New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

doi:10.1016/j.mce.2008.04.003

Molecular and Cellular Endocrinology

Volume 290, Issues 1–2, 13 August 2008, Pages 24-30

https://doi.org/10.1016/j.mce.2008.04.003 Get rights and content

Abstract

Estrogen receptor alpha (ERα) mediates estrogen (E₂) actions in the brain and is critical for normal reproductive function and behavior. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. ERα can also participate in several non-classical pathways, including ERE-independent gene transcription via protein–protein interactions with transcription factors and rapid, non-genotropic pathways. To distinguish between ERE-dependent and ERE-independent mechanisms of E₂ action in vivo, we have created ERα null mice that possess an ER knock-in mutation (E207A/G208A; “AA”), in which the mutant ERα cannot bind to DNA but retains activity in ERE-independent pathways (ERα^−/AA mice). Understanding the molecular mechanisms of ERα action will be helpful in developing pharmacological therapies that differentiate between ERE-dependent and ERE-independent processes. This review focuses on how the ERα^−/AA model has contributed to our knowledge of ERα signaling mechanisms in estrogen regulation of the reproductive axis and sexual behavior.

Section snippets

The non-classical estrogen receptor knock-in mouse

To better define non-classical signaling mechanisms of ERα action, Jakacka and colleagues generated selective DNA-binding mutations in the mouse ERα and observed their effects in vitro (Jakacka et al., 2001). One such mutation within the first zinc finger of the DNA-binding domain, E207A/G208A (“AA”), completely eliminated ERE binding and activation of ERE-containing reporter genes, but retained full transcriptional activity of reporter genes containing AP1 response elements and interacted with

Homeostatic feedback actions of estrogen in the female reproductive axis

Throughout most of the ovulatory cycle, estrogens exert suppressive effects on GnRH and LH secretion. However, as estrogen levels rise from the growing ovarian follicle, their effects become stimulatory, evoking a preovulatory GnRH surge and subsequent LH surge, which triggers ovulation. While it is known that estrogen feedback appears to be primarily mediated by ERα (Couse et al., 2003, Wintermantel et al., 2006), the underlying signaling mechanisms that contribute to estrogen positive and

Testicular function and testosterone production in the male

The importance of ERα signaling in male fertility is demonstrated by descriptions of profound testicular dysfunction in ERαKO mice. Although the reproductive tract develops normally during the prenatal period, ERαKO males display atrophy of the testes and seminiferous tubules, tubule dysmorphogenesis, and reduced sperm counts (Eddy et al., 1996). We have used the ERα^−/AA mouse model to investigate the relative contributions of classical and non-classical mechanisms to these phenotypes. The

Male sexual behavior

It is well established that both organizational and activational effects of estrogen are critical for male sexual behavior (Meisel and Sachs, 1994, Scordalakes et al., 2002). Accordingly, copulation and other sexually motivated behaviors are severely impaired in ERαKO males (Eddy et al., 1996, McDevitt et al., 2007, Ogawa et al., 1997, Ogawa et al., 1998a, Ogawa et al., 1998b, Rissman et al., 1997, Wersinger and Rissman, 2000, Wersinger et al., 1997). We have utilized the ERα^−/AA mouse model to

Conclusions

The ERα^−/AA model clearly provides an exciting new opportunity for characterizing the classical and non-classical ERα signaling mechanisms in the brain and behavior. As estrogen regulation of physiology and behaviors requires fine-tuned control, it is perhaps not surprising that ERE-independent mechanisms are sufficient to mediate estrogen's actions in some systems (e.g. negative feedback in the female) but not others (e.g. male sexual behavior). On-going studies in our laboratories are

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Citation Excerpt :
Interestingly an increased progesterone receptor induction by E2 was observed in the ventromedial hypothalamus of these mice as compared to the full KO. Non-classical estrogen receptor action thus appears to be implicated in the control of one of the mechanisms underlying female responses (McDevitt et al., 2008). Based on the research briefly summarized in the preceding section it had become clear by the 1970s that steroids activate sexual behavior, at least in part, by modifying the transcription of specific, yet unidentified, proteins via binding to nuclear receptors that then act as transcription factors.
It was assumed for a long time that sex steroids are activating reproductive behaviors by the same mechanisms that produce their morphological and physiological effects in the periphery. However during the last few decades an increasing number of examples were identified where behavioral effects of steroids were just too fast to be mediated via changes in DNA transcription. This progressively forced behavioral neuroendocrinologists to recognize that part of the effects of steroids on behavior are mediated by membrane-initiated events. In this review we present a selection of these early data that changed the conceptual landscape and we provide a summary the different types of membrane-associated receptors (estrogens, androgens and progestagens receptors) that are playing the most important role in the control of reproductive behaviors. Then we finally describe in more detail three separate behavioral systems in which membrane-initiated events have clearly been established to contribute to behavior control.
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ReviewNew insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

Abstract

Section snippets

The non-classical estrogen receptor knock-in mouse

Homeostatic feedback actions of estrogen in the female reproductive axis

Testicular function and testosterone production in the male

Male sexual behavior

Conclusions

Physiol. Behav.

Behav. Brain Res.

Cell

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

Cell

Horm. Behav.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Horm. Behav.

Vitam. Horm.

Horm. Behav.

Neuron

Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell

Endocrinology

A nongenomic action of estradiol as the mechanism underlying the acute suppression of secretion of luteinizing hormone in ovariectomized ewes

Biol. Reprod.

Both estrogen receptor-alpha and -beta are required for sexual differentiation of the anteroventral periventricular area in mice

Endocrinology

The regulation of luteinizing hormone secretion by estrogen: relationships among negative feedback, surge potential, and male stimulation in juvenile, peripubertal, and adult female mice

Endocrinology

Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors

Endocrinology

Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice

Endocrinology

Episodic luteinizing-hormone release in the ovariectomized female guinea pig: rapid inhibition by estrogen

Biol. Reprod.

Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-alpha knockout mouse

Endocrinology

Estrogen receptor null mice: what have we learned and where will they lead us?

Endocr. Rev.

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.

17beta-estradiol rapidly facilitates chemoinvestigation and mounting in castrated male rats

Am. J. Physiol.

Effects of estrogen on the sexual behavior of male rats

Endocrinology

Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha

Endocrinology

Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes

Development

Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility

Endocrinology

Estradiol requirements for induction and maintenance of the gonadotropin-releasing hormone surge: implications for neuroendocrine processing of the estradiol signal

Endocrinology

Review
New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice