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Title: Sex steroid regulation of gonadotrophin-releasing hormone (GnRH) neurons
Author: Dorling, A. A. V.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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Prior studies in the laboratory using quantitative in situ hybridisation and transgenic methodologies have shown that estrogen suppresses GnRH gene transcription and GnRH mRNA expression at times of negative feedback. Using the same approaches, I demonstrated that the positive feedback actions of estrogen were not coupled to alterations of GnRH gene expression. Recent RT-PCR studies identified estrogen receptor (ER)b transcripts in subpopulations of GnRH neurons in the mouse. To assess the presence of functional ERs in GnRH neurons, I undertook various gonadectomy-steroid replacement paradigms in several new transgenic reporter mouse line in which multiple estrogen response elements (EREs) drive the expression of LacZ (EREZ mice). Others have shown that this construct provides a functional reporter of ER-regulated gene transcription in vitro and I demonstrated its functionality in the uterus of EREZ mice. However, LacZ expression in the brain did not change in response to estrogen treatment and did not, therefore, enable us to evaluate the GnRH neurons. One possible reason for this failure is the recent discovery that the orphan nuclear receptors, termed estrogen receptor-related receptors (ERRs), constitutively transactivate EREs. To evaluate this further, I used in situ hybridisation to examine the topography of ERRa and ERRg expression in the mouse brain. I further demonstrated an estradiol-dependent decrease in ERRg expression in specific brain regions, suggesting a novel mechanism through which estradiol may regulate gene expression in the brain. Finally, I examined the negative feedback actions of estrogen upon GnRH neurons by evaluating LH levels and GnRH mRNA expression in knockout mice lacking either ERa or ERb.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available