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J. Biol. Chem., Vol. 279, Issue 28, 29740-29751, July 9, 2004

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Combinatorial Complexity of 5' Alternative Acetylcholinesterase Transcripts and Protein Products^*

Eran Meshorer, Debra Toiber, Dror Zurel, Iman Sahly¶||, Amir Dori, Emanuela Cagnano**, Letizia Schreiber, Dan Grisaru, François Tronche¶, and Hermona Soreq¶¶

From the Department of Biological Chemistry and the Israel Center of Neuronal Computation, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel, ^¶CNRS FRE2401, Molecular Genetics, Neurophysiology, and Behavior, Institute of Biology, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 5, France, the ^**Department of Pathology, Soroka University Medical Center, Beer-Sheva 64239, Israel, and the Departments of Pathology and Obstetrics and Gynecology, Sourasky Medical Center, Tel-Aviv University, Tel-Aviv 84105, Israel

To explore the scope and significance of alternate promoter usage and its putative inter-relationship to alternative splicing, we searched expression sequence tags for the 5' region of acetylcholinesterase (ACHE) genes. Three and five novel first exons were identified in human and mouse ACHE genes, respectively. Reverse transcription-PCR and in situ hybridization validated most of the predicted transcripts, and sequence analyses of the corresponding genomic DNA regions suggest evolutionarily conserved promoters for each of the novel exons identified. Distinct tissue specificity and stress-related expression patterns of these exons predict combinatorial complexity with known 3' alternative AChE mRNA transcripts. Unexpectedly one of the 5' exons encodes an extended N terminus in-frame with the known AChE sequence, extending the increased complexity to the protein level. The resultant membrane variant(s), designated N-AChE, is developmentally regulated in human brain neurons and blood mononuclear cells. Alternative promoter usage combined with alternative splicing may thus lead to stress-dependent combinatorial complexity of AChE mRNA transcripts and their protein products.

Received for publication, March 11, 2004 , and in revised form, April 26, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY389982, AY389981, AY389980, and AY389977.

^* This research was supported by Israel Science Fund Grant 618y02, United States Army Medical Research and Materiel Command Grant DAMD 17-99-1-9547, European Union Grant QLK3-CT-2002-02062, and Ester Neuroscience, Tel-Aviv (to H. S.) as well as by the Leo Meintz Fund, Tel-Aviv University (to D. G.). Research in Paris was supported by the "Fondation de la Recherche Médicale" and "ACI Integrative Biology." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Tables 1 and 2.

An incumbent of the Hebrew University's Rector Fellowship and a Golda Meir fellow. Present address: NCI, National Institutes of Health, 41 Library Dr., Bethesda, MD 20892.

^|| A fellow of the Del Duca Foundation and CNRS.

^¶¶ To whom correspondence should be addressed. Fax: 972-2-6520258; E-mail: soreq{at}cc.huji.ac.il.

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