;Strochlic et al, 2012;Zhang et al, 2012). In zebrafish, both Wnt4a and Wnt11r initiate muscle prepatterning, probably by stimulating PCP-dependent MuSK endocytosis in muscle cells (Gordon et al, 2012;Jing et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Wnts contribute to neuromuscular junction formation through distinct signaling pathways

et al. 2017

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Understanding the developmental steps that shape formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers is crucial. Wnt morphogens are key players in the formation of this specialized peripheral synapse, but their individual and collaborative functions and downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain-of-function studies in cell culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. By contrast, loss of Wnt11 or Wnt-dependent signaling in vivo decreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR mRNA levels and AChR clustering downstream of activation of the β-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the planar cell polarity (PCP) pathway, which accumulates at embryonic NMJs. Moreover, mice bearing a Vangl2 loss-of-function mutation (loop-tail) exhibit fewer AChR clusters and overgrowth of motor axons bypassing AChR clusters. Together, our results provide genetic and biochemical evidence that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways.

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Crosstalk between Agrin and Wnt signaling pathways in development of vertebrate neuromuscular junction

Cited by 61 publications

References 81 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

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

Wnts contribute to neuromuscular junction formation through distinct signaling pathways

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