Regulation and function of Egr in gonadotropes.

说明(申请人提供)：促黄体生成素(黄体生成素)是由脑下垂体前叶促性腺激素合成和分泌的，由α和LHβ亚基组成。这些亚基的表达和促黄体生成素的分泌受到下丘脑神经肽促性腺激素释放激素(GnRH)的精确控制。由于缺乏促性腺激素，人类缺乏促性腺激素释放激素(Kallmann‘s综合征)，导致生殖完全失败。多囊卵巢综合征的特征是血浆黄体生成素升高和卵巢功能异常。因此，适当分泌促黄体生成素，进而表达促黄体生成素β，对维持生殖功能至关重要。本提案的目的是描述促性腺激素释放激素调节LHβ亚基基因的机制。假设早期基因产物早期生长反应蛋白-I(Egrl)在传递促性腺激素释放激素(GnRH)刺激到促黄体生成素(LH)β启动子中起关键作用。此外，推测Egr1与LHbeta启动子结合，并与邻近的转录因子和转录辅助激活因子/辅助抑制因子形成相互作用。已知EGRL与辅抑制子NAB1和2相互作用，这可能调节依赖EGRL的基因调控。目的I的目的是阐明GnRH能够增强Egr1转录活性并随后增强LHbeta启动子表达的机制。在AIM II上提出的研究将评估垂体腺苷环化酶激活多肽调节EGRL活性的机制，特别是蛋白质-蛋白质相互作用的变化。最后，在AIM III中，将使用cre/IoxP条件表达模型来研究体内NAB在调节GnRH/Egr1诱导LHbeta中的参与。这些目的是为了揭示GnRH诱导LHbeta亚基基因的分子机制。他们有意将重点放在egrl在体内调节和维持LHP表达的基本功能上所起的作用。从这些实验中获得的信息将为为什么GnRH诱导LHbeta表达与GnRH从下丘脑脉冲式释放的特定模式密切相关提供有价值的见解。

DESCRIPTION (provided by applicant): 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.