Cell and tissue-specific expression of a heterologous gene under control of the myelin basic protein gene promoter in transgenic mice

Miskimins, Robin; Knapp, Loren W.; Dewey, Michael J.; Zhang, Xiaoping

doi:10.1016/0165-3806(92)90182-v

Cited by 31 publications

(28 citation statements)

References 11 publications

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“…Readhead et al [1987], Foran et al [1992] and Miskimins et al [1992] found that transgene expression reached the maximum at P I6 -2 3 and then decreased thereafter, a finding which is in good agreement with the pattern of endogenous MBP gene expression. On the other hand, no decrease in expression was observed by Gow et al [1992] and Goujet-Zalc et al [1993].…”

Section: Mbp Gene Regulationsupporting

confidence: 60%

“…This fragment is capable of directing brain, or more specifically, oligodendrocyte-specific expression of the transgene [Kirnura et al, 1989;Tumley et al, 1991;Yoshioka et al. 1991;Miskimins et al, 1992], However, it did not direct expression in the PNS, where MBP is produced by Schwann cells. This was not improved by the addition of further upstream fragments, up to the -3.2-kb region (table 1) [Gow et al, 1992;Foran and Peterson, 1992].…”

Section: Mbp Gene Regulationmentioning

confidence: 99%

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Transgenic Systems in Studying Myelin Gene Expression

Ikenaka

Kagawa²

1995

Dev Neurosci

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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.

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Section: Mbp Gene Regulationsupporting

confidence: 60%

Section: Mbp Gene Regulationmentioning

confidence: 99%

Transgenic Systems in Studying Myelin Gene Expression

Ikenaka

Kagawa²

1995

Dev Neurosci

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“…Immunohistochemical Staining for CAT-Rabbit polyclonal affinitypurified antibody to CAT (Miskimins et al, 1992) were purchased from 5 Prime 3 3 Prime, Inc. (Paoli, PA). Anti-rabbit IgG-digoxigenin (DIG), F(abЈ)2 fragments from sheep, anti DIG-peroxidase, F(ab) fragments, and anti-DIG-fluorescein isothiocyanate were purchased from Boehringer Mannheim (Meylan, France).…”

Section: Methodsmentioning

confidence: 99%

An Intronic Enhancer Essential for Tissue-specific Expression of the Aldolase B Transgenes

Sabourin¹,

Kern

Gregori

et al. 1996

Journal of Biological Chemistry

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Expression in mice of transgenes directed by regulatory regions of the rat aldolase B gene requires the presence of a B element located in the first intron, while constructs devoid of this intronic enhancer are silent. Histo-and immunochemical staining of transgenic tissue sections showed that the longer transgene was expressed in the proximal tubular cells of the kidney, enterocytes located in small intestine villi and liver parenchymal cells. In the liver, a maximal expression was observed in perivenous hepatocytes, while the transgene was weakly active in periportal hepatocytes, which reproduced the pattern of functional zonation already reported for other glycolytic and gluconeogenic genes in the liver. We also established that the transgene retained the necessary elements for a correct chronological expression during development but was lacking elements necessary for activation by high carbohydrate diet. Instead, transgene expression was paradoxically stimulated in fasted animals, suggesting that the endogenous gene, which must be active under both glycolytic and gluconeogenic conditions, could possess distinct elements activating it in fasted as well as in carbohydratefed animals; the former element might be conserved in the transgene and the latter one might be lost.

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“…The 5Ј-flanking regions of the mouse MBP promoter ranging from 9.5 kilobases to 256 nt were sufficient to drive oligodendrocyte-specific and developmentally regulated expression of reporter genes in transgenic mice (5)(6)(7)(8). Several studies in vitro have sought to identify specific DNA sequences within the proximal MBP promoter that might be necessary for cell-specific expression, but most of these studies were performed using cells that do not transcribe MBP or nuclear extracts prepared from the brain, which contains a complicated mixture of cell types (9 -11).…”

Section: Myelin Basic Protein (Mbp)mentioning

confidence: 99%

MEBA Derepresses the Proximal Myelin Basic Protein Promoter in Oligodendrocytes

Taveggia¹,

Pizzagalli²,

Feltri³

et al. 1998

Journal of Biological Chemistry

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The central nervous system expression of myelin basic protein (MBP) is restricted to oligodendrocytes and is developmentally regulated; these regulatory features are transcriptionally mediated. We have previously shown that the proximal 149 nucleotides of the MBP promoter were both necessary and sufficient to activate the transcription of MBP in cultured oligodendrocytes, but not in other cell types. Sequences within the distal portion of this promoter, which contains a nuclear factor 1 (NF1) binding site, repressed activation of the MBP promoter in Cos-7 cells, but not in oligodendrocytes. We now describe a sequence upstream of and partially overlapping the NF1 site that activates the MBP promoter in oligodendrocytes, but not in Myelin basic protein (MBP)1 is a structural protein of myelin expressed only by oligodendrocytes or Schwann cells. In the central nervous system, MBP expression by oligodendrocytes is required for normal myelinogenesis (1). MBP mRNA expression in the rodent brain rises approximately 100-fold between birth and 30 days and falls to 40% of the peak expression in the adult. Transcriptional run-on analysis suggests that these regulatory features are primarily transcriptionally mediated (2, 3). In the peripheral nervous system, MBP expression by Schwann cells is not strictly required for normal myelinogenesis, although when the amount of basic intracellular domains contributed by other myelin proteins is reduced, MBP becomes essential (4). MBP mRNA expression also rises rapidly in the peripheral nervous system during postnatal development, suggesting that its regulation is transcriptionally mediated, although this has not been demonstrated directly by transcriptional run-on analysis.The transcriptional regulation of the MBP gene in the central nervous system has been studied extensively, both in vivo and in vitro. The 5Ј-flanking regions of the mouse MBP promoter ranging from 9.5 kilobases to 256 nt were sufficient to drive oligodendrocyte-specific and developmentally regulated expression of reporter genes in transgenic mice (5-8). Several studies in vitro have sought to identify specific DNA sequences within the proximal MBP promoter that might be necessary for cell-specific expression, but most of these studies were performed using cells that do not transcribe MBP or nuclear extracts prepared from the brain, which contains a complicated mixture of cell types (9 -11).We have previously shown that 750 nt of human MBP promoter were sufficient to activate oligodendrocyte-specific, developmentally regulated expression of lacZ during active myelinogenesis in transgenic mice (3). In addition, we showed by transient transfection analysis in primary cultures of oligodendrocytes that 750, 420, or 149 nt of human MBP promoter was sufficient to activate a 5-10-fold increase in the expression of the CAT reporter gene in oligodendrocytes, but not in other cell types (12). We also showed that the 149-nt region contained two subregions with opposing functional activities: (a) the proximal 102-nt region ac...

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Cell and tissue-specific expression of a heterologous gene under control of the myelin basic protein gene promoter in transgenic mice

Cited by 31 publications

References 11 publications

Transgenic Systems in Studying Myelin Gene Expression

Transgenic Systems in Studying Myelin Gene Expression

An Intronic Enhancer Essential for Tissue-specific Expression of the Aldolase B Transgenes

MEBA Derepresses the Proximal Myelin Basic Protein Promoter in Oligodendrocytes

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