Determinants of the brain‐specific expression of the rat aldolase C gene: <i>ex vivo</i> and <i>in vivo</i> analysis

Thomas, Mélanie; Makeh, Iman; Briand, Pascale; Kahn, Axel; Skala, Henriette

doi:10.1111/j.1432-1033.1993.tb18360.x

Cited by 56 publications

(28 citation statements)

References 38 publications

(40 reference statements)

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“…CAT activities directed by the TABLE I CAT activity of aldolase C/CAT transgenes in brains of transgenic mice For each transgenic mouse, three other tissues were tested (heart, lung, and liver); CAT activities were at least 100 -1000-fold lower than in brain. 0.8/CAT transgene were in the same range as those obtained with the 0.115/CAT transgene containing the short promoter alone (10,11).…”

Section: Resultssupporting

confidence: 67%

“…In Vivo, an Upstream 0.6-kb Fragment and a Far Upstream 3.8-kb Fragment Are Both Necessary for High Level Expression of the Aldolase C Transgenes-Using the CAT reporter gene, we previously showed that the transcriptional activity of the rat aldolase C gene in transgenic mice was ensured by a short 115-bp promoter that was brain-specific, but that was considerably more active when present in a construct containing 5.5 kb of aldolase C upstream sequences (10,11). To localize activating sequences in this 5.5-kb fragment, we analyzed, in transgenic mice, various combinations of aldolase C gene 5Ј-noncoding sequences fused to the CAT reporter gene.…”

Section: Resultsmentioning

confidence: 99%

“…Plasmid Constructions-The 5.5/CAT, 0.8/CAT, and 0.115/CAT constructs have been described previously (10,11). The transgenes 3.8ϩ0.8/CAT, BϩCϩDϩ0.8/CAT, Aϩ0.8/CAT, AϩBϩ0.8/CAT, AϩCϩ0.8/CAT, AϩDϩ0.8/CAT, and 3.8ϩ0.5/CAT contain different restriction fragments of the aldolase C gene 5.5-kb 5Ј-flanking region inserted upstream of the CAT reporter gene.…”

Section: Methodsmentioning

confidence: 99%

“…Like other genes broadly expressed in the brain, the aldolase C gene exhibits several features of housekeeping genes, namely the absence of canonical TATA and CAAT boxes, GC-rich sequence, and multiple transcription start sites (3,4,(7)(8)(9). We have previously reported that brain-specific expression of the CAT 1 reporter gene in transgenic mice could be directed by a short (Ͻ115 bp) promoter fragment of the aldolase C gene (10); however, this short fragment was not able to direct the high level transgene expression observed with the full-length 5.5-kb 5Ј-flanking region (11,12). To identify DNA regulatory elements required to ensure high level gene expression in the brain, we have now defined in vivo, in transgenic mice, activating sequences of the aldolase C gene and some of the cognate DNA-binding transcription factors.…”

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confidence: 99%

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Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Skala

Porteu

Thomas

et al. 1998

Journal of Biological Chemistry

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The rat aldolase C gene encodes a glycolytic enzyme strongly expressed in adult brain. We previously reported that a 115-base pair (bp) promoter fragment was able to ensure the brain-specific expression of the chloramphenicol acetyltransferase (CAT) reporter gene in transgenic mice, but only at a low level (Thomas, M., Makeh, I., Briand, P., Kahn, A., and Skala, H. (1993) Eur. J. Biochem. 218, 143-151). Here we show that in vivo activation of this promoter at a high level requires cooperation between an upstream 0.6-kilobase pair (kb) fragment and far upstream sequences. In the 0.6-kb region, a 28-bp DNA element is shown to include overlapping in vitro binding sites for POU domain regulatory proteins and for the Winged Helix hepatocyte nuclear factor-3␤ factor. An hepatocyte nuclear factor-3␤-binding site previously described in the short proximal promoter fragment is also shown to interact in vitro with POU proteins, although with a lower affinity than the 28-bp motif. Additional binding sites for POU factors were detected in the upstream 0.6-kb sequences. Progressive deletion in this region resulted in decreased expression levels of the transgenes in mice, suggesting synergistic interactions between these multiple POUbinding sites. We propose that DNA elements characterized by a dual binding specificity for both POU domain and Winged Helix transcription factors could play an essential role in the brain-specific expression of the aldolase C gene and other neuronal genes.

