One of the key events defining the specificity of cell function in neuroendocrine tissues is the identity of neurotransmitter expressed in a given cell. The molecular events that control the selection of neurotransmitter phenotype are influenced by environmental stimuli. Ultimately, cellular phenotype is determined by the interaction of functionally distinct transcription factors with regulatory elements of genes that encode neurotransmitters or neurotransmitter biosynthetic enzymes. This application is focused on characterizing a transcription factor that interacts with the regulatory region of the dopamine b hydroxylase (DBH) gene. DBH catalyzes the synthesis of norepinephrine, and is expressed only in sympathetic neurons, adrenal chromaffin cells and certain brain nuclei. The applicant has cloned a cDNA for this transcription factor, designated Arix, which carries a homeobox, and has found that Arix mRNA is selectively expressed in noradrenergic tissues and cell lines. These observations suggest that Arix may play a definitive role in the determination of the noradrenergic phenotype in vivo. The main objective of this proposal is to understand the potential role of Arix in regulating the noradrenergic phenotype. This goal will be achieved by: (1) defining the pattern of Arix expression in the rat peripheral and central nervous system during embryonic and postnatal development; (2) identifying the molecular components of Arix-containing DNA-protein complexes, and (3) inactivating Arix activity in a catecholaminergic cell line. The results of these studies should lead to further understanding of the normal development of the sympathoadrenal phenotype, as well as the consequences of a failure of development to proceed. In addition, the Arix gene may prove to be a factor in inherited diseases characterized by the aberrant development of neuroendocrine cells.
| Adachi, M; Browne, D; Lewis, E J (2000) Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription. DNA Cell Biol 19:539-54 |
| Swanson, D J; Zellmer, E; Lewis, E J (1998) AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene. J Biol Chem 273:24065-74 |
