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© The Rockefeller University Press, 0021-9525/2000/3/1021/ $5.00
The Journal of Cell Biology, Volume 148, Number 5, March 6, 2000 1021-1034

Original Article

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves

Lawrence Wrabetza, Maria Laura Feltria, Angelo Quattrinia, Daniele Imperialea,b, Stefano Previtalia, Maurizio D'Antonioa, Rudolf Martinic, Xinghua Yind, Bruce D. Trappd, Lei Zhoue, Shing-Yan Chiue, and Albee Messingf
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

Correspondence to: Lawrence Wrabetz, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milano, Italy. Tel:39-02-26434870 Fax:39-02-26434767 E-mail: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


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