Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy

Steven A. Moore, Fumiaki Saito, Jianguo Chen, Daniel E. Michele, Michael D. Henry, Albee Messing, Ronald D. Cohn, Susan E. Ross-Barta, Steve Westra, Roger A. Williamson, Toshinori Hoshi and Kevin P. Campbell ()
Additional contact information
Steven A. Moore: The University of Iowa
Fumiaki Saito: The University of Iowa
Jianguo Chen: The University of Iowa
Daniel E. Michele: The University of Iowa
Michael D. Henry: The University of Iowa
Albee Messing: University of Wisconsin
Ronald D. Cohn: The University of Iowa
Susan E. Ross-Barta: The University of Iowa
Steve Westra: The University of Iowa
Roger A. Williamson: The University of Iowa
Toshinori Hoshi: The University of Iowa
Kevin P. Campbell: The University of Iowa

Nature, 2002, vol. 418, issue 6896, 422-425

Abstract: Abstract Fukuyama congenital muscular dystrophy (FCMD), muscle–eye–brain disease (MEB), and Walker–Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects1,2,3,4. Mutations reported in genes of FCMD2 and MEB5 patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin–glycoprotein complex6 that is also expressed in brain, where its function is unknown7. Here we show that brain-selective deletion of dystroglycan in mice is sufficient to cause CMD-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high-affinity binding to the extracellular matrix protein laminin, and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization indicating that dystroglycan might have a postsynaptic role in learning and memory. Our data strongly support the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in CMD.

Date: 2002
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DOI: 10.1038/nature00838

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