Agrin Acts via a MuSK Receptor Complex

Glass, David J.; Bowen, David C.; Stitt, Trevor N.; Radziejewski, Czeslaw; Bruno, Joanne; Ryan, Terence E.; Gies, David R.; Shah, Sonal; Mattsson, Karen; Burden, Steven J.; DiStefano, Peter S.; Valenzuela, David M.; DeChiara, Thomas M.; Yancopouloš, George D.

doi:10.1016/s0092-8674(00)81252-0

Cited by 628 publications

(589 citation statements)

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“…Presynaptic differentiation is also aberrant in agrin and Musk mutant mice, as motor axons fail to stop or differentiate and instead wander throughout the muscle. Taken together with experiments showing that Musk is activated by agrin, these results indicate that agrin stimulation of Musk leads to clustering of critical musclederived proteins, including AChRs, activation of synapsespecific gene expression and the induction and/or reorganization of a retrograde signal for presynaptic differentiation (DeChiara et al, 1996;Gautam et al, 1996;Glass et al, 1996). Domains in Musk that are important for Musk signaling have been defined by introducing wild-type or mutant forms of Musk into Musk mutant muscle cell lines (Herbst and Burden, 2000;Zhou et al, 1999).…”

Section: Introductionmentioning

confidence: 80%

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Herbst

Avetisova²,

Burden³

2002

Development

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Development 129, [5449][5450][5451][5452][5453][5454][5455][5456][5457][5458][5459][5460] On page 5454 of this article, the first paragraph in the section 'Motor axons extend…' should read 'Based on the expression of transgenes containing the MCK enhancer and promoter, the endogenous MCK gene is activated in skeletal muscle at ~E13.5 (S. Hauschka, personal communication), 1 day after motor axons first enter the muscle.'We apologise to the authors and readers for this mistake. ERRATUM INTRODUCTIONNeuromuscular synapses form following a series of complex interactions between motor neurons, muscle fibers and Schwann cells (Burden, 1998;Sanes and Lichtman, 1999;Schaeffer et al., 2001;Son and Thompson, 1995). Agrin, a 200 kDa protein synthesized by motor neurons, is a critical synaptic signaling molecule that organizes postsynaptic differentiation by stimulating Musk, a receptor tyrosine kinase (RTK) expressed selectively in skeletal muscle McMahan, 1990). Embryos lacking agrin or Musk fail to form neuromuscular synapses and consequently die at birth due to their failure to move or breathe (DeChiara et al., 1996;Gautam et al., 1996). Neurogenesis and myogenesis appear normal in agrin and Musk mutant embryos, but skeletal muscle-derived proteins, including acetylcholine receptors (AChRs), which are normally concentrated at synaptic sites, are instead expressed uniformly in muscle of Musk mutant mice. In addition, AChR genes, which are transcribed selectively in synaptic nuclei of wild-type mice, are expressed throughout the myofiber of Musk mutant mice. Presynaptic differentiation is also aberrant in agrin and Musk mutant mice, as motor axons fail to stop or differentiate and instead wander throughout the muscle. Taken together with experiments showing that Musk is activated by agrin, these results indicate that agrin stimulation of Musk leads to clustering of critical musclederived proteins, including AChRs, activation of synapsespecific gene expression and the induction and/or reorganization of a retrograde signal for presynaptic differentiation (DeChiara et al., 1996;Gautam et al., 1996;Glass et al., 1996). Domains in Musk that are important for Musk signaling have been defined by introducing wild-type or mutant forms of Musk into Musk mutant muscle cell lines (Herbst and Burden, 2000;Zhou et al., 1999). These studies have revealed an essential role for one of the two juxtamembrane tyrosine residues in Musk (Y553), as mutation of this tyrosine abrogates the ability of agrin to induce clustering or tyrosine phosphorylation of AChRs in cultured myotubes. This tyrosine appears to have a dual function in Musk signaling, as this tyrosine is required both to activate Musk kinase activity fully and to recruit a signaling component(s) that functions downstream from Musk (Herbst and Burden, 2000). Evidence for such a dual role is based upon analysis of Musk/TrkA chimeric receptors. Agrin stimulates tyrosine phosphorylation of a chimeric receptor composed of the extracellular and transmembrane regions of Musk, and the intrac...

