Mutations in the Myelin Proteolipid Protein Gene Alter Oligodendrocyte Gene Expression in Jimpy and Jimpy^msd Mice

Abstract

The mouse myelin proteolipid protein (PLP) gene has been studied in normal and jimpymsd mice. Potential upstream regulatory regions of the normal gene have been cloned and mapped, but when these regions were studied in jimpymsd mice by Southern blots, no alterations were observed, relative to the normal gene. To assess whether the low ratio of PLP to DM20 proteins in this mutant reflected an altered PLP/DM20 ratio mRNAs, S1 nuclease analyses were undertaken, which demonstrated that at all ages studied in both jimpy and jimpymsd mice, PLP mRNA was elevated above DM20 mRNA. When exon 3 (the site of the alternative splice signal for DM20 mRNA) of the jimpymsd PLP gene was sequenced, no mutation was identified. The transcription of the PLP gene in normal and mutant animals was studied. The transcription rate increases in normal animals with development, and in very young jimpymsd or jimpy mice, the transcription rate of the PLP gene was close to that of age-matched normal animals. However, by 10 days of age, the transcription rate of this gene in both mutants was significantly below that of age-matched controls. The transcription rate of the myelin basic protein (MBP) gene was also reduced, indicating that expression of both genes is affected by this mutation. In contrast, the transcription rate of the glycerol phosphate dehydrogenase (GPDH) gene, an early marker of oligodendrocytes, is equal to or greater than normal in both mutants. We have confirmed an earlier report of a point mutation in exon 6 of the jimpymsd PLP gene, which converts an alanine to a valine.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of a Myelin Proteolipid Protein (Plp)-lacZ Transgene is Reduced in both the CNS and PNS of Plp jp Mice

“…3). Previous studies [5] have shown that Plp gene transcription, in brain, is reduced in affected mice, with Plp jp mice at P25 having similar levels of Plp transcription as wild-type mice at P7. Other studies [38] have shown that the pattern of myelin gene expression in Plp jp oligodendrocytes is consistent with that found in immature wild-type cells.…”

“…Campagnoni's group showed two decades ago that PLP protein and mRNA are dramatically downregulated in Plp jp mice [33][34][35]. Additionally, it has been known for some time that both Plp and Mbp transcriptional activity is decreased in the brains of affected males [5,36]. While the obvious assumption has been that the mutant PLP protein is responsible for this change, it is possible that the point mutation itself could have had a cis effect on Plp gene activity.…”

“…Perhaps the reduction in transgene expression simply reflects the fact that Plp jp oligodendrocytes are compromised, triggering higher levels of cell death, and thus reducing their overall number in affected animals. However, significant numbers of GC+ oligodendrocytes are present in these animals [35,37], and transcription of glycerol phosphate dehydrogenase, an early marker of oligodendrocyte differentiation, is unaffected [5]. In contrast, genes such as Plp, Mbp, and Mog (myelin/oligodendrocyte glycoprotein), whose expression is upregulated late in the oligodendrocyte differentiation program, are expressed at lower levels in the Plp jp CNS [5,36,38], much like the PLP(+)Z transgene.…”

“…However, significant numbers of GC+ oligodendrocytes are present in these animals [35,37], and transcription of glycerol phosphate dehydrogenase, an early marker of oligodendrocyte differentiation, is unaffected [5]. In contrast, genes such as Plp, Mbp, and Mog (myelin/oligodendrocyte glycoprotein), whose expression is upregulated late in the oligodendrocyte differentiation program, are expressed at lower levels in the Plp jp CNS [5,36,38], much like the PLP(+)Z transgene. Thus it appears that it is the ability of the cells to fully differentiate, and hence express high levels of gene products found in mature oligodendrocytes that is compromised in the Plp jp mutant.…”

“…In very young animals, the transcription rate of the Plp jp gene is similar to that in mice containing the wild-type gene. However, as development proceeds, Plp gene transcription in the mutant does not increase as it does in wildtype mice [5]. In addition, the Plp jp mutation exhibits pleiotropic effects, for example, reducing the transcription rate of the myelin basic protein (Mbp) gene, which is expressed later in the oligodendrocyte differentiation pathway.…”