Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin

Henríquez, Juan Pablo; Webb, Andrew C.; Bence, Matthew; Bildsoe, Heidi; Sahores, Macarena; Hughes, Simon M.; Salinas, Patricia C.

doi:10.1073/pnas.0806300105

Cited by 116 publications

(150 citation statements)

References 47 publications

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“…In one study, Wnt3a was shown to inhibit agrin-induced AChR clustering by suppressing rapsyn expression via b-catenin-dependent signaling . By contrast, the other study showed that Wnt3 induces AChR microclusters and promotes agrin-induced clustering, with the latter effect apparently mediated by a noncanonical pathway that requires Rac1 (Henriquez et al, 2008). Moreover Wnt signaling could increase Musk expression (Kim et al, 2003).…”

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confidence: 83%

To build a synapse: signaling pathways in neuromuscular junction assembly

2010

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SummarySynapses, as fundamental units of the neural circuitry, enable complex behaviors. The neuromuscular junction (NMJ) is a synapse type that forms between motoneurons and skeletal muscle fibers and that exhibits a high degree of subcellular specialization. Aided by genetic techniques and suitable animal models, studies in the past decade have brought significant progress in identifying NMJ components and assembly mechanisms. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues, which shed light on synaptogenesis in the brain and contribute to a better understanding of muscular dystrophy. Key words: Neural development, Neuromuscular junction, Retrograde signaling, Synapse formation IntroductionThe brain contains billions of nerve cells, or neurons, which receive and integrate signals from the environment, and which govern the body's responses. Nervous system activity is made possible by synapses, contacts formed either between neurons or between a neuron and a target cell. Synapses are asymmetric structures in which neurotransmitter molecules are released from the presynaptic membrane and activate receptors on the postsynaptic membrane, thus establishing neuronal communication. As such, synapses are fundamental units of neural circuitry and enable complex behaviors. The neuromuscular junction (NMJ) is a type of synapse formed between motoneurons and skeletal muscle fibers. Large and easily accessed experimentally, this peripheral synapse has contributed greatly to the understanding of the general principles of synaptogenesis and to the development of potential therapeutic strategies for muscular disorders. The NMJ uses different neurotransmitters in different species; for example, acetylcholine (ACh) in vertebrates and glutamate in Drosophila, both of which are excitatory and cause muscle contraction. In Caenorhabditis elegans, there are two types of NMJs: at excitatory NMJs, ACh causes muscle contraction, whereas inhibitory NMJs release g-aminobutyric acid (GABA) to cause muscle relaxation. Motor nerve terminals differentiate to form presynaptic active zones, where synaptic vesicles dock and release neurotransmitters. On the apposed postsynaptic membranes, neurotransmitter receptors are packed at high densities. Aided by genetic techniques and by the use of suitable animal models, including rodents, zebrafish, Drosophila and C. elegans, studies in the past decade have brought significant progress, not only in identifying components present in pre-and postsynaptic membranes, but also in understanding the mechanisms that underpin NMJ assembly. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues from motor nerves and muscle fibers. Readers are referred to other outstanding reviews for a broad view of NMJ development (see Froehner, 1993;Hall and Sanes, 1993;Kummer et al., 2006;Salpeter and Loring, 1985;Schaeffer et al., 2001). NMJ formati...

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confidence: 83%

To build a synapse: signaling pathways in neuromuscular junction assembly

2010

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“…Recently, WNT4 has been implicated in muscle pre-patterning and to stimulate AChR clustering via activation of MuSK (Strochlic et al, 2012). In addition, agrin-induced AChR clustering was enhanced by WNT3, but reduced by WNT3a (Henriquez et al, 2008;.…”

Section: Wnt Signaling or Cadherin Signaling In Nmj Formationmentioning

confidence: 94%

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

Barik

et al. 2012

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“…Wnt7a also promotes postsynaptic development of excitatory neurons in the hippocampus (Ciani et al, 2011). At the mammalian neuromuscular junction, Wnt activates postsynaptic clustering of acetylcholine receptors and can be provided by either the innervating motor neuron (Henriquez et al, 2008) or by nearby non-neuronal tissues (Jing et al, 2009). In these instances, the Wnt signal is transduced by non-canonical pathways that act locally and apparently do not require transcription (Cerpa et al, 2008;Miech et al, 2008;Purro et al, 2008;Sahores et al, 2010;Budnik and Salinas, 2011).…”

Section: Wnt Signaling Regulates Synaptic Choicementioning

confidence: 99%

UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit

et al. 2012

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SUMMARYCoordinated movement depends on the creation of synapses between specific neurons in the motor circuit. In C. elegans, this important decision is regulated by the UNC-4 homeodomain protein. unc-4 mutants are unable to execute backward locomotion because VA motor neurons are mis-wired with inputs normally reserved for their VB sisters. We have proposed that UNC-4 functions in VAs to block expression of VB genes. This model is substantiated by the finding that ectopic expression of the VB gene ceh-12 (encoding a homolog of the homeodomain protein HB9) in unc-4 mutants results in the mis-wiring of posterior VA motor neurons with VB-like connections. Here, we show that VA expression of CEH-12 depends on a nearby source of the Wnt protein EGL-20. Our results indicate that UNC-4 prevents VAs from responding to a local EGL-20 cue by disabling a canonical Wnt signaling cascade involving the Frizzled receptors MIG-1 and MOM-5. CEH-12 expression in VA motor neurons is also opposed by a separate pathway that includes the Wnt ligand LIN-44. This work has revealed a transcriptional mechanism for modulating the sensitivity of specific neurons to diffusible Wnt ligands and thereby defines distinct patterns of synaptic connectivity. The existence of comparable Wnt gradients in the vertebrate spinal cord could reflect similar roles for Wnt signaling in vertebrate motor circuit assembly.

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Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin

Cited by 116 publications

References 47 publications

To build a synapse: signaling pathways in neuromuscular junction assembly

To build a synapse: signaling pathways in neuromuscular junction assembly

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

UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit

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