Neural cells differ from each other in such properties as signaling capability, responsiveness to hormones and neurotransmitters, expression of neurotransmitter, and the ability to make connections with other cells. In nearly all situations studied, the critical decisive regulatory event is the activation, or repression, of transcription of the genes encoding the neural specific proteins. These enzymes are responsible for the biosynthesis of dopamine and norepinephrine. The TH and DBH genes are expressed only in defined cell types, and are regulated by numerous environmental stimuli. The overall goal of our research program is to understand the controls which lead to the specificity of expression of the TH and DBH genes.
Gene expression is a balance between positive and negative influences over transcriptional activity.
We have identified tissue specific transcriptional activators, a pair of homeodomain proteins which are responsible for the development of the noradrenergic cell type, and we are studying the mechanism by which these proteins interact with intraccellular second messengers to control the expression of the TH and DBH genes. With the goal of understanding the balance between activation and repression, we have identified a protein which functions to extinguish expression of the TH and DBH in inappropriate cells. By comparing the activity of the repressor with that of the activator we will understand how tissue specific gene expression is determined. In addition, we are investigating the function of a regulatory region of the DBH gene which is polymorphic in the human population and linked to predisposition to affective disorders. The Homeodomain Protein Arix Interacts Synergistically with cAMP to Regulate Expression of Neurotransmitter Biosynthetic Genes.