Myelin Basic Protein Gene Expression, Oligodendrocyte Metabolism and Myelin Stability in the MLD Mutant Mouse
Myelin-deficient (mld) is an autosomal recessive mutation in mice exhibiting a severe deficit in the synthesis of myelin basic protein (MBP). In order to understand the mechanisms involved in the regulation of MBP synthesis in these mutants, the amounts of MBP and MBP mRNA were measured in control, heterozygous and homozygous mld brains. Using in vitro translation of poly(A+) RNA in a cell-free system, in situ hybridization, and filter hybridization with a radiolabelled probe pMBP-1, the levels of MBP and MBP-specific mRNA were found to be very low but detectable in mld homozygotes and intermediate in heterozygotes. MBP specific mRNA and its translation products were of normal size. These results indicate that the mld mutation is expressed co-dominantly in heterozygotes and affects a cis-acting regulatory element controlling the MBP gene.
In the presence of low amounts of MBP, the myelin lamellae were poorly compacted and unstable. This instability was demonstrated by increased levels of cholesterol esters, the presence of degraded myelin-associated glycoprotein (dMAG), and fast turnover rates of MAG and sulfatides. In mld, oligodendrocytes accumulated inclusion bodies, vacuoles and rough endoplasmic reticulum. This material was heavily immunostained for MAG. Simultaneously, MAG and Wolfgram protein, two proteins present in uncompacted myelin sheath and paranodal loops exhibited increased rates of synthesis. These results suggest that the regulation of the synthesis of myelin constituents cannot proceed when a major myelin protein is missing.
KeywordsMyelin Basic Protein Myelin Sheath Translation Product Myelin Protein Autosomal Recessive Mutation
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