The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo.
Formation of neuromuscular synapses requires a series of inductive interactions between growing motor axons and differentiating muscle cells, culminating in the precise juxtaposition of a highly specialized nerve terminal with a complex molecular structure on the postsynaptic muscle surface. The receptors and signaling pathways mediating these inductive interactions are not known. We have generated mice with a targeted disruption of the gene encoding MuSK, a receptor tyrosine kinase selectively localized to the postsynaptic muscle surface. Neuromuscular synapses do not form in these mice, suggesting a failure in the induction of synapse formation. Together with the results of an accompanying manuscript, our findings indicate that MuSK responds to a critical nerve-derived signal (agrin), and in turn activates signaling cascades responsible for all aspects of synapse formation, including organization of the postsynaptic membrane, synapse-specific transcription, and presynaptic differentiation.
DeChiara
Thomas M
TM
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
Bowen
David C
DC
Valenzuela
David M
DM
Simmons
Mary V
MV
Poueymirou
William T
WT
Thomas
Susan
S
Kinetz
Erika
E
Compton
Debra L
DL
Rojas
Eduardo
E
Park
John S
JS
Smith
Cynthia
C
DiStefano
Peter S
PS
Glass
David J
DJ
Burden
Steven J
SJ
Yancopoulos
George D
GD
D018171:Agrin / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D005804:Genes, Lethal / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000737:chemistry / Q000196:embryology / Q000294:innervation; D009469:Neuromuscular Junction / Q000737:chemistry* / Q000196:embryology / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000737:chemistry / Q000502:physiology; D013570:Synaptic Membranes / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D018171:Agrin; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases