Luteinizing hormone (LH) is synthesized and secreted by gonadotropes within the anterior pituitary gland and is composed of an alpha- and LHbeta-subunit. Expression of these subunits and secretion of LH is exquisitely controlled by the hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH). Absence of GnRH in humans (Kallmann's syndrome) results in complete failure of reproduction due to a lack of gonadotropins. Polycystic ovarian syndrome is characterized by elevated plasma LH and abnormal ovarian function. Therefore, appropriate secretion of LH and thus, expression of LHbeta is critical for maintenance of reproductive function. The goal of the present proposal is to delineate the mechanisms responsible for GnRH regulation of the LHbeta-subunit gene. It is hypothesized that the immediate-early gene product, early growth response protein-I (Egrl), is critical for relaying the GnRH stimulus to the LH beta promoter. Furthermore, it is postulated that Egrl binds to the LHbeta promoter and forms interactions with adjacent transcription factors and transcriptional coactivators/corepressors. Egrl is known to interact with the corepressors Nab1 and 2 and this may modulate Egrl-dependent gene regulation. The goal of Aim I is to elucidate the mechanisms by which GnRH is able to augment the transcriptional activity of Egrl and subsequently enhance expression of the LHbeta promoter. The studies proposed in Aim II will evaluate the mechanisms used by pituitary adenylate cyclase-activating polypeptide to regulate Egrl activity specifically focusing on changes in protein-protein interactions. Finally, the involvement of Nab in vivo in modulating GnRH/Egrl induction of LHbeta will be examined in Aim III using a cre/IoxP conditional expression model.
These aims are designed to reveal the molecular mechanisms responsible for GnRH induction of the LHbeta-subunit gene. They intentionally focus on the role played by Egrl due to its essential function in vivo in regulating and maintaining LHp expression. Information obtained from these experiments will provide valuable insights into why GnRH induction of LHbeta expression is intimately tied to a specific pattern of pulsatile release of GnRH from the hypothalamus.
