Schwann cell myelination requires timely and precise targeting of P₀ protein

This report investigated mechanisms responsible for failed Schwann cell myelination in mice that overexpress P₀ (P₀(tg)), the major structural protein of PNS myelin. Quantitative ultrastructural immunocytochemistry established that P₀ protein was mistargeted to abaxonal, periaxonal, and mesaxon membranes in (P₀(tg)) Schwann cells with arrested myelination. The extracellular leaflets of P₀-containing mesaxon membranes were closely apposed with periodicities of compact myelin. The myelin-associated glycoprotein was appropriately sorted in the Golgi apparatus and targeted to periaxonal membranes. In adult mice, occasional Schwann cells myelinated axons possibly with the aid of endocytic removal of mistargeted P₀. These results indicate that P₀ gene multiplication causes P₀ mistargeting to mesaxon membranes, and through obligate P₀ homophilic adhesion, renders these dynamic membranes inert and halts myelination.