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A Bessis

Publications and source records attributed to A Bessis.

14 recordsLinked to original sources
PubMed1997

The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain.

The neuron-restrictive silencer element (NRSE) has been identified in several neuronal genes and confers neuron specificity by silencing transcription in nonneuronal cells. NRSE is present in the promoter of the neuronal nicotinic acetylcholine receptor beta2-subunit gene that determines its neuron-specific expression in the nervous system. Using transgenic mice, we show that NRSE may either silence or enhance transcription depending on the cellular context within the nervous system. In vitro in neuronal cells, NRSE activates transcription of synthetic promoters when located downstream in the 5' untranslated region, or at less than 50 bp upstream from the TATA box, but switches to a silencer when located further upstream. In contrast, in nonneuronal cells NRSE always functions as a silencer. Antisense RNA inhibition shows that the NRSE-binding protein REST contributes to the activation of transcription in neuronal cells.

Animals↗
PubMed1996

Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors.

The regulatory region of the neuronal nicotinic acetylcholine (nACh) receptor alpha 2 subunit gene is activated by the Brn-3b POU family transcription factor but not by the closely related factors Brn-3a and Brn-3c. This pattern of regulation has not previously been observed for other neuronally expressed genes, several of which, such as those encoding alpha-internexin or SNAP-25, are activated by Brn-3a and Brn-3c but repressed by Brn-3b. The alpha 3 nACh receptor subunit gene is also shown to be activated by Brn-3a but is repressed by Brn-3b and Brn-3c. In contrast, the Brn-3 POU family transcription factors have no effects on either the alpha 7 or beta 4 nACh receptor subunit genes. The actions of Brn-3b on the alpha 2 subunit are thus in contrast to the inhibitory actions of Brn-3b on several promoters that are activated by Brn-3 alpha. The different actions of the Brn-3 POU factors on the range of nACh receptor genes tested suggests that the novel stimulation of the alpha 2 subunit by Brn-3b is specific to this subunit and not a general feature of nACh receptor genes.

Acetylcholine↗
PubMed1995

The neuronal nicotinic acetylcholine receptor alpha 2 subunit gene promoter is activated by the Brn-3b POU family transcription factor and not by Brn-3a or Brn-3c.

The regulatory region of the neuronal nicotinic acetylcholine receptor alpha 2 subunit gene, which contains six copies of the octamer-related sequence CCCCATGCAAT, is activated by the Brn-3b POU family transcription factor but not by the closely related factors Brn-3a and Brn-3c. This effect is in contrast to the previously documented inhibitory effect of Brn-3b on octamer-containing promoters that are activated by Brn-3a and Brn-3c. Activation of the alpha 2 gene by Brn-3b requires that both the POU domain and other N-terminal sequences are derived from Brn-3b and is dependent on the intactness of the alpha 2 gene regulatory region, being lost in truncated derivatives containing one, two, or four copies of the octamer-related sequence. Surprisingly, however, these truncated derivatives are activated by Brn-3c. These effects are discussed in terms of both the influence of the target sequence and its context in the promoter on activation by the various forms of Brn-3 as well as of the processes that restrict expression of the alpha 2 subunit gene to a few cells in the nervous system.

Animals↗
PubMed1995

Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain.

Nicotine affects many aspects of behaviour including learning and memory through its interaction with neuronal nicotinic acetylcholine receptors (nAChR). Functional nAChRs are pentameric proteins containing at least one type of alpha-subunit and one type of beta-subunit. The involvement of a particular neuronal nicotinic subunit in pharmacology and behaviour was examined using gene targeting to mutate beta 2, the most widely expressed nAChR subunit in the central nervous system. We report here that high-affinity binding sites for nicotine are absent from the brains of mice homozygous for the beta 2-subunit mutation. Further, electrophysiological recording from brain slices reveals that thalamic neurons from these mice do not respond to nicotine application. Finally, behavioural tests demonstrate that nicotine no longer augments the performance of beta 2-1- mice on passive avoidance, a test of associative memory. Paradoxically, mutant mice are able to perform better than their non-mutant siblings on this task.

Animals↗
PubMed1995

Promoter elements conferring neuron-specific expression of the beta 2-subunit of the neuronal nicotinic acetylcholine receptor studied in vitro and in transgenic mice.

Several genes encoding subunits of the neuronal nicotinic acetylcholine receptors have been cloned and regulatory elements involved in the transcription of the alpha 2 and alpha 7-subunit genes have been described. Yet, the detailed mechanisms governing the neuron-specific transcription and the spatio-temporal expression pattern of these genes remain largely uninvestigated. The beta 2-subunit is the most widely expressed neuronal nicotinic receptor subunit in the nervous system. We have studied the structural and regulatory properties of the 5' sequence of this gene. A fragment of 1163 bp of upstream sequence is sufficient to drive the cell-specific transcription of a reporter gene in both transient transfection assays and in transgenic mice. Deletion analysis and site-directed mutagenesis of this promoter reveal two negative elements and one positive element. The positively-acting sequence includes one functional E-box. One of the repressor elements is located in the transcribed region and is the NRSE/RE1 sequence already described in promoters of neuronal genes. In this paper, we describe the neuron-specific promoter of the gene encoding the neuronal nicotinic acetylcholine receptor beta 2-subunit.

