Transgenic Systems in Studying Myelin Gene Expression

Abstract

The myelin sheath is produced by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). It is necessary to introduce DNA into these cells to study gene regulation and the functions of myelin proteins. Since these cells are labile to commonly used techniques to introduce DNA, a transgenic system must be used for these studies. Myelin basic protein (MBP) and myelin proteolipid protein (PLP) are both highly abundant in CNS myelin, but are also produced in Schwann cells. Various lengths (6.5 kb to 256 bp) of the promoter region of the (classic) MBP gene directed oligodendrocyte-specific expression of the reporter gene in transgenic mice, but no expression was seen in Schwann cells. Promoter regions of the PLP gene (4.2–2.4 kb) seem to contain all the information required for correct spatiotemporal expression, but the level of expression was low. The first intron of the PLP gene is a candidate for the location of the enhancer-like element. Studies on MBP mutant mice carrying wild-type MBP gene or cDNA clearly demonstrated that one function of MBP is to make myelin lamellae compact by fusing the cytoplasmic surfaces of oligodendrocytes into the form of major dense lines. However, functional analysis of PLP gene products using a similar strategy produced confusing results. The wild-type PLP gene introduced into jimpy mutant mice (one of the PLP mutants) did not complement the mutant phenotype. Moreover, overexpression of the PLP gene itself (in wild-type background) was shown to produce a phenotype similar to that of the mutants, including arrest in oligodendrocyte maturation and hypomyelination. Thus, PLP gene products play a fundamental role in oligodendrocyte maturation as well as in the stabilization of myelin structure, and its expression must be tightly regulated.

Genetic Correlations Between Brain Volumes and the WAIS-III Dimensions of Verbal Comprehension, Working Memory, Perceptual Organization, and Processing Speed

“…As perceptual speed is likely to depend on axonal myelination, it can be hypothesized that part of the genes that influence IQ are common to the genes that influence myelination of axons by oligodendrocytes. A candidate gene known to be involved in myelination is the Plp gene (Boison & Stoffel, 1994;Griffiths et al, 1995, Ikenaka & Kagawa, 1995Lemke, 1993). Other genes implicated to be important for myelination from knock out mouse studies are the cgt-gene (Stoffel and Bosio, 1997), the MAG gene (Fujita et al, 1998, Sheikh et al, 1999Bartsch, 1996 for a review), and the tn-r gene (Weber et al, 1999).…”

Transcriptional control in myelinating glia: Flavors and spices

“…1) or human MBP gene. The regions used ranged from 6.5 kb (Friedrich et al, 1990;Zinkernagel et al, 1990) via 3.2 kb (Foran and Peterson, 1992), 1.9 kb (Gow et al, 1992), 1.3 kb (Miskimins et al, 1992), and 750 bp , to 256 bp (Goujet-Zalc et al, 1993) of 5Ј flanking sequence (for a detailed review, see Ikenaga and Kagawa, 1995). Interestingly, all the transgenes exhibited expression in cells of the oligodendrocyte lineage, and none showed expression in Schwann cells.…”

Expression and regulation of golli products of myelin basic protein gene during in vitro development of oligodendrocytes

“…Expression of the classic MBPs is restricted to the latest stages of differentiation of oligodendrocytes (OLs) and appears to be regulated by genetic elements located within 6.5-256 bp kb upstream from tss3 (Ikenaka and Kagawa, 1995). In contrast, the golli products have been detected both in OLs and in many neuronal populations.…”