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Published online 18 September 2000. doi:10.1083/jcb.150.6.1399
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© The Rockefeller University Press, 0021-9525/2000//1399 $5.00
The Journal of Cell Biology, Volume 150, Number 6, , 2000 1399-1410

Original Article

Assembly of the Dystrophin-Associated Protein Complex Does Not Require the Dystrophin Cooh-Terminal Domain



Gregory E. Crawforda, John A. Faulknerd, Rachelle H. Crosbiee, Kevin P. Campbelle, Stanley C. Froehnerf, and Jeffrey S. Chamberlaina,b,c

a Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109-0618
b Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0618
c Center for Gene Therapy, University of Michigan, Ann Arbor, Michigan 48109-0618
d Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109-0618
e Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242
f Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618.(734) 764-6898(734) 764-4297

Dystrophin is a multidomain protein that links the actin cytoskeleton to laminin in the extracellular matrix through the dystrophin associated protein (DAP) complex. The COOH-terminal domain of dystrophin binds to two components of the DAP complex, syntrophin and dystrobrevin. To understand the role of syntrophin and dystrobrevin, we previously generated a series of transgenic mouse lines expressing dystrophins with deletions throughout the COOH-terminal domain. Each of these mice had normal muscle function and displayed normal localization of syntrophin and dystrobrevin. Since syntrophin and dystrobrevin bind to each other as well as to dystrophin, we have now generated a transgenic mouse deleted for the entire dystrophin COOH-terminal domain. Unexpectedly, this truncated dystrophin supported normal muscle function and assembly of the DAP complex. These results demonstrate that syntrophin and dystrobrevin functionally associate with the DAP complex in the absence of a direct link to dystrophin. We also observed that the DAP complexes in these different transgenic mouse strains were not identical. Instead, the DAP complexes contained varying ratios of syntrophin and dystrobrevin isoforms. These results suggest that alternative splicing of the dystrophin gene, which naturally generates COOH-terminal deletions in dystrophin, may function to regulate the isoform composition of the DAP complex.

Key Words: dystrophin • muscular dystrophy • syntrophin • dystrobrevin • mdx mice

© 2000 The Rockefeller University Press

Rachelle Crosbie's current address is Department of Physiological Science, UCLA, College of Life Sciences, Los Angeles, CA 90095.

Abbreviations used in this paper: DAP, dystrophin-associated protein; EDL, extensor digitorum longus; HSA, human {alpha}-skeletal actin; NMJ, neuromuscular junction; nNOS, neuronal nitric oxide synthase.


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