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PMID:15988013

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Citation

Varoqueaux, F, Sons, MS, Plomp, JJ and Brose, N (2005) Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol. Cell. Biol. 25:5973-84

Abstract

In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and gamma-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.

Links

PubMed PMC1168806 Online version:10.1128/MCB.25.14.5973-5984.2005

Keywords

Acetylcholine/metabolism; Animals; Diaphragm/abnormalities; Diaphragm/innervation; Electrophysiology; Intracellular Signaling Peptides and Proteins/deficiency; Intracellular Signaling Peptides and Proteins/genetics; Mice; Mice, Mutant Strains; Mutation; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/genetics; Neuromuscular Junction/abnormalities; Neuromuscular Junction/embryology; Neuromuscular Junction/ultrastructure; Neurotransmitter Agents/metabolism; Phrenic Nerve/abnormalities; Spinal Cord/abnormalities; Synaptic Vesicles/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:UN13A

located_in

GO:0031594: neuromuscular junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UN13A

acts_upstream_of_or_within

GO:0007528: neuromuscular junction development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1342278

P

Seeded From UniProt

complete

MOUSE:UN13A

acts_upstream_of_or_within

GO:0060384: innervation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1342278

P

Seeded From UniProt

complete

MOUSE:UN13B

located_in

GO:0031594: neuromuscular junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UN13B

acts_upstream_of_or_within

GO:0007528: neuromuscular junction development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3051532

P

Seeded From UniProt

complete

MOUSE:UN13B

acts_upstream_of_or_within

GO:0060384: innervation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3051532

P

Seeded From UniProt

complete


See also

References

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