Review Article
Estrogen hormone physiology: Reproductive findings from estrogen receptor mutant mice

https://doi.org/10.1016/j.repbio.2013.12.002Get rights and content

Abstract

Estrogen receptors (ERs) play a crucial role in reproduction and normal physiology. The two sub-types of ER (ERα and β) are expressed in various levels in different tissues and selective cell types. Gene targeting technology allowed us to produce lines of mice with disrupted ERα (αERKO) and ERβ genes (βERKO) as well as a compound αβERKO in the whole body. Male and female αERKO mice are infertile. Estrogen, EGF and IGF-1 treatments failed to induce uterine growth and DNA synthesis in αERKO uteri. αERKO females are infertile due to hypoplastic uteri and hyperemic ovaries with no corpora lutea due to persistent LH stimulation from loss of negative feedback. αERKO males are infertile, with testicular atrophy and seminiferous tubule dysmorphogenesis producing decreased spermatogenesis and inactive sperm. βERKO females show arrested folliculogenesis and subfertility. Ovarian analyses indicate differential gene expression related to ovulatory stimulation deficits including lack of LH, PR, Cyp19 and Cox2 expression. A unique ovarian phenotype is found only in αβERKO females showing transdifferentiation of granulosa cells to Sertoli cells.

We describe here several novel mouse models which possess ERα gene modification. To understand ERα function in uterine endometrial epithelial cells, we generated a tissue selective ERα gene disrupted mouse model, the uterine epithelial-specific ERα knockout (UtEpiαERKO). To understand the physiological role of ERα functional domains, we generated a mouse model with a mutation in the ligand dependent transcription activation domain of ERα (AF2ERKI). Findings from the ERα mutant mice suggest that the absence of functional ERα is not lethal and results in significant endocrine effects and altered physiological processes.

Introduction

Estrogen is a well-known female steroid hormone synthesized from the ovary that controls the estrous or menstrual cycle in females, therefore estrogen is imperative for female reproduction. Estrogen is not only important in female reproduction but also in male reproduction and in numerous other systems including the neuroendocrine, skeletal and immune systems in males and females. Along with the influence of estrogen on many physiological processes, it is also implicated in many different diseases including obesity, metabolic disorder, cancer, osteoporosis, endometriosis and fibroids [1], [2]. The predominant mechanism of estrogen action is through nuclear estrogen receptor (ER) expression in estrogen target organs [3]. The biological effects of estrogen are mediated through two distinct ER proteins, ERα and ERβ (ERs). These receptors are encoded from separate genes on different chromosomes and the expression profiles in the tissues are different. The predominant expression tissues for ERα include: liver, uterus, mammary gland, pituitary, hypothalamus, cervix, and vagina. ERβ expression is more limited and predominant expression tissues include: ovary, lung, and prostate [4]. Controlling the functions of ERα and ERβ is the basis for many therapeutic interventions to estrogen related diseases. Thus it is quite important to reveal the physiological role of ERα and ERβ in the tissues and the in vivo functionality of ER proteins.

Section snippets

Estrogen receptors – structure and functions

The ERs are comprised of six structural domains: an amino-terminal domain (A/B-domain), a DNA binding domain (DBD; C-domain), a hinge region (D-domain), a ligand-binding domain (LBD; E-domain), and a carboxyl-terminal domain (F-domain) [3]. The C and E domains carry a high-degree of homology between ERα and ERβ; however the A/B, D and F domains are divergent [5], [6]. The A/B-domain contains the transcription activation function 1 (AF-1) which is reported to be important for ligand-independent

Estrogen receptor knock-out (ERKO) mouse models (whole tissue KO)

The development of multiple genetic models has led to an increase in understanding and knowledge of the physiological roles of estrogen receptors. These models include mice lacking functional ERα (αERKO), ERβ (βERKO) or both estrogen receptors (αβERKO). Several methods have been utilized to generate the ERKO mice. Currently, the cre-loxP system is the most widely used method to create whole tissue KO or tissue selective KO mice. The first αERKO mouse (Esr1tm1KSK) was generated by an insertion

Tissue specific ERKO mouse models

Whole animal knockout models have allowed tremendous insight into the physiological functions of the ERs. However, in the global knockout models it is not possible to look at the role of the ERs in specific tissues. With the advancement of the cre-loxP technology, the floxed ERα line can be crossed with other cre lines to produce mice lacking functional ER in specific cell types or tissues. Multiple ERα mouse models using this technique have been developed and studied [34], [35], [36], [37],

