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.
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Fukuyama, Y., Osawa, M. & Suzuki, H. Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations. Brain Dev. 3, 1–29 (1981)
Kobayashi, K. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998)
Cormand, B. et al. Clinical and genetic distinction between Walker–Warburg syndrome and muscle-eye-brain disease. Neurology 56, 1059–1069 (2001)
Haltia, M. et al. Muscle-eye-brain disease: a neuropathological study. Ann. Neurol. 41, 173–180 (1997)
Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1, 717–724 (2001)
Henry, M. D. & Campbell, K. P. Dystroglycan inside and out. Curr. Opin. Cell Biol. 11, 602–607 (1999)
Zaccaria, M. L., di Tommaso, F., Brancaccio, A., Paggi, P. & Petrucci, T. C. Dystroglycan distribution in adult mouse brain: a light and electron microscopy study. Neuroscience 104, 311–324 (2001)
Cohn, R. D. & Campbell, K. P. The molecular basis of muscular dystrophy. Muscle Nerve 23, 1456–1471 (2000)
Sugita, S. et al. A stoichiometric complex of neurexins and dystroglycan in brain. J. Cell Biol. 154, 435–445 (2001)
Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85–94 (2001)
Choi, B. H. Role of the basement membrane in neurogenesis and repair of injury in the central nervous system. Microsc. Res. Tech. 28, 193–203 (1994)
Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassel, J. R. & Yamada, Y. Perlecan is essential for cartilage and cephalic development. Nature Genet. 23, 354–358 (1999)
De Arcangelis, A., Mark, M., Kreidberg, J., Sorokin, L. & Georges-Labouesse, E. Synergistic activities of α3 and α6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse. Development 126, 3957–3968 (1999)
Miner, J. H., Cunningham, J. & Sanes, J. R. Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin α5 chain. J. Cell Biol. 143, 1713–1723 (1998)
Graus-Porta, D. et al. β1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron 31, 367–379 (2001)
Ross, M. E. & Walsh, C. A. Human brain malformations and their lessons for neuronal migration. Annu. Rev. Neurosci. 24, 1041–1070 (2001)
Aravind, L. & Koonin, E. V. The fukutin protein family—predicted enzymes modifying cell-surface molecules. Curr. Biol. 22, R837–R837 (1999)
Grewal, P. K., Holzfeind, P. J., Bittner, R. E. & Hewitt, J. E. Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse. Nature Genet. 28, 151–154 (2001)
Brockington, M. et al. Mutations in the Fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan. Am. J. Hum. Genet. 69, 1198–1209 (2001)
Hayashi, Y. K. et al. Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57, 115–121 (2001)
Michele, D. E. et al. Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies. Nature 418, 417–422 (2002)
Williamson, R. A. et al. Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice. Hum. Mol. Genet. 6, 831–841 (1997)
Grady, M. et al. Maturation and maintenance of the neuromuscular synapse: genetic evidence for roles of the dystrophin–glycoprotein complex. Neuron 25, 279–293 (2000)
Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993)
Schulz, P. E., Cook, E. P. & Johnston, D. Changes in paired-pulse facilitation suggest presynaptic involvement in long-term potentiation. J. Neurosci. 14, 5325–5337 (1994)
Haydon, P. A. Glia: listening and talking to the synapse. Nature Rev. Neurosci. 2, 185–193 (2001)
Potocnik, A. J., Brakebusch, C. & Fassler, R. Fetal and adult hematopoietic stem cells require β1 integrin function for colonizing fetal liver, spleen, and bone marrow. Immunity 6, 653–663 (2000)
Duclos, F. et al. Progressive muscular dystrophy in α-sarcoglycan-deficient mice. J. Cell Biol. 142, 1461–1471 (1998)
Ervasti, J. M. & Campbell, K. P. A role for the dystrophin–glycoprotein complex as a transmembrane linker between laminin and actin. J. Cell Biol. 122, 809–823 (1993)
Malenka, R. C. Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus. Neuron 6, 53–60 (1991)
We thank R. Fässler for his gifts of plasmids for construction of the floxed allele. Technical assistance was received from J. Carl, C. Bromley, J. Rogers, C. Bray, M. Hassebrock, S. Lowen and K. Garringer. This work was supported by the Muscular Dystrophy Association and the National Institutes of Health (to S.A.M.). K.P.C. is an Investigator of the Howard Hughes Medical Institute.
The authors declare that they have no competing financial interests.
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Moore, S., Saito, F., Chen, J. et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418, 422–425 (2002). https://doi.org/10.1038/nature00838
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