Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms.
Emerging evidence suggests that the neurotransmitter acetylcholine (ACh) negatively regulates the development of the neuromuscular junction, but it is not clear if ACh exerts its effects exclusively through muscle ACh receptors (AChRs). Here, we used genetic methods to remove AChRs selectively from muscle. Similar to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs increased motor axon branching and expanded innervation territory, suggesting that ACh negatively regulates synaptic growth through postsynaptic AChRs. However, in contrast to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs in agrin-deficient mice failed to restore deficits in pre- and postsynaptic differentiation, suggesting that ACh negatively regulates synaptic differentiation through nonpostsynaptic receptors. Consistent with this idea, the ACh agonist carbachol inhibited presynaptic specialization of motorneurons in vitro. Together, these data suggest that ACh negatively regulates axon growth and presynaptic specialization at the neuromuscular junction through distinct cellular mechanisms.
An
Mahru C
MC
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Lin
Weichun
W
Yang
Jiefei
J
Dominguez
Bertha
B
Padgett
Daniel
D
Sugiura
Yoshie
Y
Aryal
Prafulla
P
Gould
Thomas W
TW
Oppenheim
Ronald W
RW
Hester
Mark E
ME
Kaspar
Brian K
BK
Ko
Chien-Ping
CP
Lee
Kuo-Fen
KF
D000107:Acetylation; D000109:Acetylcholine / Q000819:agonists / Q000378:metabolism*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002454:Cell Differentiation; D018679:Cholinergic Agonists / Q000494:pharmacology; D051379:Mice; D009469:Neuromuscular Junction / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism
D018679:Cholinergic Agonists; D011978:Receptors, Nicotinic; D002217:Carbachol; D000109:Acetylcholine