Animals↗
PubMed1993

Negative regulatory elements upstream of a novel exon of the neuronal nicotinic acetylcholine receptor alpha 2 subunit gene.

The expression of the nicotinic acetylcholine receptor alpha 2 subunit gene is highly restricted to the Spiriform lateralis nucleus of the Chick diencephalon. As a first step toward understanding the molecular mechanism underlying this regulation, we have investigated the structural and regulatory properties of the 5' sequence of this gene. A strategy based on the ligation of an oligonucleotide to the first strand of the cDNA (SLIC) followed by PCR amplification was used. A new exon was found approximately 3kb upstream from the first coding exon, and multiple transcription start sites of the gene were mapped. Analysis of the flanking region shows many consensus sequences for the binding of nuclear proteins, suggesting that the 1 kb flanking region contains at least a portion of the promoter of the gene. We have analysed the negative regulatory elements present within this region and found that a silencer region located between nucleotide -144 and +76 is active in fibroblasts as well as in neurons. This silencer is composed of six tandem repeat Oct-like motifs (CCCCATGCAAT), but does not bind any member of the Oct family. Moreover these motifs were found to act as a silencer only when they were tandemly repeated. When two, four or five motifs were deleted, the silencer activity of the motifs unexpectedly became an enhancer activity in all cells we have tested.

Animals↗
PubMed1993

Chicken neuronal acetylcholine receptor alpha 2-subunit gene exhibits neuron-specific expression in the brain and spinal cord of transgenic mice.

Transgenic mice carrying the complete structural gene of the alpha 2 subunit of the chicken neuronal nicotinic acetylcholine receptor (nAChR) and 7 kilobase pairs (kbp) of 5' upstream and 3 kbp of 3' downstream sequences have been generated. The transgene was stably integrated in transgenic lines and transmitted to their progeny. Avian transgene expression was predominant in the central nervous system as detected by specific alpha 2-subunit cDNA amplification. Moreover, in at least two independent mouse lines, its expression appeared to be neuron-specific and reproducibly restricted to subregions in the brain and spinal cord, as revealed by in situ hybridization histochemistry. Most cranial motor nuclei were positive, and several of the alpha 2-subunit transgene-expressing structures corresponded to cholinergic areas in rodents. This study reveals that regulatory mechanisms giving rise to neuronal-specific gene expression have been conserved at least in part between birds and mammals.

Animals↗
PubMed1990

Chromosomal localization of the mouse genes coding for alpha 2, alpha 3, alpha 4 and beta 2 subunits of neuronal nicotinic acetylcholine receptor.

The chromosomal localization of four neuronal nicotinic acetylcholine receptor subunit genes was performed by following the mendelian segregation of their corresponding alleles in backcrosses involving the mouse species Mus spretus and the laboratory strains C57BL/6 or BALB/c. A similar analysis previously performed with muscle nicotinic acetylcholine receptor subunits revealed that the genes coding for the alpha and beta subunits are respectively located on chromosome 2 and 11, whereas the gamma and delta subunit coding genes are linked and located on mouse chromosome 1. In this study, we show that the genes coding for the neuronal nicotinic acetylcholine receptor alpha 2, alpha 3 and beta 2 subunits are dispersed on three different mouse chromosomes, viz. 14, 9 and 3 respectively. Moreover, the alpha 4 subunit gene is located on chromosome 2 but is not genetically linked to the alpha 1 subunit gene.

Animals↗
PubMed1990

Differential expression of the neuronal acetylcholine receptor alpha 2 subunit gene during chick brain development.

In situ hybridization histochemistry reveals localized expression of the nicotinic acetylcholine receptor (nAChR) alpha 2 subunit mRNA restricted to the lateral spiriform nucleus (SpL) of the chick diencephalon. The alpha 2 nAChR transcripts are not detected in immature SpL neurons at 4.5-5 days of embryonic development. They begin to accumulate in the SpL at embryonic day 11 and increase until the newborn stage. Specific alpha 2 cDNA amplification by the polymerase chain reaction shows that during this period, the absolute content of alpha 2 mRNA increases about 20-fold. The expression of the alpha 2 nAChR gene is thus developmentally regulated and appears concomitant with the entry of cholinergic fibers into the SpL, as demonstrated by choline acetyltransferase immunohistochemistry.

Afferent Pathways↗