Molecular regulation of postsynaptic differentiation at the neuromuscular junction

The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Unlike extensively investigated postsynaptic differentiation, less is known about mechanisms of presynaptic assembly. Genetic evidence of Wnt in mammalian NMJ development was missing due to the existence of multiple Wnts and their receptors. We show when Wnt secretion is abolished from motoneurons by mutating the Wnt ligand secretion mediator (Wls) gene, mutant mice showed muscle weakness and neurotransmission impairment. NMJs were unstable with reduced synaptic junctional folds and fragmented AChR clusters. Nerve terminals were swollen; synaptic vesicles were fewer and mislocated. The presynaptic deficits occurred earlier than postsynaptic deficits. Intriguingly, these phenotypes were not observed when deleting Wls in muscles or Schwann cells. We identified Wnt7A and Wnt7B as major Wnts for nerve terminal development in rescue experiments. These observations demonstrate a necessary role of motoneuron Wnts in NMJ development, in particular presynaptic differentiation.

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21-P028 ColQ, a specific collagen controls postsynaptic differentiation at the neuromuscular junction

Mechanisms of Development ◽

10.1016/j.mod.2009.06.893 ◽

2009 ◽

Vol 126 ◽

pp. S321

Author(s):

Severine Sigoillot ◽

Francine Bourgeois ◽

Monique Lambergeon ◽

Laure Strochlic ◽

Claire Legay

Keyword(s):

Neuromuscular Junction ◽

Postsynaptic Differentiation

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MuSK Kinase Activity is Modulated By A Serine Phosphorylation Site in The Kinase Loop

Scientific Reports ◽

10.1038/srep33583 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 5

Author(s):

B. Z. Camurdanoglu ◽

C. Hrovat ◽

G. Dürnberger ◽

M. Madalinski ◽

K. Mechtler ◽

...

Keyword(s):

Neuromuscular Junction ◽

Cluster Size ◽

Kinase Activity ◽

Phosphorylation Site ◽

Serine Phosphorylation ◽

Activation Loop ◽

Achr Cluster ◽

Kinase Activation ◽

Muscle Specific Kinase ◽

Postsynaptic Differentiation

Abstract The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). MuSK activation, kinase activity and subsequent downstream signalling are crucial for NMJ formation as well as maintenance. Therefore MuSK kinase activity is tightly regulated to ensure proper NMJ development. We have identified a novel serine phosphorylation site at position 751 in MuSK that is increasingly phosphorylated upon agrin stimulation. S751 is also phosphorylated in muscle tissue and its phosphorylation depends on MuSK kinase activity. A phosphomimetic mutant of S751 increases MuSK kinase activity in response to non-saturating agrin concentrations . In addition, basal MuSK and AChR phosphorylation as well as AChR cluster size are increased. We believe that the phosphorylation of S751 provides a novel mechanism to relief the autoinhibition of the MuSK activation loop. Such a lower autoinhibition could foster or stabilize MuSK kinase activation, especially during stages when no or low level of agrin are present. Phosphorylation of S751 might therefore represent a novel mechanism to modulate MuSK kinase activity during prepatterning or NMJ maintenance.

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