Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy.
Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects. Mutations reported in genes of FCMD and MEB patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin-glycoprotein complex that is also expressed in brain, where its function is unknown. 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.
Department of Pathology, The University of Iowa, Iowa City, Iowa 52242-1101, USA.
Steven A
SA
Moore
Fumiaki
F
Saito
Jianguo
J
Chen
Daniel E
DE
Michele
Michael D
MD
Henry
Albee
A
Messing
Ronald D
RD
Cohn
Susan E
SE
Ross-Barta
Steve
S
Westra
Roger A
RA
Williamson
Toshinori
T
Hoshi
Kevin P
KP
Campbell
D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D049030:Dystroglycans; D004594:Electrophysiology; D017353:Gene Deletion; D006031:Glycosylation; D006624:Hippocampus / Q000002:abnormalities / Q000503:physiopathology; D007797:Laminin / Q000378:metabolism; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D013577:Syndrome
D003598:Cytoskeletal Proteins; D007797:Laminin; D008562:Membrane Glycoproteins; D049030:Dystroglycans