Elsevier

Hormones and Behavior

Volume 59, Issue 3, March 2011, Pages 353-357
Hormones and Behavior

Review
Estrogen receptor-alpha gene expression in the cortex: Sex differences during development and in adulthood

https://doi.org/10.1016/j.yhbeh.2010.08.004Get rights and content

Abstract

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.

Research Highlights

►Estrogen receptor alpha is developmentally regulated in the cortex. ►Estrogen receptor down-regulation occurs by DNA methylation. ►Estrogen receptor alpha is re-expressed following injury in a a sex-specific manner.

Introduction

Estrogens have long been known to play a crucial role in coordinating many neuroendocrine events that control sexual development, sexual behaviour and reproduction. 17β-estradiol is the primary biologically active form of estrogen. In rodents, estradiol is critical for sexual differentiation of the brain (see review by (McCarthy, 2008)). For example, estradiol organizes neural circuits and regulates apoptosis of neurons leading to long-term differences in the male and female brain (Anderson et al., 1986, Rhees et al., 1990, Toran-Allerand, 1976). In addition to its role in development, estradiol modulates numerous facets of brain function in the adult brain (for review see (McEwen and Alves, 1999) and (Simpkins and Singh, 2008)). Estradiol prevents neuronal cell death in a variety of brain injury models, modulates learning and memory and promotes the formation of synapses (Li et al., 2004, Sherwin, 1994, Simpkins et al., 1994, Wise et al., 2001, Woolley & McEwen, 1993).

The physiological effects resulting from estradiol actions in target tissues are mediated primarily by two intracellular receptors, ERα and ERβ (Green et al., 1986, Koike et al., 1987, Kuiper et al., 1996, Mosselman et al., 1996, White et al., 1987). Both ERα and ERβ have been observed in neurons and glia in the brain (Chaban et al., 2004, Donahue et al., 2000), and both are expressed throughout the brain with distinct patterns in different brain regions and with differing levels of expression during development (Gonzalez et al., 2007, Osterlund et al., 2000a, Osterlund et al., 2000b, Prewitt, 2007, Shughrue et al., 1997).

The ERα gene is highly conserved between human and rodents, containing similar gene and protein structures. ERα is preceded by multiple promoters that generate several mRNA splice variants (Hirata et al., 2001, Kos et al., 2001, Monje et al., 2007). Alternative splicing occurs at the first exon, which is then spliced to a common splice acceptor site upstream of the translational initiation codon in Exon 1. This alternative promoter splicing results in mRNA splice variants that differ only in their 5’ untranslated region encoding the same protein. These different mRNAs may be important in regulating stability or processing of the mRNA (Kos et al., 2001). Differences in the 5'UTRs may also provide for areas of different epigenetic modifications that can then modulate changes in gene expression. The regulatory binding sites of transcription factors that control gene expression are also likely located in the regions surrounding these promoters. To date, relatively little is known about the molecular composition of the regulatory elements that control ERα gene expression.

The regulation of gene expression by epigenetic modification is an emerging mechanism for controlling neuronal gene expression. Epigenetic modification of chromatin involves changes to DNA bases and the associated proteins (for review see (Wolffe and Matzke, 1999) and (Klose and Bird, 2006)) in the absence of changes in the DNA sequence. Epigenetic modifications include histone acetylation, histone methylation and DNA methylation (Bird & Wolffe, 1999, Cooper & Krawczak, 1989). The first step in DNA methylation results in the enzymatic transfer of a methyl group to the 5’-position of the pyrimidine ring of a cytosine residue followed by a guanine (CpG dinucleotides). The modification of the cytosines in CpG residues are carried out initially by the enzyme DNA methyltransferase 3A (DNMT3A) and maintained by DNMT1 (Klose and Bird, 2006). CpG residues are often found upstream or downstream of the transcriptional start site.

