Developmental Expression of the P₀ Glycoprotein and Basic Protein mRNAs in Normal and Trembler Mutant Mice

Abstract

Mice affected by the autosomal dominant Trembler mutation exhibit a severe hypomyelinization of the PNS. Previous biochemical studies have shown that the accumulation of the major PNS myelin proteins, P0 and myelin basic protein (MBP), is strongly diminished in Trembler sciatic nerves during postnatal development. We performed Northern blots which showed that the size of mRNA species for P0 and MBP in normal and mutant mice are indistinguishable. Densitometric analysis of Northern blots showed that, in normal mice, the proportion of P0 mRNA increases up to the 12th day, then decreases slowly. At day 40, the proportion is 60% of the maximal value. In the mutant, the proportion of P0 mRNA increases up to the 12th day and then decreases much faster than in the control. At days 12 and 40, the P0 mRNA proportion measured in Trembler sciatic nerves represents only 40% and 7%, respectively, of the proportion measured in control littermates. The MBP mRNA proportion in the normal mice increases up to the 16th day, and then decreases to attain 45% of the maximum level at day 40. In the Trembler mouse, there is a maximum level at day 12, representing 25% of the normal level, but the MBP mRNA is barely detectable at days 8 or 40. Thus, these data seem to indicate that in the Trembler sciatic nerves, the proportions of P0 and MBP mRNAs are too small to allow the synthesis of normal levels of the corresponding proteins.

Expression of the PMP-22 Gene in Trembler Mutant Mice: Comparison with the Other Myelin Protein Genes

“…We previously showed that Po and MBP gene expres sion was affected by the mutation in heterozygous trem bler mice [15]. Our present data, fully consistent with Po protein quantitation in trembler PNS [18], indicate that the myelin genes like Po and MBP involved in the accu mulation of myelin membrane around the axons and the subsequent compaction, are more severely affected by the mutation than genes involved in the early myelination events like MAG.…”

“…This mutation leads to a hypomyelination of the PNS and continuing Schwann cell proliferation through out life [8], Biochemical studies performed with het erozygous trembler mice have shown abnormalities af fecting lipids [9][10][11], proteins [12][13][14] as well as Po and MBP mRNAs levels [15]. Very recently, it was claimed that the primary molecular defect in this mutant is a glycine to aspartic acid mutation in a putative transmem brane domain of the PMP-22 protein [16].…”

The homeotic protein dlk is expressed during peripheral nerve development

“…Four genes were predominantly expressed in normal sciatic nerves. As expected, we found the genes encoding the myelin protein zero (P0) and PMP22, whose under‐expression in the trembler nerves has been already reported [25,26]. Moreover, the normal/trembler ratios measured in the present study for 15‐day‐old animals, which were 7.4 for PMP22 and 2.6 for P0, were similar to those previously measured by the Northern blot technique, which were 11 for PMP22 and 3.9 for P0 [26].…”

A molecular basis for hereditary motor and sensory neuropathy disorders

“…Trembler mice, for example, in which one of the two PMP22 genes is mutated, are much more severely affected than mice carrying a single copy of a PMP22 knockout allele (PMP22 ±) [64]. Trembler mice have less myelin than PMP22± animals, and the steady-state levels of their myelin-specific mRNAs are dramatically reduced [65,66]. This additional effect of mutated PMP22, called a toxic gain of function, is probably caused by interactions of the mutated protein with other cellular constituents, and can account for these differences in phenotype.…”