Absence of P0 leads to the dysregulation of myelin gene expression and myelin morphogenesis.
P0, the major peripheral nervous system (PNS) myelin protein, is a member of the immunoglobulin supergene family of membrane proteins and can mediate homotypic adhesion. P0 is an essential structural component of PNS myelin; mice in which P0 expression has been eliminated by homologous recombination (P0-/-) develop a severe dysmyelinating neuropathy with predominantly uncompacted myelin. Although P0 is thought to play a role in myelin compaction by promoting adhesion between adjacent extracellular myelin wraps, as an adhesion molecule it could also have a regulatory function. Consistent with this hypothesis, Schwann cells in adult P0-/- mice display a novel molecular phenotype: PMP22 expression is down-regulated, MAG and PLP expression are up-regulated, and MBP expression is unchanged. As in quaking viable mutant mice (qk(v)), which have uncompacted myelin morphologically similar to that found in P0-/- mice, neither the qKI-6 or qKI-7 proteins are expressed in P0-/- peripheral nerve. In addition to these changes in gene expression in the P0 knockout, PLP/DM-20 accumulates in the endoplasmic reticulum of P0-/- Schwann cells, whereas MAG accumulates in redundant loops of uncompacted myelin, not at nodes of Ranvier or Schmidt-Lantermann incisures. Taken together, these results demonstrate that P0 is involved, either directly or indirectly, in the regulation of both myelin gene expression and myelin morphogenesis.
Xu
W
W
Department of Neurology and The Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA.
Manichella
D
D
Jiang
H
H
Vallat
J M
JM
Lilien
J
J
Baron
P
P
Scarlato
G
G
Kamholz
J
J
Shy
M E
ME
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008821:Mice, Quaking / Q000378:metabolism; D018993:Myelin P0 Protein / Q000235:genetics / Q000502:physiology*; D009185:Myelin Proteins / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010525:Peripheral Nerves / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D014018:Tissue Distribution
D018993:Myelin P0 Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; C489545:Pmp22 protein, mouse; C490832:QKI protein, human; C098217:Qk protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins