Human Molecular Genetics, 2001, Vol. 10, No. 10 1007-1018
© 2001 Oxford University Press
Induced myelination and demyelination in a conditional mouse model of Charcot–Marie–Tooth disease type 1A
1Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK, 2Royal Free and University College Medical School, Department of Clinical Neurosciences, Rowland Hill Street, London NW3 2PF, UK, 3Institute of Neurology, Queens Square, London WC1N 3BG, UK and 4Department of Clinical Neurophysiology, St Bartholomew’s Hospital, London, UK
Charcot–Marie–Tooth disease type 1A, a hereditary demyelinating neuropathy, is usually caused by overexpression of peripheral myelin protein 22 (PMP22) due to a genomic duplication. We have generated a transgenic mouse model in which mouse pmp22 overexpression can be regulated. In this mouse model, overexpression of pmp22 occurs specifically in Schwann cells of the peripheral nerve and is switched off when the mice are fed tetracycline. Overexpression of pmp22 throughout life (in the absence of tetracycline) causes demyelination. In contrast, myelination is nearly normal when pmp22 overexpression is switched off throughout life by feeding the mice tetracycline. When overexpression of pmp22 is switched off in adult mice, correction begins within 1 week and myelination is well advanced by 3 months (although the myelin sheaths are still thinner than normal), indicating that the Schwann cells are poised to start myelination. Upregulation of the gene in adult mice (which had previously had normal pmp22 expression) is followed by active demyelination within 1 week, which had plateaued by 8 weeks. This indicates that Schwann cells with mature myelin are sensitive to increased amounts of pmp22 such that they rapidly demyelinate. Thus, demyelination can largely be corrected within a few months, but the correction will be sensitive to subsequent upregulation of pmp22.
+ Present address: Laboratoire de Neurogénétique Moléculaire, E9913, INSERM-Université d’Evry, Genopole, 2, rue Gaston Crémieux, CP5724 91057, Evry Cedex, France
To whom correspondence should be addressed. Tel: +44 207 594 3028; Fax: +44 207 594 3015; Email: c.huxley@ic.ac.uk
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