Schwann cell myelination requires timely and precise targeting of P-0 protein

This report investigated mechanisms responsible for failed Schwann cell mye lination in mice that overexpress P-o (P-o(tg)), the major structural prote in of PNS myelin. Quantitative ultrastructural immunocytochemistry establis hed that P-o protein was mistargeted to abaxonal, periaxonal, and mesaxon m embranes in P-o(tg) Schwann cells with arrested myelination. The extracellu lar leaflets of P-o-containing mesaxon membranes were closely apposed with periodicities of compact myelin. The myelin-associated glycoprotein was app ropriately sorted in the Golgi apparatus and targeted to periaxonal membran es. In adult mice, occasional Schwann cells myelinated axons possibly with the aid of endocytic removal of mistargeted P-o. These results indicate tha t P-o gene multiplication causes P-o mistargeting to mesaxon membranes, and through obligate P-o homophilic adhesion, renders these dynamic membranes inert and halts myelination.