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J. Biol. Chem., Vol. 280, Issue 45, 37439-37448, November 11, 2005

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PHOX2B Regulates Its Own Expression by a Transcriptional Auto-regulatory Mechanism^*

Francesca Cargnin¶, Adriano Flora¶1, Simona Di Lascio¶, Elena Battaglioli||, Renato Longhi**, Francesco Clementi¶, and Diego Fornasari¶2

From the Department of Pharmacology, School of Medicine, University of Milan, CNR-Institute of Neuroscience, ^¶Center of Excellence on Neurodegenerative Diseases, University of Milan, the ^||Department of Biology and Genetics for Medical Sciences, University of Milan, and the ^**CNR-Institute of Chemistry and Molecular Recognition, Milan 20129, Italy

The specification of neuronal identity is a result of interactions between the following two distinct classes of determinants: extrinsic factors that include secreted or cell membrane-associated signals in the local environment, and intrinsic factors that generally consist of ordered cascades of transcription factors. Little is known about the molecular mechanisms underlying the interplay between these extrinsic and intrinsic factors and the transcriptional processes that establish and maintain a given neuronal phenotype. Phox2b is a vertebrate homeodomain transcription factor and a well established intrinsic factor in developing autonomic ganglia, where its expression is triggered by the bone morphogenic proteins secreted by the dorsal aorta. In this study we characterized its proximal 5'-regulatory region and found that it contained five putative DNA sites that potentially bind homeodomain proteins, including PHOX2B itself. Chromatin immunoprecipitation assays showed that PHOX2B could bind its own promoter in vivo, and electromobility gel shift assays confirmed that four of the five sites could be involved in PHOX2B binding. Functional experiments demonstrated that 65% of the transcriptional activity of the PHOX2B promoter in neuroblastoma cells depends on this auto-regulatory mechanism and that all four sites were required for full self-transactivation. Our data provide a possible molecular explanation for the maintenance of PHOX2B expression in developing ganglia, in which initially its expression is triggered by bone morphogenic proteins, but may become independent of external stimuli when it reaches a certain nuclear concentration and sustains its own transcription.

Received for publication, July 29, 2005 , and in revised form, September 2, 2005.

^* This work was supported in part by the Italian Ministry for Education, Universities, and, Research Grant FIRB 2001 RBNE01NR_04, Progetto Strategico Neuroscienze, and the European Community (TMR Nicotine Dependence) Contract HPRN-CT-2002-00258. 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.

¹ Present address: Dept. of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.

² To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, University of Milan, Via Vanvitelli 32, 20129 Milano, Italy. Tel.: 39-2-503-16960; Fax: 39-2-74-90-574; E-mail: diego.fornasari{at}unimi.it or d.fornasari{at}in.cnr.it.

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