Review ArticleEstrogen hormone physiology: Reproductive findings from estrogen receptor mutant mice
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.
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