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© The Rockefeller University Press, 0021-9525/2000//1035 $5.00
The Journal of Cell Biology, Volume 151, Number 5, , 2000 1035-1046

Epitope-Tagged P₀Glycoprotein Causes Charcot-Marie-Tooth–Like Neuropathy in Transgenic Mice

^a Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milan, Italy
^b MIA-DIBIT, San Raffaele Scientific Institute, 20132 Milan, Italy
^c University of Milano-Bicocca, Monza, Italy 20052
^d Hunter College, New York, New York 10021
^e Department of Physiology, School of Medicine,
^f Waisman Center and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53705
Department of Neurology and DIBIT 4A2, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy.02-26-43-47-6702-26-43-47-82

In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P₀) glycoprotein. Point mutations in this region of P₀ cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P₀ modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P₀myc retained partial adhesive function, and suggested that the transgene inhibits P₀-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P₀ ECD mutants and the normal interactions of P₀ in the myelin sheath.

Key Words: Charcot-Marie-Tooth disease • myelin protein zero • tomacula • transgenic mice • Myc-tag

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CMT, Charcot-Marie-Tooth; CH, congenital hypomyelination; DSS, Déjérine-Sottas syndrome; ECD, extracellular domain; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IPL, intraperiod line; MDL, major dense line; Mpz, myelin protein zero gene; nt, nucleotide; P, postnatal day; PMP-22, peripheral myelin protein 22; P₀, protein-zero; RT, reverse transcription; SC, Schwann cell; wt, wild-type.

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