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Skala

Porteu

Thomas

et al. 1998

Journal of Biological Chemistry

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“…Gel shift experiments confirmed that this region in RI␤ binds pure SP1 and additional proteins in brain nuclear extract (21). Similar sequences are present in a number of genes expressed in neural tissue (37,38), including the promoter for the RII␤ subunit of PKA (39), and are required for expression of aldolase C in mouse brain (40). Sequences such as these have also been shown to bind inhibitors of transcription (41).…”

Section: Discussionmentioning

confidence: 95%

Promoter Sequences in the RIβ Subunit Gene of cAMP-dependent Protein Kinase Required for Transgene Expression in Mouse Brain

Clegg

Haugen

Boring³

1996

Journal of Biological Chemistry

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Neural-specific expression of the mouse regulatory type-I␤ (RI␤) subunit gene of cAMP-dependent protein kinase is controlled by a fragment of genomic DNA comprised of a TATA-less promoter flanked by 1.5 kilobases of 5-upstream sequence and a 1.8-kilobase intron. This DNA contains a complex arrangement of transcription factor binding motifs, and previous experiments have shown that many of these are recognized by proteins found in brain nuclear extract. To identify sequences critical for RI␤ expression in functional neurons, we performed a deletion analysis in transgenic mice. Evidence is presented that the GC-rich proximal promoter is responsible for cell type-specific expression in vivo because RI␤ DNA containing as little as 17 base pairs (bp) of 5-upstream sequence was functional in mouse brain. One likely regulatory element coincides with the start of transcription and includes an EGR-1 motif and 3 consecutive SP1 sites within a 21-bp interval. Maximal RI␤ promoter activity required the adjacent 663 bp of 5-upstream DNA where most, but not all, of the regulatory activity was localized between position ؊663 and ؊333. A 37-bp direct repeat lies within this region that contains 2 basic helix-loop-helix binding sites, each of which are overlapped by two steroid hormone receptor half-sites, and a shared AP1 consensus sequence. Intron I sequences were also tested, and deletion of a 388-bp region containing numerous Sp1-like sequences lowered transgene activity significantly. These results have identified specific regions of the RI␤ promoter that are required for the expression of this signal transduction protein in mouse neurons.The variety of neuronal cell types that comprise the mammalian nervous system is determined by highly refined spatial and temporal patterns of gene expression (1, 2). This idea is supported by the restricted expression patterns of numerous transcription factors within the developing nervous system. Members of the homeobox (3, 4), POU domain (5, 6), and bHLH 1 (7, 8) families of DNA binding proteins help initiate the cascades of gene expression that establish region-specific classes of neurons. The diversity of neuronal phenotypes is further enhanced during the life of the organism by stimulusdependent modifications in differentiated neurons. This adaptive plasticity, controlled by various neurotransmitters and cytokines, elicits new patterns of gene expression and long-term changes in cell behavior (9, 10). A better understanding of how neuronal diversity and function is achieved will be facilitated by the identification of the mechanisms that regulate neural-specific gene expression. A mouse gene that we have focused on encodes the regulatory type I␤ (RI␤) subunit of cAMP-dependent protein kinase (PKA) (11). Protein phosphorylation by PKA serves a pivotal role in neuronal function (12)(13)(14). The R subunits of the holoenzyme, of which four genes have been identified, prevent catalysis in the absence of cAMP (15). Each type of regulatory subunit contributes distinct qualities that broade...

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The role of early growth response gene 1 (egr-1) in regulation of the immune response

McMahon

Monroe

1996

Journal of Leukocyte Biology

143

115

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The induction of immediate early genes in cells of the immune system is critical to determining the ultimate outcome of exposure to antigen. The importance of many of these genes relates to the role their transcription factor products play in dictating patterns of expression of downstream, function-related genes. Evidence from several systems indicates that the immediate early gene, egr-1 may be of particular importance in the immune system. Recently, the egr-1 promoter has been shown to be highly responsive to the diverse biochemical signals generated by antigen and cytokines in cells of the immune system. Furthermore, an important role for egr-1 in determining the differentiation pathway of myeloid cell precursors has been recently elaborated. Finally, potential targets of regulation by the zinc-finger transcription factor encoded by egr-1 include the interleukin-2, CD44, ICAM-1, and tumor necrosis factor genes. The role of egr-1 in regulation of the immune response will be discussed in the context of these recent studies.

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Determinants of the brain‐specific expression of the rat aldolase C gene: ex vivo and in vivo analysis

Cited by 56 publications

References 38 publications

Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Promoter Sequences in the RIβ Subunit Gene of cAMP-dependent Protein Kinase Required for Transgene Expression in Mouse Brain

The role of early growth response gene 1 (egr-1) in regulation of the immune response

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