Review
Who’s in charge? Nuclear receptor coactivator and corepressor function in brain and behavior

https://doi.org/10.1016/j.yfrne.2009.04.008Get rights and content

Abstract

Steroid hormones act in brain and throughout the body to regulate a variety of functions, including development, reproduction, stress and behavior. Many of these effects of steroid hormones are mediated by their respective receptors, which are members of the steroid/nuclear receptor superfamily of transcriptional activators. A variety of studies in cell lines reveal that nuclear receptor coregulators are critical in modulating steroid receptor-dependent transcription. Thus, in addition to the availability of the hormone and the expression of its receptor, nuclear receptor coregulators are essential for efficient steroid-dependent transactivation of genes. This review will highlight the importance of nuclear receptor coregulators in modulating steroid-dependent gene expression in brain and the regulation of behavior.

Introduction

Steroid hormones have profound effects on homeostasis, development, reproduction and behavior. Many of the biological effects of steroid hormones are mediated through their respective receptors, which are members of the steroid/nuclear receptor superfamily of transcriptional activators [111], [205]. Receptors for the gonadal steroids, estrogens (ER), progestins (PR) and androgens (AR), can act in a classic, genomic mechanism by interacting directly with DNA to regulate gene transcription [111], [205]. Nuclear receptor coregulators enhance (coactivators) or repress (corepressors) the transcriptional activity of these steroid receptors, as well as other nuclear receptors [176], [156]. In brain, while ER, PR and AR can also function independent of ligand on DNA or at the membrane to rapidly activate cytoplasmic signaling pathways [112], [155], [128], [86], [210], [54], these receptors elicit many changes in behavior and physiology by acting through a classic, genomic mechanism of action. Approximately 300 coactivators and corepressors have been identified to date [157], [101], indicating the growing complexity of these coregulators in receptor action. This review will focus on the function of some of these important nuclear receptor coregulators in genomic mechanisms of steroid action in brain and behavior.

Section snippets

Classic genomic mechanism of steroid action

Steroid receptors, including ER, PR and AR, have a modular domain structure consisting of an amino-terminal region (N-domain), a central DNA-binding domain (DBD) and a carboxy-terminal ligand-binding domain (LBD) [111], [205]. In general, steroid receptors have two transcriptional activation domains: one in the amino terminal (AF-1) and one in the carboxyl terminal LBD (AF-2) [202]. Intracellular ER exist in two forms, α and β, which are transcribed from different genes [79], [95]. These

General mechanisms of molecular action of nuclear receptor coregulators

Nuclear receptor coregulators are required for efficient transcriptional regulation by nuclear receptors [176], [156] (Fig. 1). Nuclear receptor coactivators dramatically enhance the transcriptional activity of nuclear receptors, including ER and PR [176], [156]. In vitro studies using antibodies against nuclear receptor coactivators indicate that recruitment of coactivators is rate-limiting in steroid receptor-mediated gene transcription [176], [203]. In further support for nuclear receptor

The p160 family

Steroid receptor coactivator-1 (SRC-1/NcoA-1) was one of the first coactivators found to interact with hormone-bound steroid receptors [159]. SRC-1 is a member of a larger family of p160 proteins that includes SRC-2 (also known as GRIP1, TIF2 and NCoA-2) [216], [71] and SRC-3 (AIB1, TRAM-1, p/CIP, ACTR and RAC3) [6], [194]. The SRC family of coactivators physically interacts with steroid receptors, including ER, PR and GR, in a ligand-dependent manner [176], [156], [159]. The SRCs physically

Neuroanatomical expression and regulation of coactivators

While much is known about the molecular mechanisms of nuclear receptor coactivators from a variety of cell culture studies [176], [156], we are just beginning to understand their role in hormone action in brain. SRC-1 mRNA and protein are expressed at high levels in the cortex, hypothalamus, hippocampus and cerebellum of rodents [147], [129], [185], [116], [124], [11], [133], [153] and birds [25], [26]. SRC-2 is also expressed at high levels in the hypothalamus and hippocampus [147], [118], [7]

Corepressor expression and regulation in brain

Few studies have examined the expression and regulation of corepressor expression in brain. One particular study found that both NCoR and SMRT were expressed ubiquitously throughout the brain with some small anatomical differences in expression, such as higher levels of SMRT in the paraventricular nucleus and the substantia nigra [208]. The regulation of corepressor expression appears to be complex. Some early studies reported no influence of estradiol or thyroid hormone on NCoR and SMRT mRNA

Summary and future directions

The mechanisms by which steroids act in a region-specific, and cell type-specific, manner is a fundamental issue in steroid hormone action in brain. Recent investigations indicate that, in addition to the bioavailability of hormone and receptor levels, nuclear receptor coregulators are critical molecules in modulating steroid receptor-mediated transcription. Studies from cell lines have revealed much about the molecular mechanisms of action of these coactivators and corepressors. Furthermore,

Acknowledgements

Studies contributed by the author’s laboratory were supported by grants from National Science Foundation IBN 0080818 and National Institutes of Health R01 DK61935 (MJT) and R01 MH072956 (APA) and a Fonds National de la Recherche Scientifique-FRS postdoctoral fellowship (TDC).

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