Synaptic differentiation: the role of agrin in the formation and maintenance of the neuromuscular junction

Denzer, Alain J.; Hauser, D. M.; Gesemann, Matthias; Rüegg, Markus A.

doi:10.1007/s004410050941

Cited by 21 publications

(10 citation statements)

References 107 publications

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“…Particularly interesting is the reduced laminin-binding capability of miniagrin after MMP-12 processing. Denzer and coworkers have shown that the NtA domain alters the size of induced AChR clusters but not the overall extent of the induction [33]. AChR aggregates induced by full-length agrin are more than twofold smaller than those induced by a fragment without the NtA domain (equivalent to cleavage products A–C).…”

Section: Discussionmentioning

confidence: 99%

Site Specific Cleavage Mediated by MMPs Regulates Function of Agrin

et al. 2012

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BackgroundAgrin is the key inducer of postsynaptic differentiations at the neuromuscular junction. The multidomain heparan sulfate proteoglycan is mediating via its N-terminal segment the interaction with laminin, whereas the C-terminal portion is responsible for Dystroglycan binding and clustering of the Acetylcholine receptor. Matrix metalloproteinases (MMP) are known to play essential roles in matrix remodeling, degradation and regulation of extracellular signaling networks.Principal FindingsSite-specific processing of Agrin provides key insight into regulatory effects of Matrix metalloproteinases (MMPs). Here, we present a detailed study of agrin processing by different MMPs together with a molecular understanding of binding and cleavage at both terminal fragments. The data suggest for a regulatory effect of MMP cleavage at particularly important functional sites of agrin. Cleave of agrin abolishes the agrin-laminin complex formation and the Acetylcholine receptor clustering at the neuromuscular junction.Conclusion/SignificanceAgrin is a target of specific MMP processing resulting in agrin subfragments with different regulatory activities. MMP processing is a powerful tool to regulate extracellular signaling networks.

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Section: Discussionmentioning

confidence: 99%

Site Specific Cleavage Mediated by MMPs Regulates Function of Agrin

et al. 2012

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“…Reduction with dithiothreitol (DTT) showed that the observed mass corresponds to the calculated mass of C6, however, no precise measurement for fragment C5 could be obtained, which is attributable to incomplete cleavage by CNBr that resulted in a fragment of C3‐C4‐C5. Heterogeneous N ‐glycosylation on C3 might explain the lack of a well‐defined mass spectrum of the C3‐C4‐C5 fragment 6, 7. However, cleavage of NtA‐FS by CNBr followed by reduction demonstrates that C5 is linked via disulfide bridges to C6.…”

Section: Resultsmentioning

confidence: 99%

“…Remarkably, NtA is a target of alternative mRNA splicing that causes an insert of seven amino acid residues 4, 5. The NtA domain is followed by nine repeats of follistatin‐like (FS) domains 6, 7. Mapping of the laminin‐binding site of NtA revealed that two amino acid residues are critical for binding 8.…”

Section: Introductionmentioning

confidence: 99%

An interdomain disulfide bridge links the NtA and first FS domain in agrin

McFarlane

Stetefeld

2009

Protein Science

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Agrin is a multidomain heparan sulfate proteoglycan involved in postsynaptic differentiation at the neuromuscular junction. Binding of agrin to synaptic basal lamina is mediated by the N-terminal agrin (NtA) domain. The NtA domain of agrin is followed by a tandem of nine follistatin-like (FS) domains forming a rod-like spacer to the laminin G-like domains of the molecule. Here we report that the most C-terminal cysteine residue of NtA (Cys123) forms an interdomain disulfide bond with the FOLN subdomain of the FS module. Remarkably, this single cysteine is flanked by Leu117 and Val124, which are two essential b-branched amino acids forming the heterocomplex of NtA with the c1 chain of laminin. Moreover, we show that this covalent linkage compensates for the seven amino acid residue splice insert at the very C-terminal helix H3 and causes a rigid interface between NtA and FS independent of the alternative mRNA splice event. These results suggest that the interdomain disulfide bond between the NtA and the first FS domain might be important for the proper folding of agrin.

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“…Hence, it is important to note that a lot of evidence in recent years suggested that multiple cellular interactions between the pre‐ and postsyanptic elements, involving some local controls (via agrin, neuregulin, etc. ), are necessary for synaptic reformation of the regenerating SCs, axons, and AChR sites in NMJs ( Kleiman and Reichardt, 1996 ; Denzer et al, 1997 ; Burden, 1998 ) . This study does not address the possibility that the observed changes may provide direct and distinct proof for the synaptic interactions.…”

Section: Discussionmentioning

confidence: 99%

The spatiotemporal characterization of endplate reoccupation, with special reference to the superposition patterns of the presynaptic elements and the postsynaptic receptor regions during muscle reinnervation

Wang

Kawabuchi

Zhou

et al. 2004

J Peripheral Nervous Sys

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In this study, an immunohistochemical investigation was carried out to define spatiotemporal characteristics of superposition patterns of the presynaptic elements and the postsynaptic acetylcholine receptor (AChR) sites during the period of endplate regeneration after sciatic nerve crush. The extent of close correspondence of terminal Schwann cell (TSC)-, or axon terminal-, apposing AChR sites was quantitated with three-dimensional images of neuromuscular junctions (NMJs) taken under confocal laser-scanning microscopy. After 3-weeks post-crush (wpc), reoccupation of regenerating TSCs and later arriving axon terminals proceeded within the scope of previously denervated AChR plaques. During this period, the areas of presynaptic elements and the areas of postsynaptic elements were highly correlated. TSCs rapidly reoccupied a greater part of the postsynaptic receptors. In contrast, there was a slower increase of the contact areas of AChR sites overlapped by the axon terminals. Reoccupation by the presynaptic elements at 20 wpc was almost completed in a majority of NMJs, but some anomalous changes still continued to occur in a small proportion of the NMJs (20-30%). Our results suggest that: (a) with gradual increase of the contact areas between presynaptic and postsynaptic elements, imperfect reinnervation and regeneration, due to spatial mismatching or unbalanced growth between presynaptic and postsynaptic elements, result in sporadic remodeling; (b) the difference in superposition patterns between TSCs and axon terminals depends on the ability of making alignment to the endplate gutters in regenerating NMJs; and (c) a complex set of anatomical relationships among the three endplate components affects the process of endplate reoccupation synthetically.

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Synaptic differentiation: the role of agrin in the formation and maintenance of the neuromuscular junction

Cited by 21 publications

References 107 publications

Site Specific Cleavage Mediated by MMPs Regulates Function of Agrin

Site Specific Cleavage Mediated by MMPs Regulates Function of Agrin

An interdomain disulfide bridge links the NtA and first FS domain in agrin

The spatiotemporal characterization of endplate reoccupation, with special reference to the superposition patterns of the presynaptic elements and the postsynaptic receptor regions during muscle reinnervation

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