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© The Rockefeller University Press, 0021-9525/2000//1021 $5.00
The Journal of Cell Biology, Volume 148, Number 5, , 2000 1021-1034

P₀ Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves

^a Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milano, Italy
^b First Division of Neurology, University of Torino, 10126 Torino, Italy
^c Department of Neurology, Section of Developmental Neurobiology, University of Wurzburg, Wurzburg, Germany
^d Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195
^e Department of Physiology, School of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706
^f Waisman Center and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705
San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milano, Italy.39-02-2643476739-02-26434870

l.wrabetz{at}hsr.it

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 P₀ glycoprotein. Mpz mRNA overexpression ranged from 30–700%, whereas an increased level of P₀ 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.

Key Words: axon sorting • myelin • neuropathy • Schwann cell • transgene

© 2000 The Rockefeller University Press

Abbreviations used in this paper: ^+/–, heterozygous; CHN, congenital hypomyelination neuropathy; CMAP, compound muscle action potential; CMT1A, Charcot-Marie-Tooth 1A neuropathy; CNS, central nervous system; F80, founder 80; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MBP, myelin basic protein; Mpz, myelin protein zero gene; NCV, nerve conduction velocity; nt, nucleotide; P, postnatal day; P₀, P₀ glycoprotein; PLP, proteolipid protein; PMP22, peripheral myelin protein 22 kD; RT, reverse transcription; Tg80, transgenic line 80.

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