β-Catenin gain of function in muscles impairs neuromuscular junction formation

Wu, Haitao; Lu, Yanfeng; Barik, Arnab; Joseph, Aviva; Taketo, Makoto Mark; Xiong, Wen Cheng; Mei, Lin

doi:10.1242/dev.080705

Cited by 46 publications

(49 citation statements)

References 97 publications

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“…In contrast, R −/− ;HSA-R C366A mice died soon after birth with cyanosis, a sign of inability to breathe, suggesting that the C366A mutant is unable to rescue. We examined the NMJ morphology in the diaphragm by staining with Alexa Fluor 594-conjugated α-bungarotoxin (BTX) to label AChR and with anti-synaptophysin/neurofilament antibodies to label axons and nerve terminals (Li et al, 2008; Luo et al, 2008; Wu et al, 2012a, 2012b, 2015). In WT mice, AChR clusters were located in the central region, surrounding primary phrenic nerve branches (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Cao

et al. 2016

Neuron

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SUMMARY Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.

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Section: Resultsmentioning

confidence: 99%

“…Electron microscopic studies were carried out as described previously (Wu et al, 2012a). Further details are described in the Supplemental Experimental Procedures.…”

Section: Methodsmentioning

confidence: 99%

Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Cao

et al. 2016

Neuron

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“…Electron microscopic studies were carried as described previously (Wu 2012, in press). Briefly, entire diaphragms (P0 and P15) were isolated and fixed in 2% glutaraldehyde and 2% paraformaldehyde in 0.1 M phosphate buffer for 1 hr at 25°C and 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

Shen

et al. 2012

Neuron

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SUMMARY Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act incis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, and axon terminal development. LRP4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of co-cultured neurons, suggesting a synaptogenic function. Analysis of LRP4 muscle and motoneuron double mutants and mechanistic studies suggest that NMJ formation may also be regulated by LRP4 in motoneurons, which could serve as agrin’s receptor in trans to induce AChR clusters. These observations uncovered distinct roles of LRP4 in motoneurons and muscles in NMJ development.

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“…Whether Dvl and Apc are critical for NMJ formation in mice remains unknown. However, AChR clusters do form in mice whose b-catenin levels are increased or diminished (despite reduced density and larger in size, see below) (Li et al, 2008;Liu et al, 2012;Wu et al, 2012). Interacting with MuSK and Pak1 at the same time, Dvl is thought to serve as an adapter protein for Agrin signaling (Luo et al, 2002).…”

Section: Potential Functions Of Wnt Signaling Proteinsmentioning

confidence: 99%

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

Barik

Zhang

Sohal

et al. 2014

Developmental Neurobiology

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Neuromuscular junction (NMJ) is a cholinergic synapse where motor neurons elicit muscle contraction. Agrin and its coreceptors LRP4 and MuSK are critical for vertebrate NMJ formation. This paper reviews recent evidence for Wnts and Wnt signaling molecules in NMJ formation including a possible retrograde mechanism by muscle β-catenin. We also present data that Wnt3a, 7a, 8a and 10b could inhibit agrin-mediated AChR clustering. Together with the stimulating effect of Wnt9a, 9b, 10b, 11 and 16 on AChR clustering in the absence of agrin, these results suggest diverse roles for Wnt ligands in NMJ development.

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β-Catenin gain of function in muscles impairs neuromuscular junction formation

Abstract: There was an error published in Development 139, 2392-2404.In Fig. 5F, two of the panels (bottom left and top right) were misplaced and therefore attributed to the wrong genotype. The correct Fig. 5F appears below.The authors apologise to readers for this mistake.

Cited by 46 publications

References 97 publications

Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Distinct Roles of Muscle and Motoneuron LRP4 in Neuromuscular Junction Formation

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

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