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The Journal of Neuroscience, September 15, 2001, 21(18):7037-7045

SP Proteins and PHOX2B Regulate the Expression of the Human PHOX2a Gene

Adriano Flora¹, Helen Lucchetti¹, Roberta Benfante¹, Christo Goridis², Francesco Clementi¹, and Diego Fornasari¹

¹ Department of Medical Pharmacology, University of Milan and Consiglio Nazionale delle Ricerche Cellular and Molecular Pharmacology Center, 20129 Milan, Italy, and ² Laboratoire de Génétique et Physiologie du Développement, Institut de Biologie du Développement de Marseille, Centre National de la Recherche Scientifique /Institut National de la Santé et de la Recherche Médicale/Université de la Méditeranée, Marseille, France 13288

Phox2a is a vertebrate homeodomain transcription factor that is involved in the specification of the autonomic nervous system. We have isolated the 5' regulatory region of the human Phox2a gene and studied the transcriptional mechanisms underlying its expression. We first identified the minimal gene promoter by means of molecular and functional criteria and demonstrated that its activity relies on a degenerate TATA box and a canonical Sp1 site. We then concentrated on the region immediately upstream of the promoter and found that it stimulates transcription in a neurospecific manner because its deletion caused a substantial decline in reporter gene expression only in neuronal cells. This DNA region contains a putative binding site for homeodomain transcription factors, and its mutation severely affects the transcriptional activity of the entire 5' regulatory region, thus indicating that this site is necessary for the expression of Phox2a in this cellular context. The use of the electrophoretic mobility shift assay showed that Phox2b/PMX2b is capable of specifically interacting with this site, and cotransfection experiments demonstrated that it is capable of transactivating the human Phox2a promoter. Many data obtained from knock-out mice support the hypothesis that Phox2a acts downstream of Phox2b during the development of most of the autonomic nervous system. We have provided the first molecular evidence that Phox2b can regulate the expression of Phox2a by directly binding to its 5' regulatory region.

Key words: human; transcription factors; autonomic nervous system; transcriptional regulation; homeoproteins; promoter

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21187037-09$05.00/0

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