Endocytic depletion of L-MAG from CNS myelin in quaking mice.
Quaking is an autosomal recessive hypo/dysmyelinating mutant mouse which has a 1-Mbp deletion on chromosome 17. The mutation exhibits pleiotrophy and does not include genes encoding characterized myelin proteins. The levels of the 67-kD isoform of the myelin-associated glycoprotein (S-MAG) relative to those of the 72-kD isoform (L-MAG) are increased in the quaking CNS, but not in other dysmyelinating mutants. Abnormal expression of MAG isoforms in quaking may result from altered transcription of the MAG gene or from abnormal sorting, transport, or targeting of L-MAG or S-MAG. To test these hypotheses, we have determined the distribution of L-MAG and S-MAG in cervical spinal cord of 7-, 14-, 21-, 28-, and 35-d-old quaking mice. In 7-d-old quaking and control spinal cord, L- and S-MAG was detectable in periaxonal regions of myelinated fibers and in the perinuclear cytoplasm of oligodendrocytes. Between 7 and 35 d, L-MAG was removed from the periaxonal membrane of quaking but not control mice. Compared to control mice, a significant increase in MAG labeling of endosomes occurred within oligodendrocyte cytoplasm of 35-d-old quaking mice. S-MAG remained in periaxonal membranes of both quaking and control mice. Analysis of the cytoplasmic domain of L-MAG identifies amino acid motifs at tyrosine 35 and tyrosine 65 which meet the criteria for "tyrosine internalization signals" that direct transmembrane glycoproteins into the endocytic pathway. These results establish that L-MAG is selectively removed from the periaxonal membrane of CNS-myelinated fibers by receptor-mediated endocytosis. The loss of L-MAG from quaking periaxonal membranes results from increased endocytosis of L-MAG and possibly a decrease in L-MAG production.
Bö
L
L
Department of Neurosciences, Cleveland Clinic Foundation, Ohio 44195, USA.
Quarles
R H
RH
Fujita
N
N
Bartoszewicz
Z
Z
Sato
S
S
Trapp
B D
BD
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001369:Axons / Q000737:chemistry / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D007150:Immunohistochemistry; D007536:Isomerism; D051379:Mice; D008821:Mice, Quaking / Q000502:physiology*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000032:analysis / Q000276:immunology; D009186:Myelin Sheath / Q000737:chemistry*; D018992:Myelin-Associated Glycoprotein / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D013116:Spinal Cord / Q000737:chemistry; D013347:Subcellular Fractions / Q000737:chemistry
D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein