Defining the Role of Estrogen Receptor β in the Regulation of Female Fertility

Abstract

Estrogens are essential hormones for the regulation of fertility. Cellular responses to estrogens are mediated by estrogen receptor α (ESR1) and estrogen receptor β (ESR2). In mouse and rat models, disruption of Esr1 causes infertility in both males and females. However, the role of ESR2 in reproductive function remains undecided because of a wide variation in phenotypic observations among Esr2-mutant mouse strains. Regulatory pathways independent of ESR2 binding to its cognate DNA response element have also been implicated in ESR2 signaling. To clarify the regulatory roles of ESR2, we generated two mutant rat models: one with a null mutation (exon 3 deletion, Esr2ΔE3) and the other with an inframe deletion selectively disrupting the DNA binding domain (exon 4 deletion, Esr2ΔE4). In both models, we observed that ESR2-mutant males were fertile. ESR2-mutant females exhibited regular estrous cycles and could be inseminated by wild-type (WT) males but did not become pregnant or pseudopregnant. Esr2-mutant ovaries were small and differed from WT ovaries by their absence of corpora lutea, despite the presence of follicles at various stages of development. Esr2ΔE3- and Esr2ΔE4-mutant females exhibited attenuated preovulatory gonadotropin surges and did not ovulate in response to a gonadotropin regimen effective in WT rats. Similarities of reproductive deficits in Esr2ΔE3 and Esr2ΔE4 mutants suggest that DNA binding-dependent transcriptional function of ESR2 is critical for preovulatory follicle maturation and ovulation. Overall, the findings indicate that neuroendocrine and ovarian deficits are linked to infertility observed in Esr2-mutant rats.

ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation

“…Wildtype and Erβ null Holtzman Sprague-Dawley (HSD) rats were studied for intraovarian kisspeptin signaling. Erβ null rat model was generated by targeted deletion of the exon 3 in the Erβ gene (Rumi et al, 2017). Exon 3 deletion caused a frameshift and null mutation (Rumi et al, 2017).…”

“…Estrogen receptor β (ERβ) is the predominant estrogen receptor in the ovary (Byers et al, 1997;Couse et al, 2004;Pelletier and El-Alfy, 2000;Slomczynska et al, 2001) and disruption of ERβ signaling leads ovulatory defects (Asadi et al, 2013;Lang-Muritano et al, 2018). Failure of ovulation in Erβ null mice and rats is associated with defective follicle maturation and an attenuated preovulatory gonadotropin surge (Couse et al, 2005;Rumi et al, 2017). However, treatment with exogenous gonadotropins fails to induce ovulation, suggesting a primary ovarian defect due to the loss of ERβ (Rumi et al, 2017).…”

“…Failure of ovulation in Erβ null mice and rats is associated with defective follicle maturation and an attenuated preovulatory gonadotropin surge (Couse et al, 2005;Rumi et al, 2017). However, treatment with exogenous gonadotropins fails to induce ovulation, suggesting a primary ovarian defect due to the loss of ERβ (Rumi et al, 2017). To identify the ERβ-regulated genes that may affect ovarian follicle development, oocyte maturation, and ovulation, we performed RNAsequencing analyses of gonadotropin stimulated granulosa cells (GCs) and oocytes (Chakravarthi et al, 2020;Chakravarthi et al, 2019;Khristi et al, 2018).…”

17α Estradiol promotes plasticity of spared inputs in the adult amblyopic visual cortex

“…This analysis was performed in adult (>P180), gonadally-intact, male and female LE rats, as gonadectomy has been shown to significantly reduce excitatory synaptic density 11,12,54 ERβ staining was absent in the brains of ERβ -/adult female rats (Representative example of n = 3; Fig. 2A, right 39 ). Thus, robust non-nuclear expression of ERs persists throughout the brain of adult male and female LE rats, including primary visual cortex.…”

“…PSD95 is detected in nascent synaptic connections, and plays a fundamental role in many aspects of excitatory synapse maturation and LTP induction/expression by co-localizing critical synaptic effectors. Quantitative immunofluorescence revealed that cMD significantly reduced PSD95 puncta size distribution in deprived and non-deprived primary visual cortex (AVG±SEM; Binoc 0.092±0.01 μm 2 vs. Contra cMD 0.087±0.01 μm 2 , p<0.001, K-S Test, Cohen's d =0.51; Binoc 0.092±0.01 μm 2 vs. Ipsi cMD 0.088±0.01 μm 2 ; p<0.001, K-S Test, Cohen's d =0 39 ,. Fig.1C; males versus females: F(1,16) = 0.29, p = 0.87, 2-way ANOVA).…”