Neuroendocrine Regulation of the Hypothalamic Pituitary Adrenal Axis by the nurr1/nur77 Subfamily of Nuclear Receptors

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Abstract
The present study was designed to examine the role of the nurr1/nur77 subfamily of nuclear recep- tor transcription factors in the regulation of the hypothalamic/pituitary/adrenal axis at the neu- roendocrine level. We demonstrate that this nu- clear receptor subfamily can regulate the expres- sion of the CRF and POMC genes by interacting with a specific cis-acting sequence in their proxi- mal promoter regions. To examine the physiologi- cal significance of this response, we have focused on the POMC gene. We provide evidence that nurr1 and nur77 are rapidly induced by CRF in primary pituitary cells and that this induction is mimicked by forskolin in an anterior pituitary cell line. Fur- ther, we demonstrate that both nurr1- and forsko- lin-dependent induction of a POMC-chloramphen- icol acetyltransferase reporter gene are inhibited by mutation of the nurr1-binding site within the POMC promoter and that this site alone can confer cAMP responsiveness to a heterologous promoter. Finally, we provide evidence that the nurr1/nur77 response sequence is pivotal to both nurr1/nur77- dependent positive regulation and glucocorticoid receptor-dependent negative regulation of the POMC gene. These data strongly support the con- clusion that the nurr1/nur77 subfamily plays an im- portant coordinate neuroendocrine-regulatory role at all levels of the hypothalamic/pituitary/adrenal axis. (Molecular Endocrinology 11: 39-47, 1997)

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