|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Rockefeller University Press,
0021-9525/2000//1021 $5.00
The Journal of Cell Biology, Volume 148, Number 5,
, 2000 1021-1034
Original Article |
P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves
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
Lawrence Wrabetz and Maria Laura Feltri contributed equally to this work.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.
|
|