Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy

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.

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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.

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Acknowledgements

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). https://doi.org/10.1038/nature00838

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