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Published online 18 September 2000. doi:10.1083/jcb.150.6.1385
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© The Rockefeller University Press, 0021-9525/2000//1385 $5.00
The Journal of Cell Biology, Volume 150, Number 6, , 2000 1385-1398

Original Article

Absence of {alpha}-Syntrophin Leads to Structurally Aberrant Neuromuscular Synapses Deficient in Utrophin



Marvin E. Adamsa, Neal Kramarcya, Stuart P. Kralla, Susana G. Rossib, Richard L. Rotundob, Robert Sealocka, and Stanley C. Froehnera

a Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545
b Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33143
Department of Physiology and Biophysics, Box 357290, University of Washington, Seattle, WA 98195-7290.(206) 685-0619(206) 543-0950

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.

Key Words: dystrophin • dystrobrevin • nitric oxide synthase • acetylcholine receptor • acetylcholinesterase

© 2000 The Rockefeller University Press

Current address for Marvin E. Adams and Stanley C. Froehner is Department of Physiology and Biophysics, Box 357290, University of Washington, Seattle, WA 98195-7290.

Abbreviations used in this paper: AChE, acetylcholinesterase; AChR, acetylcholine receptor; Bgtx, {alpha}-bungarotoxin; ES, embryonic stem; NMJ, neuromuscular junction; nNOS, neuronal nitric oxide synthase; PDZ, domain found in postsynaptic density protein-95, discs large, and zonula occludens-1 proteins; PH, pleckstrin homology.


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