Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1.
An important aspect of synapse development is the clustering of neurotransmitter receptors in the postsynaptic membrane. Although MuSK is required for acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ), the underlying molecular mechanisms remain unclear. We report here that in muscle cells, MuSK interacts with Dishevelled (Dvl), a signaling molecule important for planar cell polarity. Disruption of the MuSK-Dvl interaction inhibits Agrin- and neuron-induced AChR clustering. Expression of dominant-negative Dvl1 in postsynaptic muscle cells reduces the amplitude of spontaneous synaptic currents at the NMJ. Moreover, Dvl1 interacts with downstream kinase PAK1. Agrin activates PAK, and this activation requires Dvl. Inhibition of PAK1 activity attenuates AChR clustering. These results demonstrate important roles of Dvl and PAK in Agrin/MuSK-induced AChR clustering and reveal a novel function of Dvl in synapse development.
Luo
Zhen G
ZG
Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, 1530 Third Avenue South, Birmingham, AL 35294, USA.
Wang
Qiang
Q
Zhou
Jian Z
JZ
Wang
Jianbo
J
Luo
Zhijun
Z
Liu
Mingyao
M
He
Xi
X
Wynshaw-Boris
Anthony
A
Xiong
Wen C
WC
Lu
Bai
B
Mei
Lin
L
D048868:Adaptor Proteins, Signal Transducing; D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000870:Anterior Horn Cells / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D000072261:Dishevelled Proteins; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D009865:Oocytes; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D029867:Xenopus Proteins; D014982:Xenopus laevis; D054462:p21-Activated Kinases
D048868:Adaptor Proteins, Signal Transducing; D018171:Agrin; C000606586:DVL1 protein, Xenopus; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D046911:Macromolecular Substances; D010750:Phosphoproteins; D011950:Receptors, Cholinergic; D029867:Xenopus Proteins; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases