A HOMEODOMAIN PROTEIN SELECTIVELY EXPRESSED IN NORADRENERGIC TISSUE REGULATES TRANSCRIPTION OF NEUROTRANSMITTER BIOSYNTHETIC GENES

In order to characterize the specificity of expression of the neurotra nsmitter biosynthetic gene dopamine beta-hydroxylase (DBH), the identi fication of proteins that interact with the DB1 enhancer was initiated . A homeobox-containing cDNA was isolated from a PC12 expression cDNA library screened with the DB1 enhancer. The homeodomain is a member of the paired-like class, and is encoded by several nonidentical cDNAs. The cDNAs contain the same sequence in the homeodomain and 3' coding a nd noncoding sequences, but diverge in sequence 5' to the homeodomain. This family of homeobox-containing cDNAs is named Arix. Arix mRNA tra nscripts are found only in noradrenergic, DBH-positive tissues, and in cell lines derived from those tissue. The DB1 enhancer contains two b inding sites for the Arix homeodomain, and both sites contribute to ba sal activity of the DBH promoter. When introduced into tissue culture, Arix regulates the transcriptional activity from the DBH promoter, an d also from the promoter of the tyrosine hydroxylase gene, encoding th e initial enzyme of the catecholamine biosynthetic pathway. The patter n of expression of the Arix transcripts, the presence of the homeodoma in, and the transcriptional regulatory properties suggest that this fa mily of proteins may be involved in the specificity of expression of t he catecholamine biosynthetic genes.