Neuregulin-1 potentiates agrin-induced acetylcholine receptor clustering through muscle-specific kinase phosphorylation.
At neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signalling through the muscle-specific kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act through muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signalling can modulate n-agrin-induced AChR clustering independently of its effects on transcription. Here we report that neuregulin-1 increased the size of developing AChR clusters when injected into muscles of embryonic mice. We investigated this phenomenon using cultured myotubes, and found that in the ongoing presence of n-agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. This potentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence might function as a second-order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signalling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.
School of Biomedical Sciences, University of Queensland, St. Lucia, 4072, Queensland,  Australia.
Shyuan T
ST
Ngo
Rebecca N
RN
Cole
Nana
N
Sunn
William D
WD
Phillips
Peter G
PG
Noakes
D018171:Agrin / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D020890:Neuregulin-1 / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*
D018171:Agrin; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011950:Receptors, Cholinergic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases