Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin.
The syntrophins are a family of structurally related proteins that contain multiple protein interaction motifs. Syntrophins associate directly with dystrophin, the product of the Duchenne muscular dystrophy locus, and its homologues. We have generated alpha-syntrophin null mice by targeted gene disruption to test the function of this association. The alpha-Syn(-/)- mice show no evidence of myopathy, despite reduced levels of alpha-dystrobrevin-2. Neuronal nitric oxide synthase, a component of the dystrophin protein complex, is absent from the sarcolemma of the alpha-Syn(-/)- mice, even where other syntrophin isoforms are present. alpha-Syn(-/)- neuromuscular junctions have undetectable levels of postsynaptic utrophin and reduced levels of acetylcholine receptor and acetylcholinesterase. The mutant junctions have shallow nerve gutters, abnormal distributions of acetylcholine receptors, and postjunctional folds that are generally less organized and have fewer openings to the synaptic cleft than controls. Thus, alpha-syntrophin has an important role in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse.
Adams
M E
ME
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545, USA.
Kramarcy
N
N
Krall
S P
SP
Rossi
S G
SG
Rotundo
R L
RL
Sealock
R
R
Froehner
S C
SC
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D015139:Blotting, Southern; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins / Q000172:deficiency*; D016189:Dystrophin / Q000378:metabolism; D049029:Dystrophin-Associated Proteins; D005455:Fluorescent Antibody Technique; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000201:enzymology; D009469:Neuromuscular Junction / Q000002:abnormalities* / Q000737:chemistry / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000032:analysis / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D013569:Synapses / Q000737:chemistry / Q000378:metabolism*; D049411:Utrophin
D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; C098884:Dtna protein, mouse; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009479:Neuropeptides; D011950:Receptors, Cholinergic; C483600:Utrn protein, mouse; D049411:Utrophin; C091825:syntrophin alpha1; D019001:Nitric Oxide Synthase; D000110:Acetylcholinesterase