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Steroid signalling via nuclear hormone receptors

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Title: Steroid signalling via nuclear hormone receptors
Authors: Fernandes Freitas, Isabel
Item Type: Thesis or dissertation
Abstract: Hormone-sensing in the brain is essential for reproduction and consequent survival of species. In females, estrogen must exert simultaneous positive- and negative-feedback on the anteroventral periventricular nucleus (AVPV) and the arcuate Nucleus (ARC) of the hypothalamus, respectively, to maintain fertility. However, even though the positive effects of estrogen in the hypothalamus have been extensively investigated, the mechanistic basis for the opposing feedback of estrogen in the arcuate nucleus has, for decades, remained elusive. In order to understand what is driving the differential effects of estrogen in the ARC and AVPV, we analysed and compared the expression of estrogen target genes and coregulatory proteins in these two female hypothalamic nuclei under basal and estrogen treated conditions. We found that the arcuate nucleus and anteroventral periventricular nucleus respond differently to estrogen. And that, the nuclear receptor Dax1, which acts as a region-specific ligand-dependant repressor of estrogen-receptor (ERα) activity, is, by far, the most enriched gene in the arcuate nucleus. Here, we show for the first time that the negative-feedback in the ARC is mediated by the nuclear receptor Dax1. It couples gonadotropin release to the developmental stage of the oocyte, and mice lacking this mechanism have abnormal estrogen-stimulated gonadotropin secretion and fail to cycle normally. As such, the interaction between Dax1 and ERα in the female hypothalamus explains the paradoxical observation of estrogen negative-feedback, and is shown here to be essential for normal fertility. Further to this, we show that the C57BL/6J background is highly sensitive to male-to-female sex-reversal in the absence of the nuclear receptor Dax1, and that a minority of sex-reversed XY (Dax1-/Y) mice have markers of fertility and can produce live offspring without any assisted fertility treatment. As such, our observations in sex-reversed XY (Dax1-/Y) mice support the notion that XY sex-reversal is not formally incompatible with reproduction. However, our data also suggest that the inter-individual milieu of mechanical and development complications caused by the presence of the Y-chromosome makes successful reproduction highly unlikely.
Content Version: Open Access
Issue Date: May-2019
Date Awarded: Aug-2019
URI: http://hdl.handle.net/10044/1/91787
DOI: https://doi.org/10.25560/91787
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Owen, Bryn
Dhillo, Waljit
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: P53409
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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