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 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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Figure 1: Tissue-selective deletion of dystroglycan.
Figure 2: Abnormalities of cerebral and cerebellar development.
Figure 3: Disruptions of the glia limitans, leptomeningeal heterotopia and abnormal laminin binding.
Figure 4: Long-term potentiation is blunted in GFAP-Cre/DG-null mice, but baseline neurotransmission and PPF are not affected.


  1. 1

    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)

    CAS  Article  Google Scholar 

  2. 2

    Kobayashi, K. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Cormand, B. et al. Clinical and genetic distinction between Walker–Warburg syndrome and muscle-eye-brain disease. Neurology 56, 1059–1069 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Haltia, M. et al. Muscle-eye-brain disease: a neuropathological study. Ann. Neurol. 41, 173–180 (1997)

    CAS  Article  Google Scholar 

  5. 5

    Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1, 717–724 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Henry, M. D. & Campbell, K. P. Dystroglycan inside and out. Curr. Opin. Cell Biol. 11, 602–607 (1999)

    CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    Cohn, R. D. & Campbell, K. P. The molecular basis of muscular dystrophy. Muscle Nerve 23, 1456–1471 (2000)

    CAS  Article  Google Scholar 

  9. 9

    Sugita, S. et al. A stoichiometric complex of neurexins and dystroglycan in brain. J. Cell Biol. 154, 435–445 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85–94 (2001)

    CAS  Article  Google Scholar 

  11. 11

    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)

    CAS  Article  Google Scholar 

  12. 12

    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)

    CAS  Article  Google Scholar 

  13. 13

    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)

    CAS  Google Scholar 

  14. 14

    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)

    CAS  Article  Google Scholar 

  15. 15

    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)

    CAS  Article  Google Scholar 

  16. 16

    Ross, M. E. & Walsh, C. A. Human brain malformations and their lessons for neuronal migration. Annu. Rev. Neurosci. 24, 1041–1070 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Aravind, L. & Koonin, E. V. The fukutin protein family—predicted enzymes modifying cell-surface molecules. Curr. Biol. 22, R837–R837 (1999)

    Google Scholar 

  18. 18

    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)

    CAS  Article  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    Hayashi, Y. K. et al. Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57, 115–121 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Michele, D. E. et al. Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies. Nature 418, 417–422 (2002)

    ADS  CAS  Article  Google Scholar 

  22. 22

    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)

    CAS  Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

  24. 24

    Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993)

    ADS  CAS  Article  Google Scholar 

  25. 25

    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)

    CAS  Article  Google Scholar 

  26. 26

    Haydon, P. A. Glia: listening and talking to the synapse. Nature Rev. Neurosci. 2, 185–193 (2001)

    CAS  Article  Google Scholar 

  27. 27

    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)

    Article  Google Scholar 

  28. 28

    Duclos, F. et al. Progressive muscular dystrophy in α-sarcoglycan-deficient mice. J. Cell Biol. 142, 1461–1471 (1998)

    CAS  Article  Google Scholar 

  29. 29

    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)

    CAS  Article  Google Scholar 

  30. 30

    Malenka, R. C. Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus. Neuron 6, 53–60 (1991)

    CAS  Article  Google Scholar 

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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.

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Correspondence to Kevin P. Campbell.

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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).

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