Agrin and acetylcholine receptors are removed from abandoned synaptic sites at reinnervated frog neuromuscular junctions

Stanco, Anne M.; Werle, M. J.

doi:10.1002/(sici)1097-4695(199712)33:7<999::aid-neu10>3.0.co;2-#

Cited by 11 publications

(4 citation statements)

References 37 publications

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“…A quick removal of agrin from the synaptic basal lamina occurs after synaptic retraction at frog neuromuscular junctions (Werle and Sojka, 1996). After permanent denervation in the frog, agrin will persist for months in abandoned gutters, where the nerve has degenerated and left the synaptic basal lamina exposed (Reist et al, 1987;Stanco and Werle, 1997). Our current results are consistent with these observations.…”

Section: Discussionsupporting

confidence: 89%

Activation of matrix metalloproteinase‐3 is altered at the frog neuromuscular junction following changes in synaptic activity

VanSaun

Humburg

Arnett

et al. 2007

Developmental Neurobiology

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The extracellular matrix surrounding the neuromuscular junction is a highly specialized and dynamic structure. Matrix Metalloproteinases are enzymes that sculpt the extracellular matrix. Since synaptic activity is critical to the structure and function of this synapse, we investigated whether changes in synaptic activity levels could alter the activity of Matrix Metalloproteinases at the neuromuscular junction. In particular, we focused on Matrix Metalloproteinase 3 (MMP3), since antibodies to MMP3 recognize molecules at the frog neuromuscular junction, and MMP3 cleaves a number of synaptic basal lamina molecules, including agrin. Here we show that the fluorogenic compound (M2300) can be used to perform in vivo proteolytic imaging of the frog neuromuscular junction to directly measure the activity state of MMP3. Application of this compound reveals that active MMP3 is concentrated at the normal frog neuromuscular junction, and is tightly associated with the terminal Schwann cell. Blocking presynaptic activity via denervation, or TTX nerve blockade, results in a decreased level of active MMP3 at the neuromuscular junction. The loss of active MMP3 at the neuromuscular junction in denervated muscles can result from decreased activation of pro-MMP3, or it could result from increased inhibition of MMP3. These results support the hypothesis that changes in synaptic activity can alter the level of active MMP3 at the neuromuscular junction.

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Section: Discussionsupporting

confidence: 89%

Activation of matrix metalloproteinase‐3 is altered at the frog neuromuscular junction following changes in synaptic activity

VanSaun

Humburg

Arnett

et al. 2007

Developmental Neurobiology

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“…At normal neuromuscular junctions the AChR-rich postsynaptic membrane is precisely aligned with AChE in the adjacent basal lamina (Rossi and Rotundo, 1993; Peng et al, 1999; Legay, 2000; Rotundo, 2003). However, AChE can persist in the basal lamina long after the disappearance of pre- and post- synaptic specializations (Marshall et al, 1977; Burden et al, 1979; Stanco and Werle, 1997). Figure 3 shows that AChE and AChR were tightly co-aligned in wild type synapses.…”

Section: Resultsmentioning

confidence: 99%

Biglycan Is an Extracellular MuSK Binding Protein Important for Synapse Stability

Amenta¹,

Creely²,

Mercado³

et al. 2012

J. Neurosci.

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The receptor tyrosine kinase MuSK is indispensable for nerve-muscle synapse formation and maintenance. MuSK is necessary for pre-patterning of the endplate zone anlage and as a signaling receptor for agrin-mediated postsynaptic differentiation. MuSK-associated proteins such as Dok7, LRP4, and Wnt11r are involved in these early events in neuromuscular junction formation. However, the mechanisms regulating synapse stability are poorly understood. Here we examine a novel role for the extracellular matrix protein biglycan in synapse stability. Synaptic development in fetal and early postnatal biglycan null (bgn-/o) muscle is indistinguishable from wild type controls. However, by 5 wks after birth nerve-muscle synapses in bgn-/o mice are abnormal as judged by the presence of perijunctional folds, increased segmentation and focal misalignment of acetylcholinesterase and AChRs. These observations indicate that previously occupied pre- and post- synaptic territory has been vacated. Biglycan binds MuSK and the levels of this receptor tyrosine kinase are selectively reduced at bgn-/o synapses. In bgn-/o myotubes, the initial stages of agrin-induced MuSK phosphorylation and AChR clustering are normal, but the AChR clusters are unstable. This stability defect can be substantially rescued by the addition of purified biglycan. Together, these results indicate that biglycan is an extracellular ligand for MuSK that is important for synapse stability.

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“…They are most commonly found at the very tips of the nerve terminal. Staining with antibodies to agrin revealed a lack of agrin staining at these abandoned sites 5,6 . Further, AChRs were absent at the abandoned synaptic sites.…”

mentioning

confidence: 93%

“…Staining with antibodies to agrin revealed a lack of agrin staining at these abandoned sites. 5,6 Further, AChRs were absent at the abandoned synaptic sites. This was of interest because of the fact that following denervation, agrin will stay bound to the synaptic basal lamina for months.…”

mentioning

confidence: 94%

Cell‐to‐Cell Signaling at the Neuromuscular Junction

Werle

2008

Annals of the New York Academy of Sciences

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The extracellular matrix at the neuromuscular junction plays many roles. The matrix plays a structural role in that it maintains the spatial relationship between the muscle cell, Schwann cell, and presynaptic motor neuron. The matrix also plays a role in cell-to-cell signaling. The most studied member of this group is the heparan sulfate proteoglycan, agrin. Agrin is an integral member of the synaptic matrix, and it plays the pivotal role of instructing the muscle cell to aggregate acetylcholine receptors (AChRs) to the synapse. Agrin is released by the motor neuron, where it binds stably to the extracellular matrix. Agrin interacts with the muscle-specific tyrosine kinase (MuSK). Mice that lack agrin, or MuSK, fail to form neuromuscular junctions. Thus, the extracellular matrix is critical to both the structure and function of the neuromuscular junction. Remodeling of the extracellular matrix at the neuromuscular junction is needed to maintain stability, to allow growth, or to destabilize and remove synapses. Matrix metalloproteinases are key regulators of the extracellular matrix. In particular, matrix metalloproteinase 3 (MMP3) has been implicated in regulation of synaptic structure. MMP3 cleaves agrin. Antibodies to MMP3 recognize molecules concentrated at the synapses of frog neuromuscular junctions. Neuromuscular junctions in MMP3 null mutant mice have increased junctional folds, and AChR aggregates. Changes in synaptic activity will alter the activity of MMP3 at the synapse. Thus, the extracellular matrix is critical to the formation of the synapse, and synaptic activity controls the structure and function of the molecules in the extracellular matrix.

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Agrin and acetylcholine receptors are removed from abandoned synaptic sites at reinnervated frog neuromuscular junctions

Cited by 11 publications

References 37 publications

Activation of matrix metalloproteinase‐3 is altered at the frog neuromuscular junction following changes in synaptic activity

Activation of matrix metalloproteinase‐3 is altered at the frog neuromuscular junction following changes in synaptic activity

Biglycan Is an Extracellular MuSK Binding Protein Important for Synapse Stability

Cell‐to‐Cell Signaling at the Neuromuscular Junction

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