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J. Biol. Chem., Vol. 282, Issue 18, 13290-13302, May 4, 2007

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Transcription Factor PHOX2A Regulates the Human 3 Nicotinic Receptor Subunit Gene Promoter^*

Roberta Benfante^¶1, Adriano Flora^¶12, Simona Di Lascio^¶, Francesca Cargnin^¶, Renato Longhi^||, Sara Colombo, Francesco Clementi^¶, and Diego Fornasari^¶3

From the Department of Pharmacology, School of Medicine, University of Milan, 20129 Milan, CNR-Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milan, ^¶Center of Excellence on Neurodegenerative Diseases, University of Milan, 20129 Milan, and ^||CNR-Institute of Chemistry and Molecular Recognition, 20131 Milan, Italy

PHOX2A is a paired-like homeodomain transcription factor that participates in specifying the autonomic nervous system. It is also involved in the transcriptional control of the noradrenergic neurotransmitter phenotype as it regulates the gene expression of tyrosine hydroxylase and dopamine--hydroxylase. The results of this study show that the human orthologue of PHOX2A is also capable of regulating the transcription of the human 3 nicotinic acetylcholine receptor gene, which encodes the ligand-binding subunit of the ganglionic type nicotinic receptor. In particular, we demonstrated by chromatin immunoprecipitation and DNA pulldown assays that PHOX2A assembles on the SacI-NcoI region of 3 promoter and, by co-transfection experiments, that it exerts its transcriptional effects by acting through the 60-bp minimal promoter. PHOX2A does not seem to bind to DNA directly, and its DNA binding domain seems to be partially dispensable for the regulation of 3 gene transcription. However, as suggested by the findings of our co-immunoprecipitation assays, it may establish direct or indirect protein-protein interactions with Sp1, thus regulating the expression of 3 through a DNA-independent mechanism. As the 3 subunit is expressed in every terminally differentiated ganglionic cell, this is the first example of a "pan-autonomic" gene whose expression is regulated by PHOX2 proteins.

Received for publication, September 6, 2006 , and in revised form, January 24, 2007.

^* This work was supported in part by the University of Milan Grant FIRST 2005 and by the Ministry for University and Research Grants FISR-CNR Neurobiotecnologia 2003 and FIRB 2001 RBNE01NR_04. 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 Both authors contributed equally to this work.

² Present address: Dept. of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.

³ To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, University of Milan, Via Vanvitelli 32, 20129 Milano, Italy. Tel.: 39-02-503-16960; Fax: 39-02-74-90-574; E-mail: diego.fornasari{at}unimi.it.

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