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J. Biol. Chem., Vol. 280, Issue 7, 5693-5702, February 18, 2005

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Genes Regulated in Neurons Undergoing Transcription-dependent Apoptosis Belong to Signaling Pathways Rather than the Apoptotic Machinery^*

Solange Desagher, Dany Severac¶, Alexey Lipkin, Cyril Bernis, William Ritchie, Anne Le Digarcher, and Laurent Journot

From the Institut de Génomique Fonctionnalle, CNRS, Unité Mixte de Recherche 5203 and ^¶Montpellier Génopole Microarray Facility, 141 rue de la Cardonille, F-34094 Montpellier Cedex 5, France

Neuronal apoptosis has been shown to require de novo RNA/protein synthesis. However, very few genes whose expression is necessary for inducing apoptosis have been identified so far. To systematically identify such genes, we have used genome-scale, long oligonucleotide microarrays and characterized the gene expression profile of cerebellar granule neurons in the early phase of apoptosis elicited by KCl deprivation. We identified 368 significantly differentially expressed genes, including most of the genes previously reported to be transcriptionally regulated in this paradigm. In addition, we identified several hundreds of genes whose transcriptional regulation has never been associated with neuronal apoptosis. We used automated Gene Ontology annotation, analysis of promoter sequences, and statistical tools to characterize these regulations. Although differentially expressed genes included some components of the apoptotic machinery, this functional category was not significantly over-represented among regulated genes. On the other hand, categories related to signal transduction were the most significantly over-represented group. This indicates that the apoptotic machinery is mainly constitutive, whereas molecular pathways that lead to the activation of apoptotic components are transcriptionally regulated. In particular, we show for the first time that signaling pathways known to be involved in the control of neuronal survival are regulated at the transcriptional level and not only by post-translational mechanisms. Moreover, our approach provides insights into novel transcription factors and novel mechanisms, such as the unfolded protein response and cell adhesion, that may contribute to the induction of neuronal apoptosis.

Received for publication, August 5, 2004 , and in revised form, November 1, 2004.

^* This work was supported by CNRS and by European Community Biotech Grant QLG3-CT-1999 00602 (to L. J.). 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.

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

To whom correspondence should be addressed: Institut de Génétique Moléculaire de Montpellier, CNRS, Unité Mixte de Recherche 5535, 1919 route de Mende, F-34293 Montpellier Cedex 5, France. Tel.: 33-4-6761-3676; Fax: 33-4-6704-0231; E-mail: solange.desagher{at}igmm.cnrs.fr.

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