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Section: Introductionmentioning

confidence: 80%

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Herbst

Avetisova²,

Burden³

2002

Development

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“…These studies implicated motor neuron-derived Agrin, a glycosylated proteoglycan, as the critical neural signal for inducing postsynaptic differentiation and the muscle-specific receptor tyrosine kinase, MuSK, a component of the Agrin receptor, as the transducer for clustering AChRs and activating AChR gene expression at synaptic sites (Burden, 1998;Glass et al, 1996a;Glass et al, 1996b;Glass and Yancopoulos, 1997;Sanes and Lichtman, 2001;Schaeffer et al, 2001;Valenzuela et al, 1995). This neuro-centric view of neuromuscular synapse formation, however, has been challenged by recent experiments, which showed that mammalian muscle is spatially patterned independent of innervation.…”

Section: Introductionmentioning

confidence: 99%

MuSK controls where motor axons grow and form synapses

2007

Self Cite

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SummaryIt had long been thought that motor axons approach muscles that are regionally unspecialized and induce postsynaptic differentiation by releasing signals that focally initiate transcriptional and post-translational responses in muscle. This neuro-centric view of synapse formation, however, has been challenged by recent experiments, which showed that AChR clusters are concentrated in the central region of muscle independent of innervation. This nerve-independent prepattern of AChR expression requires MuSK, a receptor tyrosine kinase that is critical for synapse formation. How muscle prepatterning is established and whether motor axons recognize this prepattern are not known. Here, we show that MuSK itself is prepatterned in muscle and that high, ectopic MuSK expression is sufficient to promote ectopic motor axon growth and synapse formation, indicating that the muscle prepattern is recognized by motor axons and promotes synapse formation in the central region of developing mammalian muscle. Further, we provide evidence that early expression of MuSK in developing myotubes is sufficient to re-establish muscle prepatterning independent of the MuSK promoter. Moreover, we show that ectopic MuSK expression stimulates synapse formation in the absence of Agrin and rescues the neonatal lethality of agrin mutant mice, demonstrating that MuSK, independent of Agrin, is sufficient to direct presynaptic and postsynaptic differentiation. In contrast to a neuro-centric view for synapse formation, these data demonstrate that the postsynaptic cell can play a dominant role in regulating synapse formation.

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“…For booster injections in 4 -8 wk intervals, the same amount of Nsk2Fc was dissolved in incomplete Freund's adjuvant. This antiserum is referred to as anti-MuSK / Nsk2 to indicate the homology of MuSK cloned from Torpedo, human, rat, and chicken (Jennings et al, 1993;Valenzuela et al, 1995;DeChiara et al, 1996;Glass et al, 1996) with Nsk2 cloned in mouse (Ganju et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

“…The AChR-aggregating function of agrin requires the synapsespecific receptor tyrosine kinase MuSK, which is tyrosinephosphorylated by agrin isoforms active in AChR aggregation (Valenzuela et al, 1995;DeChiara et al, 1996;Glass et al, 1996). Similarly, phosphorylation of the AChR ␤-subunit seems to be required for agrin-induced AChR aggregation (Wallace et al, 1991;Meier et al, 1995Meier et al, , 1996.…”

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confidence: 99%

Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

Meier¹,

et al. 1997

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Neural agrin, in the absence of a nerve terminal, can induce the activity-resistant expression of acetylcholine receptor (AChR) subunit genes and the clustering of synapse-specific adult-type AChR channels in nonsynaptic regions of adult skeletal muscle fibers. Here we show that, when expression plasmids for neural agrin are injected into the extrasynaptic region of innervated muscle fibers, the following components of the postsynaptic apparatus are aggregated and colocalized with ectopic agrininduced AChR clusters: laminin-␤2, MuSK, phosphotyrosinecontaining proteins, ␤-dystroglycan, utrophin, and rapsyn. These components have been implicated to play a role in the differentiation of neuromuscular junctions. Furthermore, ErbB2 and ErbB3, which are thought to be involved in the regulation of neurally induced AChR subunit gene expression, were colocalized with agrin-induced AChR aggregates at ectopic nerve-free sites. The postsynaptic muscle membrane also contained a high concentration of voltage-gated Na ϩ channels as well as deep, basal lamina-containing invaginations comparable to the secondary synaptic folds of normal endplates. The ability to induce AChR aggregation in vivo was not observed in experiments with a muscle-specific agrin isoform. Thus, a motor neuron-specific agrin isoform is sufficient to induce a full ectopic postsynaptic apparatus in muscle fibers kept electrically active at their original endplate sites.

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Agrin Acts via a MuSK Receptor Complex

Cited by 628 publications

References 44 publications

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

Restoration of synapse formation inMuskmutant mice expressing a Musk/Trk chimeric receptor

MuSK controls where motor axons grow and form synapses

Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

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