Epitope-tagged P-0 glycoprotein causes Charcot-Marie-Tooth-like neuropathyin transgenic mice

In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular d omains (ECD) of the protein zero (P-0) glycoprotein. Point mutations in thi s region of P-0 cause human hereditary demyelinating neuropathies such as C harcot-Marie-Tooth. We describe transgenic mice expressing a full-length P- 0 modified in the ECD with a myc epitope tag. The presence of the myc seque nce caused a dysmyelinating peripheral neuropathy similar to two distinct s ubtypes of Charcot-Marie-Tooth. with hypomyelination, altered intraperiod l ines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In viv o and in vitro experiments showed that P(0)myc retained partial adhesive fu nction, and suggested that the transgene inhibits P-0-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying b oth the pathogenesis of P-0 ECD mutants and the normal interactions of P-0 in the myelin sheath.