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Volume 16, Number 17, Issue of September 1, 1996 pp. 5351-5360
Copyright ©1996 Society for NeuroscienceImpaired Differentiation of Schwann Cells in Transgenic Mice with Increased PMP22 Gene Dosage
Received April 9, 1996; revised May 31, 1996; accepted June 11, 1996.
Josef P. Magyar1, Rudolf Martini2, Thomas Ruelicke3, Adriano Aguzzi4, Katrin Adlkofer1, Zlatko Dembic5, Jürgen Zielasek6, Klaus V. Toyka6, and Ueli Suter1 Departments of 1 Cell Biology and 2 Neurobiology, Swiss Federal Institute of Technology, ETH-Hoenggerberg, CH-8093 Zurich, Switzerland, 3 Central Biological Laboratory and 4 Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland, 5 Hoffmann-LaRoche, CH-4000 Basel, Switzerland, and 6 Department of Neurology, Julius-Maximilians-University, D-97080 Würzburg, Germany
An intrachromosomal duplication containing the PMP22 gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increased PMP22 gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of the pmp22 gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of the pmp22 gene display a severe congenital hypomyelinating neuropathy as characterized by an almost complete lack of myelin and marked slowing of nerve conductions. Affected nerves contain an increased number of nonmyelinating Schwann cells, which do not form onion bulbs but align in association with axons. The mutant Schwann cells are characterized by a premyelination-like state as indicated by the expression of embryonic Schwann cell markers. Furthermore, continued Schwann cell proliferation is observed into adulthood. We hypothesize that Schwann cells are impaired in their differentiation into the myelinating phenotype, leading to a disorder comparable to severe cases of hereditary motor and sensory neuropathies. Our findings, combined with the analysis of heterozygous and homozygous PMP22-deficient mice, indicate that aberrant pmp22 gene copy numbers cause various forms of myelination defects.
Key words: PMP22; myelin; Schwann cell; dysmyelination; Charcot-Marie-Tooth disease; gene dosage; transgenic mouse
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