ER domain mutated mouse models (estrogen receptor knock-in mouse)

It is impossible to examine the physiological role of ER functional domains using the ERKO mice since no protein is made. Therefore, mouse models have been made with genetically modified estrogen receptor domains to allow dissection of the physiological function of the ER domains. These include models with altered DNA binding domains (NERKI and EAAE) which disrupt binding to the estrogen responsive DNA element, as well as one model with a point mutation in the ligand binding domain (ENERKI)

Conclusions

Multiple mouse models with different mutations to the ERs have allowed great advances in deciphering the role of estrogen receptor in hormonal physiology as summarized in Table 1 (female) and Table 2 (male). Generation of ERKO mice demonstrated that loss of function through ER gene mutations is not lethal and phenotypes of these lines have given insight into the roles of the individual estrogen receptors. In particular, we now have advanced knowledge of the role and function of each estrogen

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Thanks to Dr. Yin Li and Ms. Brianna Pockette for critical reading of this manuscript.

References (48)

  • J.F. Couse et al.

    Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse

    Endocrinology

    (1997)
  • P. Germain et al.

    Overview of nomenclature of nuclear receptors

    Pharmacol Rev

    (2006)
  • K.A. Green et al.

    Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state

    Nat Rev Can

    (2007)
  • B.S. Katzenellenbogen et al.

    Estrogen receptors: selective ligands, partners, and distinctive pharmacology

    Recent Prog Horm Res

    (2000)
  • C.L. Smith

    Cross-talk between peptide growth factor and estrogen receptor signaling pathways

    Biol Reprod

    (1998)
  • Z. Madak-Erdogan et al.

    Nuclear and extranuclear pathway inputs in the regulation of global gene expression by estrogen receptors

    Mol Endocrinol

    (2008)
  • S.R. Hammes et al.

    Extranuclear steroid receptors: nature and actions

    Endocr Rev

    (2007)
  • D.B. Lubahn et al.

    Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene

    Proc Natl Acad Sci USA

    (1993)
  • J.F. Couse et al.

    Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene

    Mol Endocrinol

    (1995)
  • S.C. Hewitt et al.

    Biological biochemical consequences of global deletion of exon 3 from the E.R. alpha gene

    FASEB J

    (2010)
  • E.H. Goulding et al.

    Ex3alphaERKO male infertility phenotype recapitulates the alphaERKO male phenotype

    J Endocrinol

    (2010)
  • S.W. Curtis et al.

    Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor or knockout mouse uterus

    Proc Natl Acad Sci USA

    (1999)
  • J.F. Couse et al.

    Characterization of the hypothalamic–pituitary–gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERalpha but not ERbeta

    Mol Endocrinol

    (2003)
  • Q. Zhou et al.

    Estrogen action and male fertility: roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function

    Proc Natl Acad Sci USA

    (2001)

    • Cited by (113)

    • Dichloroacetic acid and trichloroacetic acid as disinfection by-products in drinking water are endocrine-disrupting chemicals

      2024, Journal of Hazardous Materials

    • BDE-209 disturbed proliferation and differentiation of spermatogonia during mitotic process through estrogen receptor α

      2023, Reproductive Biology

    • Effects of varying doses of conjugated estrogen on body weight, hormonal and histological alterations of reproductive organs in adult swiss albino female mice

      2023, Heliyon

    • Continuous 17α-ethinylestradiol exposure impairs the sperm quality of marine medaka (Oryzias melastigma)

      2022, Marine Pollution Bulletin

    • Polymorphism analysis and expression profile of the estrogen receptor 2 gene in Leizhou black duck

      2022, Poultry Science
      Citation Excerpt :

      Given this, SNP as a molecular marker is a powerful tool to improve egg production traits. As reported earlier, estrogens are primarily found in the ovary and regulate several functions of the reproductive system such as ovulation, oogenesis, vitellogenesis, estrous behavior among others (Gustafsson, 2003; Heldring et al., 2007; Nelson and Habibi, 2013; Hamilton et al., 2014) indicating that estrogen participates in egg-laying performance by binding to its receptors. Therefore, ESR2 may be a possible marker for selecting ducks for egg-laying performance.

    • Estrogens and phytoestrogens in body functions

      2022, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    View full text
    Published by Elsevier Urban & Partner Sp. z o.o.