Gene expression during tellurium-induced primary demyelination.
A compound may be "developmentally neurotoxic" because it interferes with a metabolic step exclusively or preferentially expressed during development in a particular class of neural cells. The initial metabolic specificity is often complicated by: (1) secondary responses in the affected cells, (2) involvement of other functionally-related cell types, and (3) the presence of compensatory and/or regenerative responses. In this context we study tellurium, which systemically blocks cholesterol biosynthesis at the squalene epoxidase step. Because of the high demand in developing peripheral nerves for newly synthesized cholesterol required for myelin assembly, this metabolic block leads to demyelination of the sciatic nerve. This insult is confounded by the fact that the myelin-forming Schwann cells do not upregulate their cholesterol biosynthetic pathway. This is contrary to expectations; liver (the main source of cholesterol for many tissues outside the nervous system) upregulates synthesis of cholesterol and overcomes the metabolic block. The shortage of cholesterol in Schwann cells results in an immediate secondary response down-regulation of steady-state mRNA levels for specific myelin proteins. Remyelination occurs after cessation of tellurium exposure. This model of primary demyelination allows study of Schwann-cell specific responses during the processes of myelin breakdown and subsequent steps leading to remyelination, without the complications of axonal degeneration and regeneration. Because tellurium specifically blocks the synthesis of a major required membrane component, it is also well suited for examining the coordinate control of membrane synthesis and assembly at the genomic level.
Morell
P
P
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7250.
Toews
A D
AD
Wagner
M
M
Goodrum
J F
JF
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D051381:Rats; D013691:Tellurium / Q000633:toxicity*
D002784:Cholesterol; D013691:Tellurium