ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING
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Extracellular signal-regulated kinase (ERK) signaling is required for function of the hypothalamic-pituitary-gonadal axis. This axis is regulated by interconnected hormonal feedback loops, permitting reproduction. Gonadotropin releasing hormone (GnRH) is secreted by the hypothalamus to act on the pituitary, resulting in gonadotropin secretion. The gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) are produced and secreted by pituitary gonadotropes, and act on the gonads, promoting steroidogenesis and gametogenesis. This dissertation focuses on two isoforms of ERK, ERK 1 and ERK 2. Although they do appear to have some redundant functions, ERK 1 is not able to compensate for loss of ERK 2. ERK1 null mice are viable and fertile, whereas loss of ERK2 is embryonic lethal. Therefore, ERK 2 has to be knocked out in a tissue or time dependent manner. For the studies included here, we utilize a mouse model of GnRHR associated ERK loss. This model allows us to investigate the role of ERK in pituitary gonadotropin production and secretion. ERK loss significantly reduced gonadotropin production, and this model allowed us to characterize the effects of hypogonadotropism as animals aged. We followed those studies with an investigation into GnRHR localization and function in the murine placenta, and the effects of ERK loss on placentation, gestation, and parturition. These experiments revealed abnormal histology and vascularization, prolonged gestation and dystocia, and absolute fetal mortality. Finally, we utilized unbiased screening techniques (RNA sequencing) to identify novel targets of GnRH signaling downstream of the ERK cascade. This revealed a bile acid receptor, TGR5, which has a functional role in gonadotropin production in the pituitary. Female TGR5 knockout are subfertile, with a marked delay in the onset of puberty. The studies in this dissertation describe the role of ERK in multiple aspects of the HPG axis. All of the studies have clinical implications, either in the understanding and treatment of idiopathic hypogonadotropic hypogonadism (IHH) or in understanding links between puberty, nutrition, metabolism and fertility.
Placenta; Developmental biology; Biology; Metabolism; ERK; GnRH; pituitary; reproduction
Roberson, Mark SCohen, Paula E.
Cheong, Soon Hon; Kurpios, Natasza; Navratil, Amy M
Comparative Biomedical Sciences
Ph. D., Comparative Biomedical Sciences
Doctor of Philosophy
dissertation or thesis