Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice.
In this study we examined the developmental roles of acetylcholine (ACh) by establishing and analyzing mice lacking choline acetyltransferase (ChAT), the biosynthetic enzyme for ACh. As predicted, ChAT-deficient embryos lack both spontaneous and nerve-evoked postsynaptic potentials in muscle and die at birth. In mutant embryos, abnormally increased nerve branching occurs on contact with muscle, and hyperinnervation continues throughout subsequent prenatal development. Postsynaptically, ACh receptor clusters are markedly increased in number and occupy a broader muscle territory in the mutants. Concomitantly, the mutants have significantly more motor neurons than normal. At an ultrastructural level, nerve terminals are smaller in mutant neuromuscular junctions, and they make fewer synaptic contacts to the postsynaptic muscle membrane, although all of the typical synaptic components are present in the mutant. These results indicate that ChAT is uniquely essential for the patterning and formation of mammalian neuromuscular synapses.
Brandon
Eugene P
EP
Laboratory of Genetics and Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Lin
Weichun
W
D'Amour
Kevin A
KA
Pizzo
Donald P
DP
Dominguez
Bertha
B
Sugiura
Yoshie
Y
Thode
Silke
S
Ko
Chien-Ping
CP
Thal
Leon J
LJ
Gage
Fred H
FH
Lee
Kuo-Fen
KF
D000818:Animals; D002452:Cell Count; D002470:Cell Survival; D002795:Choline O-Acetyltransferase / Q000172:deficiency* / Q000235:genetics; D003964:Diaphragm / Q000196:embryology / Q000294:innervation / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D018390:Gene Targeting; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000473:pathology; D009468:Neuromuscular Diseases / Q000151:congenital / Q000235:genetics / Q000473:pathology*; D009469:Neuromuscular Junction / Q000473:pathology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis; D011940:Receptor Aggregation; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics; D016708:Synaptophysin / Q000096:biosynthesis
D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D016708:Synaptophysin; D002795:Choline O-Acetyltransferase