P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves |
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Authors: | Wrabetz L Feltri M L Quattrini A Imperiale D Previtali S D'Antonio M Martini R Yin X Trapp B D Zhou L Chiu S Y Messing A |
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Institution: | Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milano, Italy. l.wrabetz@hsr.it |
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Abstract: | We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy. |
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Keywords: | axon sorting myelin neuropathy Schwann cell transgene |
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