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Shared Long-Range Regulatory Elements Coordinate Expression of a Gene Cluster Encoding Nicotinic Receptor Heteromeric Subtypes

Case School of Medicine, Department of Neurosciences, Cleveland, Ohio 44106

Received 15 March 2006/ Returned for modification 22 April 2006/ Accepted 13 May 2006

The nicotinic acetylcholine receptor (nAChR) ß4/3/5 gene cluster encodes several heteromeric transmitter receptor subtypes that are essential for cholinergic synaptic transmission in adrenal gland, autonomic ganglia, pineal gland, and several nuclei in the central nervous system. However, the transcriptional mechanisms coordinating expression of these subunit genes in different cell populations are unknown. Here, we used transgenic methods to investigate long-range transcriptional control of the cluster. A 132-kb P1-derived artificial chromosome (PAC) encoding the rat cluster recapitulated the neurally- and endocrine-restricted expression patterns of the endogenous ß4/3/5 genes. Mutation of ETS factor binding sites in an enhancer, ß43', embedded in the ß4 3'-untranslated exon resulted in greatly diminished ß4, 3, and 5 expression in adrenal gland and to a lesser extent in the superior cervical ganglion (SCG) but not in other tissues. Phylogenetic sequence analyses revealed several conserved noncoding regions (CNRs) upstream of ß4 and 5. Deletion of one of them (CNR4) located 20 kb upstream of ß4 resulted in a dramatic decrease in ß4 and 3 expression in the pineal gland and SCG. CNR4 was sufficient to direct LacZ transgene expression to SCG neurons, which express the endogenous ß435 subunits, and pineal cells, which express the endogenous ß43 combination. Finally, CNR4 was able to direct transgene expression to major sites of expression of the endogenous cluster in the brain. Together, our findings support a model in which cell type-specific shared long-range regulatory elements are required for coordinate expression of clustered nAChR genes.

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