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Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination

Nature Genetics volume 33, pages 366–374 (2003)Cite this article

Abstract

Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2′,3′-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.

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Figure 1: Targeted inactivation of Cnp1.
Figure 2: Myelin ultrastructure and biochemical composition.
Figure 3: General morphology and microtubular cytoskeleton of wild-type and CNP-deficient oligodendrocytes.
Figure 4: Loss of motor performance and increased mortality of CNP-deficient mice.
Figure 5: Hydrocephalus and neurodegeneration.
Figure 6: Axonal swellings and degeneration.
Figure 7: Transmission electron microscopy.
Figure 8: Reactive gliosis.

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Acknowledgements

We thank U. Bode and C. Stünkel for technical assistance. We also thank A. Berns for lacZ indicator mice. This work was funded by contributions of a Bundesministerium für Bildung und Forschung program (Gentherapie) and a grant from the European Union (COSMO; to K.A.N.), by Action Research and the Wellcome Trust (I.R.G.) and by the Multiple Sclerosis Society of Canada and the Canadian Institutes of Health Research (P.E.B.). C.L.-S. and S.G. received stipends of the Deutsche Forschungsgemeinschaft graduate program in Neurobiology at the University of Heidelberg.

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  1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Goettingen, D-37075, Germany

    Corinna Lappe-Siefke, Sandra Goebbels, Eva Nicksch & Klaus-Armin Nave

  2. Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Canada

    Michel Gravel, John Lee & Peter E. Braun

  3. Applied Neurobiology Group,Institute of Comparative Medicine, University of Glasgow, Bearsden, G61 1QH, Glasgow, Scotland

    Ian R. Griffiths

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Correspondence to Klaus-Armin Nave.

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Lappe-Siefke, C., Goebbels, S., Gravel, M. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 33, 366–374 (2003). https://doi.org/10.1038/ng1095

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