Type
Text
Type
Dissertation
Advisor
Kritzer, Mary | Acosta-Martinez, Maricedes | Shelly, Maya | White, Thomas | El-Maghrabi, Raafat.
Date
2014-12-01
Keywords
Kisspeptin, Phosphoinositide 3-Kinase, Reproductive Physiology | Biology
Department
Department of Molecular Genetics and Microbiology.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76539
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Kisspeptin neurons are potent regulators of gonadotropin-releasing hormone (GnRH) neurons, necessary for pubertal development and adult reproductive competence. Estradiol (E2) and testosterone (T), along with peripheral metabolic signals, such as leptin and insulin, regulate GnRH release indirectly, in part through the activation or inhibition of kisspeptin neurons. The changes in GnRH release and consequently in gonadotropin levels caused by these peripheral signals are strongly linked to changes in hypothalamic kisspeptin (Kiss1) gene expression. However, little is known about the intracellular signaling pathways that regulate Kiss1. The phospholipid enzyme phosphoinositide 3-kinase (PI3K) is a major downstream effector of steroid hormones and metabolic cues. We hypothesize that PI3K in kisspeptin neurons integrates peripheral signals to regulate Kiss1 expression, thus altering GnRH release. To test our hypothesis, we used transgenic mice and Cre-LoxP technology to delete PI3K catalytic subunits, p110α and p110β , in kisspeptin cells (Kiss-p110α /β KO). Ablation of PI3K from kisspeptin neurons did not alter overall pubertal development in either male or female mice. In adult animals, LH levels were lower in Kiss-p110α /β KO male mice regardless of gonadal status when compared to wild type. However, basal LH levels in Kiss-p110α /β KO female mice were not significantly different from wild type. We also examined Kiss1 mRNA expression among groups of gonad-intact, gonadectomized (GDX), and GDX + steroid-replaced mice. Compared to wild type, Kiss1 cell number was lower in the anteroventral periventricular nucleus (AVPV) of intact Kiss-p110α /β KO males. In the arcuate (ARC) nucleus KO males showed lower Kiss1 cell numbers regardless of gonadal status. A significant genotype effect was observed in the ARC of females from the GDX group, but not in the intact or in the E2-replaced group. In addition, compared to wild type, a substantial reduction in kisspeptin immunoreactivity was observed in the ARC of intact adult Kiss-p110α /β KO males and females. Our data supports a key role of PI3K signaling in the regulation of Kiss1 expression in both sexes and LH levels in males. These studies have the potential to identify novel therapeutic targets to treat reproductive disorders of unknown etiology. | 103 pages
Recommended Citation
Beymer, Matthew John Alan, "The Role of Phosphoinositide 3-Kinase in Regulating Kisspeptin Neurons within the Hypothalamic-Pituitary-Gonadal Axis" (2014). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2440.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2440