OLIGODENDROCYTE DEVELOPMENT IN PLP PT MUTANT RABBITS - GLYCOLIPID ANTIGENS AND PLP GENE-EXPRESSION

Paralytic tremor (pt), a hereditary neurological disorder of rabbits i s a recessive, X-linked point mutation of the gene for proteolipid pro tein (PLP) biosynthesis. This mutation results in substitution of hist idine(36) by glutamine in the PLP molecule and produces severe hypomye lination. In the present study, we investigated the developmental expr ession of myelin - oligodendrocyte - specific glycolipid markers by me ans of ELISA assay. While immunoreactivity with antibodies recognising proligodendroblast (POA) antigen was unchanged, only minute amounts o f the other glycolipid markers characteristic for more advanced stages of OLs maturation, such as 04 and 01 antigens, were expressed in pt b rain. The degree of down-regulation was similar to that for MBP. Conco mitantly, the level of in situ expression of the mutated PLP gene mRNA in glial cells of 14 day old pt brain was found to be as high as in a ge-matched controls. Northern blot analysis of developmental PLP gene expression showed a significant deficit of this message in pt brain, b ut only at more advanced developmental stages. However, aside from cha nges in myelin structure, no changes in glial cell number or morpholog y were evident by light microscopic examination of pt mutants. In cont rast, electron microscopy revealed substantial abnormalities in pt oli godendrocyte cytoarchitecture, indicating functional impairment of int racellular transport and utilisation of myelin constituents. Thus, onl y POA expression is positively correlated with the unchanged content o f OLs in pt brain, whereas decreases of 04 and 01 antigens, together w ith MBP immunoreactivity, are indicators of the degree of hypomyelinat ion. Furthermore, oligodendrocyte differentiation appears to proceed n ormally in pt mutant brain up to the stage of PLP gene expression. The n, due to intracellular accumulation of this abnormal gene product, sy nthesis of PLP as well as the other myelin-specific constituents is in hibited by a ''feed-back'' control mechanism.