The ability of neural stimuli to regulate gene expression provides one means of integrating the many types of information typically received by a single neuron. Often the production of mRNA serves as the first step in gene regulation. Frequently transcriptional regulatory sites on DNA function as focal points to coordinate a gene's response to these influences. Currently I investigate regulation of the gene encoding phenylethanolamine N-methyltransferase (PNMT), the final enzyme in the catecholamine biosynthetic pathway. The objective of our research is to learn how neural stimuli, primarily neurotransmitters, can regulate the expression of other neural genes, using transcription of the PNMT gene as a model system. Physiologically, it has been established that catecholamine enzymes are stimulated by "chronic stress", a general term encompassing the ability of neurotransmitters and/or neural impulses to induce PNMT expression transynaptically. We have determined that cholinergic stimuli (e.g. acetylcholine) induce production of PNMT mRNA through two separate receptor systems, i.e. nicotinic and muscarinic, which involve distinct second messenger intermediates. Knowing that neural influences affect transcription of the PNMT gene has served as the basis for mapping the cis-active elements on this gene that convey responsiveness to nicotinic, muscarinic, and depolarizing stimuli. Our future research directions involve identification of those nuclear proteins that interact with neurally responsive sites on the PNMT gene. These studies should contribute significantly toward understanding the molecular basis of transmitter production and regulation in the central and peripheral nervous systems.
Additionally, we explore expression profiles of developmental-specific transcription factors in neuronal tumors and cell lines. Medulloblastoma and neuroblastoma tissues serve as CNS and PNS models of altered gene expression that may prove instrumental for understanding transformaion to the malignant neuronal phenotype.
- Evinger, M.J., Cikos, S., Nuafor-Anene,V., Powers, J.F., and Tischler, A.S. (2002) Hypoxia activates multiple transcriptional pathways in mouse pheochromacytoma cells. Ann. New York Acad. Sci. (O'Connor, D.T. and Eiden, L., eds) 971. In Press.
- Powers, J.F., Evinger, M.J., Tsokas, P., Bedri, S., Alroy, J.F., Shahsavi, M., and Tischler, A.S. (2000) Pheochromatocytoma cell lines from neurofibromatosis knock out mice. Cell and Tissue Res 302:309-320.
- Lee, Y-S. E., Raia, G., Tonshoff, C., and Evinger, M.J. (1999) Neural regulation of phenylethanolamine N-methyltransferase (PNMT) gene expression in bovine chromaffin cells differs from other catecholamine biosynthetic enzyme genes. J. Molecular Neuroscience 12: 53-68.
- Evinger, M.J. (1998) Determinants of phenylethanolamine N-methyltransferase expression. Adv. Pharmacol. 42: 73-76.
- Tonshoff, C., Hemmick, L., and Evinger, M.J. (1997) Pituitary adenylate cyclase activating polypeptide (PACAP) regulates expression of catecholamine biosynthetic enzyme genes in bovine adrenal chromaffin cells. J. Molecular Neuroscience, 9: 127-140.
- Evinger, M.J., Ernsberger, P., Regunathan, S., Joh, T.H., and Reis, D.J. (1994) A single transmitter regulates gene expression through two separate mechanisms: Cholinergic regulation of phenylethanolamine N-methyltransferase mRNA via nicotinic and muscarinic pathways. J. Neurosci. 14: 2106-2116.