Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

Journal of Neuroscience - Tập 16 Số 17 - Trang 5351-5360 - 1996
J P Magyar1, Rudolf Martini, Thomas Rülicke, Adriano Aguzzi, Katrin Adlkofer, Zlatko Dembić, Jürgen Zielasek, Klaus V. Toyka, Ueli Suter
1Department of Cell Biology, Swiss Federal Institute of Technology, ETH-Hoenggerberg, Zurich, Switzerland.

Tóm tắt

An intrachromosomal duplication containing thePMP22gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increasedPMP22gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of thepmp22gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of thepmp22gene 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 aberrantpmp22gene copy numbers cause various forms of myelination defects.

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Tài liệu tham khảo

10.1038/ng1195-274

Baechner, 1995, Widespread expression of the peripheral myelin protein-22 gene (PMP22) in the neural and non-neural tissues during murine development., J Neurosci Res, 42, 735, 10.1002/jnr.490420602

Bascles, 1992, Expression of the PMP22 gene in trembler mutant mice: comparison with the other myelin protein genes., Dev Neurosci, 14, 336, 10.1159/000111680

Bermingham, 1995, Mutation of the POU domain transcription factor TST-1/OCT6/SCIP in mice produces neuronal and myelinating Schwann cell defects., Soc Neurosci Abstr, 21, 5

10.1146/annurev.ne.09.030186.001513

10.1016/0092-8674(93)90058-X

Cremer, 1993, Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning., Nature, 367, 455, 10.1038/367455a0

10.1101/gad.9.15.1846

10.1016/0022-510X(92)90282-P

Gabreels-Festen AAWM, Bolhuis PA, Hoogendijk JE, Valentijn LJ, Eshuis EJHM, Gabreels FJM (1995) Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations. Acta Neuropathol, in press.

10.1016/0092-8674(92)90591-Y

10.1126/science.7123245

10.1097/00005072-199603000-00004

10.1093/brain/111.5.1039

10.1126/science.3388045

10.1097/00005072-198311000-00008

10.1002/glia.440040210

10.1002/ana.410050604

Kimura J (1989) Electrodiagnosis in diseases of nerve and muscle: principles and practice. (F.A. Davis, Philadelphia).

10.1111/j.1365-2990.1977.tb00572.x

10.1016/0022-510X(75)90057-X

10.1016/0092-8674(91)90613-4

10.1128/MCB.10.6.2924

10.1007/BF01189813

10.1074/jbc.270.48.28910

10.1038/ng0692-176

10.1016/0896-6273(92)90279-M

10.1016/0896-6273(94)90472-3

Nadon, 1994, A combination of PLP and DM20 transgene promotes partial myelination in the jimpy mouse., J Neurosci Res, 63, 822

10.1016/0022-510X(94)00272-P

10.1177/107385849600200111

Pareek, 1993, Detection and processing of peripheral myelin protein PMP22 in cultured Schwann cells., J Biol Chem, 268, 10372, 10.1016/S0021-9258(18)82211-6

10.1038/ng0692-159

10.1016/0022-510X(80)90062-3

10.1016/0960-8966(91)90055-W

10.1038/ng1093-189

10.1056/NEJM199307083290205

10.1038/ng1193-269

10.1016/S0896-6273(00)80128-2

10.1016/0092-8674(93)90329-O

10.1083/jcb.117.1.225

Spreyer, 1991, Axon-regulated expression of a Schwann cell transcript that is homologous to a “growth arrest-specific” gene., EMBO J, 10, 3661, 10.1002/j.1460-2075.1991.tb04933.x

10.1002/humu.1380030203

10.1146/annurev.ne.18.030195.000401

10.1002/jnr.490400202

10.1038/356241a0

10.1073/pnas.89.10.4382

10.1016/0166-2236(93)90015-E

Suter, 1994, Regulation of tissue-specific expression of alternative peripheral meyelin protein-22 (PMP22) gene transcripts by two promoters., J Biol Chem, 269, 25795, 10.1016/S0021-9258(18)47318-8

Taylor V, Suter U (1996) Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family. Gene, in press.

10.1074/jbc.270.48.28824

10.1038/ng0692-171

10.1038/371796a0

10.1038/ng0692-166

10.1038/ng1292-288

10.1073/pnas.88.16.7195

Zoidl, 1995, Retroviral-mediated gene transfer of the peripheral myelin protein PMP22 in Schwann cells: modulation of cell growth., EMBO J, 14, 1122, 10.1002/j.1460-2075.1995.tb07095.x

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Journal of Neuroscience

Tập 16 Số 17

5351-5360

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