Differential Transcriptional Regulation of Rat Vasopressin Gene Expression by Estrogen Receptor a and b*

Neuronal expression of vasopressin messenger RNA (mRNA) and peptide has been shown to be estrogen dependent. A 5.5-kb genomic DNA fragment, 59 of the AVP coding region, was used in luciferase reporter assays to measure transcriptional activation by either estrogen receptor a or b in response to various treatments. ERa and ERb displayed differential regulation of the AVP promoter. SK-N-SH cells transfected with ERa exhibited increased luciferase activity in response to estrogen, and the selective estrogen receptor modulators (SERMs), Tamoxifen, and ICI 182,780. Cells transfected with ERb exhibited a high constitutive activity, which is unchanged by exposure to SERMs but can be inhibited by estrogen. Deletion of 1.5 kb from the 59 end or mutation of a single estrogen response element (ERE)like sequence resulted in loss of estrogen-dependent induction by ERa and increased the ability of estrogen to inhibit the high constitutive activity of ERb. The distal ERE-containing 1.5-kb fragment, when coupled to luciferase, is able to support both ERa and ERb mediated activation of transcription by estrogen. These results suggest that a single ERE in the distal 1.5-kb portion of the 5.5-kb fragment contains the primary positive estrogen responsive sequences for ERa and ERb. The data also suggest that sequences proximal to this element serve to inhibit transcription mediated by ERb. (Endocrinology 141: 4056– 4064, 2000) A8 (AVP) is a nonapeptide, which acts as a neurohypophyseal hormone involved in water metabolism and blood pressure regulation, and also as a CNS neurotransmitter or neuromodulator. The classical VP projections to the neurohypophysis arising from the magnocellular neurons of the supraoptic (SON) and the paraventricular (PVN) nuclei of the hypothalamus have been well described (1, 2). Extrahypothalamic expression of this gene has also been documented in the bed nucleus of the stria terminalis (BNST) and medial amygdala (MA) (3). Vasopressin secretion by those neurons into the septum and hippocampus has been implicated in learning and memory, affiliative and aggressive behavior (4–7). Vasopressin gene transcription is positively regulated by osmotic stimulation, increases in cAMP and negatively regulated by glucocorticoids via the glucocorticoid receptor, both in vivo and in vitro