Steroid signalling via nuclear hormone receptors
File(s)
Author(s)
Fernandes Freitas, Isabel
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2019-05
Date Awarded
2019-08
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Owen, Bryn
Dhillo, Waljit
Sponsor
Wellcome Trust (London, England)
Grant Number
P53409
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)