Estrogen receptor-alpha gene expression in the cortex: Sex differences during development and in adulthood
Open accessAbstract
17β-estradiol is a hormone with far-reaching organizational, activational and protective actions in both male and female brains. The organizational effects of early estrogen exposure are essential for long-lasting behavioral and cognitive functions. Estradiol mediates many of its effects through the intracellular receptors, estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ). In the rodent cerebral cortex, estrogen receptor expression is high early in postnatal life and declines dramatically as the animal approaches puberty. This decline is accompanied by decreased expression of ERα mRNA. This change in expression is the same in both males and females in the developing isocortex and hippocampus. An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERα) gene expression is critical for understanding the developmental, as well as changes in postpubertal expression of the estrogen receptor. One mechanism of suppressing gene expression is by the epigenetic modification of the promoter regions by DNA methylation that results in gene silencing. The decrease in ERα mRNA expression during development is accompanied by an increase in promoter methylation. Another example of regulation of ERα gene expression in the adult cortex is the changes that occur following neuronal injury. Many animal studies have demonstrated that the endogenous estrogen, 17β-estradiol, is neuroprotective. Specifically, low levels of estradiol protect the cortex from neuronal death following middle cerebral artery occlusion (MCAO). In females, this protection is mediated through an ERα-dependent mechanism. ERα expression is rapidly increased following MCAO in females, but not in males. This increase is accompanied by a decrease in methylation of the promoter suggesting a return to the developmental program of gene expression within neurons. Taken together, during development and in adulthood, regulation of ERα gene expression in the cortex can occur by DNA methylation and in a sex-dependent fashion in the adult brain.
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Because mRNA was assayed in whole brain and ERα expression is not global, BPA-induced changes in ERα expression may have been missed.
“In neonatal cortex, estradiol hypermethylates ERα [61] and perhaps the same thing occurs here, but, given that we assayed mRNA in whole brain and ERα expression is not global we may have missed BPA induced changes in expression.”
From Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice (2011) · cites this paper as [61]
The Introduction’s developmental-regulation section describes ERα expression in specific brain regions, supporting the premise that its expression is not uniform. It does not say that a whole-brain assay missed BPA-induced changes; that is the citing authors’ own possibility, while the citation in the printed sentence is attached to the earlier methylation clause. No page number is available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPrior to weaning (~P18), ERalpha expression declines precipitously and shortly after ERbeta rises, resulting in higher ERbeta expression in neocortex in adults.
“Prior to weaning (~P18), ERalpha expression declines precipitously and shortly after ERbeta rises (Prewitt and Wilson, 2007; Wilson et al., 2011; Zsarnovszky and Belcher, 2001), resulting in higher ERbeta expression in neocortex in adults (Kritzer, 2002; Shughrue et al., 1997)”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Wilson et al., 2011
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References 84 · Cited by 85
- Authors
- Wilson, M. E., Westberry, J. M., & Trout, A. L.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Wilson, Melinda E.
- ORCID
- Trout, Amanda L.
- Venue
- Hormones and Behavior
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 59
- Issue
- 3
- Pages
- 353-357
- ISSN
- 0018-506X (ISSN-L)
- PMC
- PMC3016448
- OpenAlex
- W2034471064
- Cited by
- 85
- References
- 84
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 9 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 3 · 2016: 10 · 2015: 4 · 2014: 7 · 2013: 10 · 2012: 9
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hormones and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Heart, Lung, and Blood Institute (R01HL073693)
- National Center for Research Resources (P20RR015592, P20RR15592)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- estrogen receptor alpha, cerebral cortex, sex differences, estradiol, DNA methylation, promoter methylation, gene silencing, postnatal development, puberty, hippocampus, middle cerebral artery occlusion, neuroprotection, neuronal injury, estrogen receptor beta, epigenetic regulation
- MeSH terms
- Animals, Cerebral Cortex, Critical Period, Psychological, Female, Male, Sex Characteristics, Gene Expression, DNA Methylation, Epigenesis, Genetic, Estrogen Receptor alpha, Mice, Rats
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