Academic Background

BA., SUNY at Buffalo, 1975
PhD, Columbia University, 1981

Regulation of Neuroendocrine Gene Expression

The overall goal of this laboratory is to understand the mechanisms controlling gene expression in the nervous system. Neurons share many common functions but differ in two major ways. First, each neuron makes a unique set of connections with the other neurons and target tissues. Second, different sets of neurons express distinct combinations of classical neurotransmitters, neuropeptide modulators, and receptors. The genes encoding different neurotransmitter systems, therefore provide important models for understanding differential gene expression in the nervous system. We first cloned cDNAs and genomic sequences encoding two related neuropeptides, neurotensin and neuromedin N, and we are currently using this gene to understand the regulatory pathways that set the complex pattern of expression of the gene throughout the limbic regions of the central nervous system. Several lines of evidence suggest that multiple environmental factors including estrogen, dopamine, and glucocorticoids are involved in region-specific expression of the gene. Experiments in PC12 cells, where the gene is regulated synergistically by multiple environmental factors, have implicated a highly conserved 200 bp region of 5' flanking sequences immediately upstream of the start site of transcription in the control of neurotensin gene expression. A consensus AP-1 site, the target of the products of the c-fos and c-jun proto-oncogenes and their relatives, is a critical control element required for responses to combinations of inducers. Current studies are aimed at understanding the role AP-1 plays in controlling neurotensin gene expression. Recently, co-transfection experiments in PC12 cells have provided evidence that c-Jun is a critical positive transcriptional activator of neurotensin gene expression. To directly assess the regulatory role of c-Jun in the nervous system, antisense oligonucleotides will be used to inhibit c-Jun synthesis and to examine potential effects on the regulation of the gene in response to neuroleptic drugs. Transgenic mouse models will also be used to assess the importance of the AP-1 site for the generation of the complex pattern of expression observed in the adult rat central nervous system. These studies coupled with mutational analysis of a 50 bp region of 5' flanking sequence that is nearly identical in rat and human should allow us to delineate the sequence elements responsible for pattern generation in the central nervous system.