Expression of only one myelin basic protein allele in mouse is compatible with normal myelination

Myelin deficiency (mld) is an autosomal recessive mutation in mice characterized by a severe myelin deficit in the central nervous system (CNS). The primary defect in mld is a reduction of the synthesis of the myelin basic protein (MBP) and probably lies in a regulatory element of the MBP gene. In young mld heterozygotes, the MBP mRNA and MBP levels are intermediate. In order to study whether reduced levels of MBP gene expression affect myelination, we determined the levels of MBP mRNA and MBP itself in mld heterozygous and control brains, at different ages during development. Total proteins and MBP were also measured in myelin isolated at 25 and 85 days of age. Myelin proteins were analyzed by SDS-PAGE. In addition, we carried out a morphometric analysis on 25- and 85-day-old optic nerves. Our results indicate that in spite of a roughly 50% reduction of MBP gene expression (compared to controls), the amounts of myelin isolated and the concentration of MBP in myelin were normal in heterozygous brains. Nevertheless, morphometric analyses of optic nerves, which myelinate later than the brainstem, showed thinner myelin sheaths in 25-day-old heterozygotes when compared to controls. This difference disappeared at 85 days of age. These results indicate that normal mice synthesize MBP in excess. The synthesis of this extramyelinic pool of MBP represents a safety factor allowing normal myelination to proceed even when MBP synthesis is severely reduced. In mld heterozygotes, a 30-50% reduction of this rate of synthesis can represent a limiting factor and locally delay myelin deposition without affecting the overall myelin content or myelin composition in heterozygous adult brains.