Gene expression in brain during cuprizone-induced demyelination and remyelination.
When C57BL/6J mice, 8 weeks of age, received 0.2% Cuprizone in their diet, extensive demyelination in corpus callosum was detectable after 3 weeks, and there was massive demyelination by 4 weeks. As expected, the accumulation of phagocytically active microglia/macrophages correlated closely with demyelination. When Cuprizone was removed from the diet, remyelination was soon initiated; after 6 weeks of recovery, myelin levels were near-normal and phagocytic cells were no longer prominent. Steady-state levels of mRNA for myelin-associated glycoprotein, myelin basic protein, and ceramide galactosyltransferase were already profoundly depressed after 1 week of Cuprizone exposure and were only 10-20% of control values after 2 weeks. Unexpectedly, upregulation of mRNA for these myelin genes did not correlate with initiation of remyelination but rather with accumulation of microglia/macrophages. After 6 weeks of exposure to Cuprizone, mRNA levels were at control levels or higher-in the face of massive demyelination. This suggests that in addition to effecting myelin removal, microglia/macrophages may simultaneously push surviving oligodendroglia or their progenitors toward myelination.
Morell
P
P
Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7250, USA.
Barrett
C V
CV
Mason
J L
JL
Toews
A D
AD
Hostettler
J D
JD
Knapp
G W
GW
Matsushima
G K
GK
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D003471:Cuprizone / Q000008:administration & dosage / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D004032:Diet; D005700:Galactosyltransferases / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D004676:Myelin Basic Protein / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D018992:Myelin-Associated Glycoprotein / Q000235:genetics; D051146:N-Acylsphingosine Galactosyltransferase; D010587:Phagocytosis; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D012333:RNA, Messenger; D003471:Cuprizone; D005700:Galactosyltransferases; D051146:N-Acylsphingosine Galactosyltransferase