Gonadotropin surges are critically important biological events that depend upon the appropriate cellular integration of ovarian and neuroendocrine signals. Primary LH and FSH surges are dependent upon integration of neural and hormonal (estrogen, progesterone) stimuli in the brain, and secondary FSH surges require coordinated actions of ovarian steroids, inhibin, and activin in pituitary gonadotropes. We recently obtained evidence that stimulation of both the preovulatory and secondary gonadotropin surges requires activation of progesterone (P) receptors (PRs), even in the absence of circulating P. We have thus proposed that signals leading to release of GnRH surges from hypothalamus, and to secondary FSH surges from pituitary, must converge at the level of PR in neurons and gonadotropes, respectively. We hypothesize that these integrative processes depend upon E/2,s capacity to induce PR expression, and the ability of neuroendocrine signals to activate these PRs in a ligand-independent manner. Specifically, we will test the idea that neurotransmitter signals can activate neuronal PRs, leading to stimulation of GnRH and primary gonadotropin surges, and that activin and P can activate PRs, contributing to release to release of secondary FSH surges.
In Aim 1, we will use a microdialysis approach to determine if contributing to release of secondary FSH surges.
In Aim 1, we will use a microdialysis approach to determine if GnRH surges in steroid-treated ovariectomized (OVX) rats are blocked by pretreatment with P antagonists,or i.c.v. infusions of PR antisense oligonucleotides to disrupt PR synthesis.
In Aims 2 and 3, we will use a gene transfer method to introduce a fusion gene containing a progesterone response element (PRE) linked to a reporter gene, into hypothalamic neurons in vitro and in vivo. We will use this approach to directly determine ligand-independent activation of PRs occurs in central neurons, and ascertain whether this process is associated with the preovulatory surge-generating process.
In Aim 4, we will directly assess the involvement of the PR in mediating the effects of activin on FSH secretion. Activin stimuli will be presented to anterior pituitary cell cultures derived from wild-type and progesterone receptor knock-out (PRKO) mice, and FSH responses will be measured and compared. If a response deficit is noted in the PRKO-derived cultures, then we will conduct gene transfer experiments in which we will introduce the mPR into PRKO-derived cells, and determine the ability of these treatments to rescue FSH responsiveness to activin.
In Aims 5 & 6, we will transfer the PRE-reporter fusion gene into anterior pituitary cells both in vitro and in vivo to determine if activin can activate PRs, and if this process is indeed associated with the estrous release of FSH. The information gained in these studies will be of major significance in our understanding of the integrative, cellular, and molecular events that comprise the periovulatory surge-generating process. As such, it could have important implications for the understanding of infertilities associated with disruptions of steroid feedback and production of mid- cycle ovulatory hormone surges. Of broader significance, these experiments may also may also provide new insights into the cellular mechanisms which function to integrate endocrine and neural signals, and thereby bring about a variety of biological responses, such as those involved in motivated behaviors, reproductive development, stress responses, or learning and memory.

Project Start
2001-12-01
Project End
2002-11-30
Budget Start
Budget End
Support Year
14
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Que, Emily L; Duncan, Francesca E; Bayer, Amanda R et al. (2017) Zinc sparks induce physiochemical changes in the egg zona pellucida that prevent polyspermy. Integr Biol (Camb) 9:135-144
Vanorny, Dallas A; Mayo, Kelly E (2017) The role of Notch signaling in the mammalian ovary. Reproduction 153:R187-R204
Xiao, Shuo; Duncan, Francesca E; Bai, Lu et al. (2015) Size-specific follicle selection improves mouse oocyte reproductive outcomes. Reproduction 150:183-92
Que, Emily L; Bleher, Reiner; Duncan, Francesca E et al. (2015) Quantitative mapping of zinc fluxes in the mammalian egg reveals the origin of fertilization-induced zinc sparks. Nat Chem 7:130-9
Xiao, Shuo; Zhang, Jiyang; Romero, Megan M et al. (2015) In vitro follicle growth supports human oocyte meiotic maturation. Sci Rep 5:17323
Cordeiro, Marília H; Kim, So-Youn; Ebbert, Katherine et al. (2015) Geography of follicle formation in the embryonic mouse ovary impacts activation pattern during the first wave of folliculogenesis. Biol Reprod 93:88
Kong, Betty Y; Duncan, Francesca E; Que, Emily L et al. (2015) The inorganic anatomy of the mammalian preimplantation embryo and the requirement of zinc during the first mitotic divisions. Dev Dyn 244:935-47
Kim, So-Youn; Ebbert, Katherine; Cordeiro, Marilia H et al. (2015) Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles. Endocrinology 156:1464-76
Hong, Young Pyo; Gleber, Sophie-Charlotte; O'Halloran, Thomas V et al. (2014) Alignment of low-dose X-ray fluorescence tomography images using differential phase contrast. J Synchrotron Radiat 21:229-34
Kong, B Y; Duncan, F E; Que, E L et al. (2014) Maternally-derived zinc transporters ZIP6 and ZIP10 drive the mammalian oocyte-to-egg transition. Mol Hum Reprod 20:1077-89

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