Schwann cell myelination requires timely and precise targeting of P(0) protein.
This report investigated mechanisms responsible for failed Schwann cell myelination in mice that overexpress P(0) (P(0)(tg)), the major structural protein of PNS myelin. Quantitative ultrastructural immunocytochemistry established that P(0) protein was mistargeted to abaxonal, periaxonal, and mesaxon membranes in P(0)(tg) Schwann cells with arrested myelination. The extracellular leaflets of P(0)-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 P(0). These results indicate that P(0) gene multiplication causes P(0) mistargeting to mesaxon membranes, and through obligate P(0) homophilic adhesion, renders these dynamic membranes inert and halts myelination.
Yin
X
X
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Kidd
G J
GJ
Wrabetz
L
L
Feltri
M L
ML
Messing
A
A
Trapp
B D
BD
D000375:Aging; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005784:Gene Amplification; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000648:ultrastructure
D018993:Myelin P0 Protein; D018992:Myelin-Associated Glycoprotein; D012333:RNA, Messenger