Arcuate ER alpha-mediated estrogen signaling pathways and regulation of KNDy-associated gene expression in female mice
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Yang, Jennifer A..
Arcuate ER alpha-mediated estrogen signaling pathways and regulation of KNDy-associated gene expression in female mice. Retrieved from
https://doi.org/doi:10.7282/T3VT1VD7
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TitleArcuate ER alpha-mediated estrogen signaling pathways and regulation of KNDy-associated gene expression in female mice
Date Created2016
Other Date2016-10 (degree)
Extent1 online resource (xi, 213 p. : ill.)
DescriptionCentral signaling of 17β-estradiol (E2) in the arcuate nucleus (ARC) is important in many homeostatic functions including reproduction, energy balance, and thermoregulation, among others. KNDy neurons that coexpress kisspeptin, neurokinin B, and dynorphin function in control of multiple homeostatic functions and are integrators of reproduction and energy balance. In this dissertation, I characterize ER-mediated and ER-independent signaling in the ARC and identify the impact of energy balance and E2 on KNDy neurons. First, I characterize ER-mediated E2 signaling in the ARC, where E2 binds to estrogen receptor-alpha (ERα), translocates to the nucleus, and regulates gene transcription by binding to the Estrogen Response Element (ERE) on DNA through ERE-independent signaling. However, E2 also functions through ERE-independent signaling, such as interacting with nuclear transcription factors and binding to E2- responsive G-protein coupled receptors. I use three genotypes of mice: 1) wild-type, 2) knock in/knock out (KIKO), which lack ERE-dependent signaling, and 3) ERα total knock out (ERKO) to determine differential E2 signaling in the ARC. I found that multiple genes involved in reproduction and energy balance are controlled by E2 through ERE- dependent and ERE-independent mechanisms and identify novel signaling pathways that are modulated by E2. In the last section, I examined the interactions of E2 and energy balance on KNDy-associated gene expression in the ARC. I determined that in overnutrition and undernutrition, ARC expression of KNDy neuropeptides and receptors is disrupted, leading to downstream changes in gonadotropin (LH and FSH) production. Our previous studies found that in NPY/AgRP neurons, E2 interacted with fasting and diet-induced obesity to regulate genes involved in ghrelin signaling. Overnutrition and undernutrition did not regulate these ghrelin signaling genes in Tac2 neurons. However, E2 augments the expression of growth hormone secretagogue receptor (Ghsr), ghrelin’s receptor, in Tac2 neurons by six- to eight-fold, suggesting that E2 modulates ghrelin signaling in KNDy neurons. In summary, our results suggest differential E2 signaling mechanisms in the ARC are important to maintain energy homeostasis and reproduction and that expression of KNDy genes are regulated by both positive and negative energy balance, leading to downstream changes in reproduction.
NotePh.D.
NoteIncludes bibliographical references
Noteby Jennifer A. Yang
Genretheses, ETD doctoral
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.