New Insights into the Classical and Non-classical Actions of Estrogen: Evidence from Estrogen Receptor Knock-out and Knock-in Mice

Overview

Journal Mol Cell Endocrinol

Specialties Cell Biology
Endocrinology
Molecular Biology

Date 2008 Jun 7

PMID 18534740

Citations 68

Authors

Melissa A McDevitt

Christine Glidewell-Kenney

Mariana A Jimenez

Patrick C Ahearn

Jeffrey Weiss

J Larry Jameson

Jon E Levine

Affiliations

Soon will be listed here.

Abstract

Estrogen receptor alpha (ERalpha) mediates estrogen (E2) actions in the brain and is critical for normal reproductive function and behavior. In the classical pathway, ERalpha binds to estrogen response elements (EREs) to regulate gene transcription. ERalpha 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 ERalpha null mice that possess an ER knock-in mutation (E207A/G208A; "AA"), in which the mutant ERalpha cannot bind to DNA but retains activity in ERE-independent pathways (ERalpha(-/AA) mice). Understanding the molecular mechanisms of ERalpha action will be helpful in developing pharmacological therapies that differentiate between ERE-dependent and ERE-independent processes. This review focuses on how the ERalpha(-/AA) model has contributed to our knowledge of ERalpha signaling mechanisms in estrogen regulation of the reproductive axis and sexual behavior.

Citing Articles

Role of Membrane Estrogen Receptor Alpha on the Positive Feedback of Estrogens on Kisspeptin and GnRH Neurons.

Faure M, Corona R, Roomans C, Lenfant F, Foidart J, Cornil C eNeuro. 2024; 11(10).

PMID: 39375032 PMC: 11520851. DOI: 10.1523/ENEURO.0271-23.2024.

Aromatase enzyme: Paving the way for exploring aromatization for cardio-renal protection.

Eissa M, Gohar E Biomed Pharmacother. 2023; 168:115832.

PMID: 37931519 PMC: 10843764. DOI: 10.1016/j.biopha.2023.115832.

Musashi Exerts Control of Gonadotrope Target mRNA Translation During the Mouse Estrous Cycle.

Silva Moreira A, Lim J, Urbaniak A, Banik J, Bronson K, Lagasse A Endocrinology. 2023; 164(9).

PMID: 37477898 PMC: 10402870. DOI: 10.1210/endocr/bqad113.

Role of Estradiol Hormone in Human Life and Electrochemical Aptasensing of 17β-Estradiol: A Review.

Waifalkar P, Noh D, Derashri P, Barage S, Oh E Biosensors (Basel). 2022; 12(12).

PMID: 36551086 PMC: 9776368. DOI: 10.3390/bios12121117.

Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions.

Farkas S, Szabo A, Hegyi A, Torok B, Fazekas C, Ernszt D Biomedicines. 2022; 10(4).

PMID: 35453610 PMC: 9029610. DOI: 10.3390/biomedicines10040861.

References

Tsai M, OMalley B . Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994; 63:451-86. DOI: 10.1146/annurev.bi.63.070194.002315. View

Glidewell-Kenney C, Hurley L, Pfaff L, Weiss J, Levine J, Jameson J . Nonclassical estrogen receptor alpha signaling mediates negative feedback in the female mouse reproductive axis. Proc Natl Acad Sci U S A. 2007; 104(19):8173-7. PMC: 1876590. DOI: 10.1073/pnas.0611514104. View

Bronson F . 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. 1981; 108(2):506-16. DOI: 10.1210/endo-108-2-506. View

Delbes G, Levacher C, Duquenne C, Racine C, Pakarinen P, Habert R . Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha. Endocrinology. 2005; 146(5):2454-61. DOI: 10.1210/en.2004-1540. View

McKenna N, Lanz R, OMalley B . Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999; 20(3):321-44. DOI: 10.1210/edrv.20.3.0366. View

Gaub M, BELLARD M, Scheuer I, Chambon P, Sassone-Corsi P . Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell. 1990; 63(6):1267-76. DOI: 10.1016/0092-8674(90)90422-b. View

Ogawa S, Washburn T, Taylor J, Lubahn D, Korach K, Pfaff D . Modifications of testosterone-dependent behaviors by estrogen receptor-alpha gene disruption in male mice. Endocrinology. 1998; 139(12):5058-69. DOI: 10.1210/endo.139.12.6358. View

Chappell P, Schneider J, Kim P, Xu M, Lydon J, OMalley B . Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice. Endocrinology. 1999; 140(8):3653-8. DOI: 10.1210/endo.140.8.6895. View

Webb P, Lopez G, Uht R, Kushner P . Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol. 1995; 9(4):443-56. DOI: 10.1210/mend.9.4.7659088. View

10.

Weigel N, Zhang Y . Ligand-independent activation of steroid hormone receptors. J Mol Med (Berl). 1998; 76(7):469-79. DOI: 10.1007/s001090050241. View

11.

Davidson J . Effects of estrogen on the sexual behavior of male rats. Endocrinology. 1969; 84(6):1365-72. DOI: 10.1210/endo-84-6-1365. View

12.

Ray A, Prefontaine K, Ray P . Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem. 1994; 269(17):12940-6. View

13.

Syed F, Modder U, Fraser D, Spelsberg T, Rosen C, Krust A . Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways. J Bone Miner Res. 2005; 20(11):1992-2001. PMC: 1352155. DOI: 10.1359/JBMR.050713. View

14.

Wintermantel T, Campbell R, Porteous R, Bock D, Grone H, Todman M . Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron. 2006; 52(2):271-80. PMC: 6116893. DOI: 10.1016/j.neuron.2006.07.023. View

15.

Lubahn D, Moyer J, Golding T, Couse J, Korach K, SMITHIES O . Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A. 1993; 90(23):11162-6. PMC: 47942. DOI: 10.1073/pnas.90.23.11162. View

16.

Nett T, Crowder M, Wise M . Role of estradiol in inducing an ovulatory-like surge of luteinizing hormone in sheep. Biol Reprod. 1984; 30(5):1208-15. DOI: 10.1095/biolreprod30.5.1208. View

17.

Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K . The nuclear receptor superfamily: the second decade. Cell. 1995; 83(6):835-9. PMC: 6159888. DOI: 10.1016/0092-8674(95)90199-x. View

18.

Ogawa S, Lubahn D, Korach K, Pfaff D . Behavioral effects of estrogen receptor gene disruption in male mice. Proc Natl Acad Sci U S A. 1997; 94(4):1476-81. PMC: 19816. DOI: 10.1073/pnas.94.4.1476. View

19.

Safe S . Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm. 2001; 62:231-52. DOI: 10.1016/s0083-6729(01)62006-5. View

20.

Couse J, Korach K . Estrogen receptor null mice: what have we learned and where will they lead us?. Endocr Rev. 1999; 20(3):358-417. DOI: 10.1210/edrv.20.3.0370. View