Defective neuromuscular synaptogenesis in agrin-deficient mutant mice.
During neuromuscular synapse formation, motor axons induce clustering of acetylcholine receptors (AChRs) in the muscle fiber membrane. The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons and triggers formation of AChR clusters on cultured myotubes. We show here postsynaptic AChR aggregates are markedly reduced in number, size, and density in muscles of agrin-deficient mutant mice. These results support the hypothesis that agrin is a critical organizer of postsynaptic differentiation does occur in the mutant, suggesting the existence of a second-nerve-derived synaptic organizing signal. In addition, we show that intramuscular nerve branching and presynaptic differentiation are abnormal in the mutant, phenotypes which may reflect either a distinct effect of agrin or impaired retrograde signaling from a defective postsynaptic apparatus.
Gautam
M
M
Department of Anatomy and Neurobiology, Washington University Medical School St. Louis, Missouri 63110, USA.
Noakes
P G
PG
Moscoso
L
L
Rupp
F
F
Scheller
R H
RH
Merlie
J P
JP
Sanes
J R
JR
D018171:Agrin / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D005333:Fetus / Q000737:chemistry / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000502:physiology; D018482:Muscle, Skeletal / Q000196:embryology / Q000294:innervation / Q000502:physiology; D009469:Neuromuscular Junction / Q000737:chemistry / Q000196:embryology*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000502:physiology; D011950:Receptors, Cholinergic / Q000502:physiology; D013569:Synapses / Q000737:chemistry / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D018171:Agrin; D011950:Receptors, Cholinergic