The methylated CpGs are stabilized by methyl-CpG-binding proteins. The family of methyl-CpG-binding proteins contains several members including methyl binding domain (MBD) proteins 1, 2, 3, 4 and MeCP2 (Nan et al., 1998, Ng et al., 2000, Ng et al., 1999). These proteins bind to the methylated CpG residues potentially disrupting transcription. These proteins can also associate with co-repressor protein complexes of promoters that include histone deacetylases (HDAC) (Ballestar & Wolffe, 2001, Wade, 2001). Together, these complexes suppress transcription of genes with methylated promoter DNA.

Epigenetic modification of chromatin in neurons has been shown to play an important role in regulating gene expression during neuronal development and in learning and memory (Kiefer, 2007, Levenson & Sweatt, 2005). MeCP2 gene mutations are also the cause of some cases of Rett syndrome, a progressive neurological developmental disorder that appears during early childhood when sensory experience is driving the synaptic reorganization required for creating mature circuits in the brain (Zoghbi, 2003) (Guy et al., 2001). Furthermore, MeCP2 is present in high levels in mature neurons (Meehan et al., 1992), and studies suggest that the MeCP2 protein plays a role in forming synapses between neurons (Zhou et al., 2006). Additionally, MeCP2 is differentially expressed in the hypothalamus during a critical time in sexual differentiation of the brain (Kurian et al., 2008). Furthermore, DNMT3 expression has also been shown to be dynamically regulated in the developing brain as well as in the adult cortex (Feng et al., 2005, Siegmund et al., 2007).

The ERα gene undergoes changes in promoter methylation under normal and pathological conditions. For example, methylation of the ERα promoter has been reported to occur in the colon during aging (Issa et al., 1994) and changes in the expression of ERα have been associated with the progression of numerous types of cancerous tissues including breast and lung (Issa et al., 1994, Issa et al., 1996, Lapidus et al., 1998, O'Doherty et al., 2002, Oh et al., 2001, Ottaviano et al., 1994, Sasaki et al., 2002). Although evidence exists for multiple mechanisms of epigenetic modification of the ERα gene, DNA methylation has been the most widely described epigenetic phenomenon, and is the first epigenetic mechanism we have investigated.

Section snippets

Developmental regulation of estrogen receptor-alpha mRNA

ERα protein and mRNA levels change dramatically during postnatal brain development (Shughrue et al., 1997, Simerly et al., 1990, Toran-Allerand et al., 1992). High levels of estradiol binding in non-hypothalamic regions such as the cortex and hippocampus during the first two weeks of life have been identified by receptor autoradiography (Pfaff & Keiner, 1973, Sheridan, 1979, Shughrue et al., 1990). This expression declines as animals approach puberty. In later studies in rats and mice, ERα mRNA

Regulation of estrogen receptor-alpha mRNA following stroke

In addition to the developmental changes in expression in ERα mRNA widely described, ERα mRNA expression is also dramatically regulated following brain injury. Middle cerebral artery occlusion (MCAO) is a well-established model of focal ischemia. Studies in rats and mice have demonstrated a gender difference in neuronal cell death following MCAO. Female brains are consistently protected against cell death (Alkayed et al., 1998, Rusa et al., 1999, Simpkins et al., 1997). Pretreatment with low

Summary

Estrogens mediate many diverse and critical actions in the brain. Most of these actions require the presence of classical estrogen receptors. Thus, coordinated regulation of the estrogen receptor genes is critical for mediating these responses to estrogens in an age, gender, and brain region-specific manner (Fig. 2). Alterations in the normal regulation either during development, disease or aging could potentially interfere with estradiol action. We have begun to identify numerous physiological

Acknowledgments

This work cited from our laboratory was supported by the National Science Foundation (NSF IOS0919944), COBRE grant P20 RR15592 from the National Center for Research Resources (NCRR), and R01 HL073693 (MEW). All opinions, findings and conclusions expressed in this material are those of the authors and not those necessarily of NSF or NCRR.

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