β43′: An Enhancer Displaying Neural-Restricted Activity Is Located in the 3′-Untranslated Exon of the Rat Nicotinic Acetylcholine Receptor β4 Gene

McDonough, Jennifer; Deneris, Evan S.

doi:10.1523/jneurosci.17-07-02273.1997

Cited by 39 publications

(38 citation statements)

References 51 publications

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“…The importance of this tightly linked region in the potential regulation of the CHRNA5/A3/B4 gene cluster stems from transcriptional analysis of nicotinic receptors in rodents, where McDonough and Deneris (44) discovered a novel enhancer positioned in the 3′-untranslated exon of the CHRNB4 gene. The location of this enhancer within the CHRNB4 gene may be under selective pressure for maintaining tight linkage of the clustered neuronal CHRNA5/A3/B4 genes (19,44). To date, there is no functional evidence for a human CHRNB4 3′UTR-enhancer, but this region appears to be conserved between rodents and humans (Dr. Deneris, personal communication).…”

Section: Discussionmentioning

confidence: 99%

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

Schlaepfer

Hoft

Collins

et al. 2008

Biological Psychiatry

174

179

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Background-One potential site of convergence of the nicotine and alcohol actions is the family of the neuronal nicotinic acetylcholine receptors. Our study examines the genetic association between variations in the genomic region containing the CHRNA5, A3 and B4 gene cluster (A5A3B4) and several phenotypes of alcohol and tobacco use in an ethnically diverse young adult sample. Significant results were then replicated in a separate adult population-representative sample.

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Section: Discussionmentioning

confidence: 99%

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

Schlaepfer

Hoft

Collins

et al. 2008

Biological Psychiatry

174

179

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“…nAChR subunit ␤2 has been so far found in every neurons, this wide-spread expression being due to its particular promoter (Bessis et al, 1997). At the same time ␤4 is coexpressed with ␣3 because the two genes are located in a cluster and share common regulatory elements (McDonough and Deneris, 1997). Consequently, every neuron that expresses ␣3 will also express ␤2 and ␤4, even if the presence of the two latter subunits is not required (see the section on KO animals).…”

Section: Promoters and Regulation Of Expressionmentioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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“…The ␤43Ј enhancer and ␣3 promoter reporters used here were derived from the Ϫ2732/ϩ47 region of the ␣3 gene (12,18,19). For most reporters, enhancer sequences were placed upstream of either the SV40 or ␣3 promoters using synthetic oligonucleotides and convenient restriction sites or by polymerase chain reaction.…”

Section: Plasmidsmentioning

confidence: 99%

“…Cell Lines-The PC12 and Rat 2 cell lines were maintained in culture, transfected, and assayed for reporter activity as described previously (12).…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…Using adrenal chromaffin cell-derived PC12 cells, which express the clustered genes, we identified an enhancer positioned within the ␤4 3Ј-untranslated exon. This enhancer, ␤43Ј, is responsible for cell-type specific activity in cell lines of a 2.8-kilobase pair fragment that constitutes the immediate ␣3 upstream region (12,13). ␤43Ј contains consensus ETS domain transcription factor-binding sites and can be activated in co-transfection assays by the ETS factor Pet-1 (14).…”

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confidence: 99%

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Regulation of Transcription in the Neuronal Nicotinic Receptor Subunit Gene Cluster by a Neuron-selective Enhancer and ETS Domain Factors

McDonough

Francis

Miller

et al. 2000

Journal of Biological Chemistry

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Expression of neurotransmitter receptors encoded by the nicotinic acetylcholine receptor (nAchR) subunit gene cluster depends on coexpression of the ␤4, ␣3, and ␣5 subunits in certain kinds of neurons. One way in which coexpression might be achieved is through the regulation of promoters in the cluster by neuron-selective enhancers. The ␤43 enhancer is located between the ␤4 and ␣3 promoters and it directs cell type-specific expression in cell lines. It is not known, however, whether ␤43 is active in neurons. Therefore, we assayed ␤43 in dissociated rat sympathetic ganglia cultures, which contain nAchR-positive neurons as well as nAchR-negative non-neuronal cells. Reporters controlled by the ␣3 promoter and ␤43 were expressed in a neuron-selective manner; greater than 90% and up to 100% of luciferase expression was detected in neurons. Neuron selectivity was maintained when ␤43 was placed next to ubiquitously active viral promoters. In contrast, replacing ␤43 with the SV40 enhancer eliminated neuron selectivity. The enhancer is composed of at least two separate but functionally interdependent elements, each of which interacts with a different type of ETS domain factor. These findings support a model in which ␤43 controls neuronal expression of one or more genes in the cluster through interactions with a combination of ETS factors.Neuronal differentiation depends on selective expression of certain genes such as those encoding ion channels, axon guidance molecules, neurotransmitter synthetic enzymes, transporters, and receptors in subsets of neurons. Selective expression is likely to occur through a combinatorial interaction of transcriptional activators and repressors with specific regulatory sequences in or near a particular gene (1). A rich assortment of transcriptional activator proteins are expressed in the nervous system. However, little is known about the sequences they interact with to direct expression of their target genes to certain kinds of neurons. Elucidating these interactions is likely to provide additional insight into the mechanisms underlying neuronal differentiation and development of neuronal diversity.The family of neuronal nicotinic acetylcholine receptors (nAchR) 1 subunit genes is an example of genes whose members are expressed in different populations of neurons. The subunits encoded by these genes are assembled into different heteromeric excitatory ligand-gated ion channels (2). These neurotransmitter receptors mediate and modulate synaptic communication between a wide variety of central and peripheral neurons (3, 4). Three of these genes are clustered in the order ␤4, ␣3, and ␣5 in the vertebrate genome (5). They are coexpressed in sympathetic neurons, adrenal chromaffin cells, and probably in some central neuron cell types (6 -8). The three encoded subunits are likely assembled together into at least one heteromeric neurotransmitter receptor subtype (9). Gene targeting suggests that the ␣3 and ␤4 genes are essential for the expression of the majority of nAChRs in autonomic neurons (10,...

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β43′: An Enhancer Displaying Neural-Restricted Activity Is Located in the 3′-Untranslated Exon of the Rat Nicotinic Acetylcholine Receptor β4 Gene

Cited by 39 publications

References 51 publications

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

Regulation of Transcription in the Neuronal Nicotinic Receptor Subunit Gene Cluster by a Neuron-selective Enhancer and ETS Domain Factors

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