Neuritic deposition of agrin on culture substrate: implications for nerve-muscle synaptogenesis

Cohen, Maxime C.; Moody-Corbett, F; Godfrey, EW

doi:10.1523/jneurosci.14-05-03293.1994

Cited by 32 publications

(22 citation statements)

References 30 publications

(30 reference statements)

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“…The shape and size of AChR clusters, however, are similar in wild-type mice and in Musk mutant mice that express MCK-Musk. The mechanisms that regulate release and retention of agrin from motor axons are poorly understood (Cohen et al, 1994;Ma et al, 2000), but our results are consistent with the idea that agrin accumulates, or is more active, at or near the growth cone and that an ensuing bias in Musk activation leads to focal clustering of Musk and AChRs.…”

Section: Discussionsupporting

confidence: 88%

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: Discussionsupporting

confidence: 88%

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

Herbst

Avetisova²,

Burden³

2002

Development

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“…These findings are in keeping with the presence of otDG in Western blots of Xenopus muscle but not brain probed with mAb IIH6 and suggest that the muscle cells are the major source of otDG at neurite-muscle synapses. Further to this point, in these Xenopus cultures the neurites deposit agrin not only on the muscle cells they contact, but also on the culture substrate along their path of growth (Cohen et al, 1994). Although otDG was colocalized with agrin at sites of neurite-muscle contact, there was no hint of otDG immunofluorescence where the neurites deposited agrin on the culture substrate ( Fig.…”

Section: Adg Versus Agrin Distributionmentioning

confidence: 87%

Distribution of alpha-dystroglycan during embryonic nerve-muscle synaptogenesis.

Cohen

Jacobson

Godfrey

et al. 1995

The Journal of Cell Biology

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Abstract. The distribution of ot-dystroglycan (aDG) relative to acetylcholine receptors (ACHEs) and neural agrin was examined by immunofluorescent staining with mAb IIH6 in cultures of nerve and muscle cells derived from Xenopus embryos. In Western blots• probed with mAb IIH6, o~DG was evident in membrane extracts of Xenopus muscle but not brain, c~DG immunofluorescence was present at virtually all synaptic clusters of ACHEs and neural agrin. Even microclusters of ACHEs and agrin at synapses no older than 1-2 h (the earliest examined) had ctDG associated with them. c~DG was also colocalized at the submicrometer level with ACHES at nonsynaptic clusters that have little or no agrin. The number of large (>4 gin) nonsynaptic clusters of oLDG, like the number of large nonsynaptic clusters of ACHES, was much lower on innervated than on noninnervated cells. When mAb IIH6 was included in the culture medium, the large nonsynaptic clusters appeared fragmented and less compact, but the accumulation of agrin and ACHES along nerve-muscle contacts was not prevented. It is concluded that during nerve-muscle synaptogenesis, txDG undergoes the same nerve-induced changes in distribution as ACHES. We propose a diffusion trap model in which the otDG-transmembrane complex participates in the anchoring and recruitment of AChEs and txDG during the formation of synaptic as well as nonsynaptic AChR clusters.

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“…During synapse formation, agrin secreted by nerve terminals induces clustering of AChRs and several other postsynaptic elements on the muscle cell surface (refs. [2][3][4]; reviewed in ref. 5).…”

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confidence: 99%

Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

O'Toole

Deyst

Bowe

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Agrin is a basal lamina molecule that directs key events in postsynaptic differentiation, most notably the aggregation of acetylcholine receptors (AChRs) on the muscle cell surface. Agrin's AChR clustering activity is regulated by alternative mRNA splicing. Agrin splice forms having inserts at two sites (y and z) in the C-terminal region are highly active, but isoforms lacking these inserts are weakly active. The biochemical consequences of this alternative splicing are unknown. Here, the binding of four recombinant agrin isoforms to heparin, to a-dystroglycan (a component of an agrin receptor), and to myoblasts was tested. The presence of a four-amino acid insert at they site is necessary and sufficient to confer heparin binding ability to agrin. Moreover, the binding of agrin to a-dystroglycan is inhibited by heparin when this insert is present. Agrin binding to the cell surface showed analogous properties: heparin inhibits the binding of only those agrin isoforms containing this four-amino acid insert. The results show that alternative splicing of agrin regulates its binding to heparin and suggest that agrin's interaction with ca-dystroglycan may be modulated by cell surface glycosaminoglycans in an isoform-dependent manner.

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Neuritic deposition of agrin on culture substrate: implications for nerve-muscle synaptogenesis

Cited by 32 publications

References 30 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

Distribution of alpha-dystroglycan during embryonic nerve-muscle synaptogenesis.

Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

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