Journal Mobile Options
Table of Contents
Vol. 94, No. 1, 2011
Issue release date: July 2011
Section title: Original Paper
Free Access
Neuroendocrinology 2011;94:49–57
(DOI:10.1159/000323780)

Nuclear Receptor Coactivators Are Coexpressed with Steroid Receptors and Regulated by Estradiol in Mouse Brain

Tognoni C.M. · Chadwick, Jr. J.G. · Ackeifi C.A. · Tetel M.J.
Neuroscience Program, Wellesley College, Wellesley, Mass., USA
email Corresponding Author

Abstract

Background/Aims: The steroid hormones, including estradiol (E) and progesterone, act in the brain to regulate female reproductive behavior and physiology. These hormones mediate many of their biological effects by binding to their respective intracellular receptors. The receptors for estrogens (ER) and progestins (PR) interact with nuclear receptor coactivators to initiate transcription of steroid-responsive genes. Work from our laboratory and others reveals that nuclear receptor coactivators, including steroid receptor coactivator-1 (SRC-1) and SRC-2, function in brain to modulate ER-mediated induction of the PR gene and hormone-dependent behaviors. In order for steroid receptors and coactivators to function together, both must be expressed in the same cells. Methods: Triple-label immunofluorescence was used to determine if E-induced PR cells also express SRC-1 or SRC-2 in reproductively relevant brain regions of the female mouse. Results: The majority of E-induced PR cells in the medial preoptic area (61%), ventromedial nucleus of the hypothalamus (63%) and arcuate nucleus (76%) coexpressed both SRC-1 and SRC-2. A smaller proportion of PR cells expressed either SRC-1 or SRC-2, while a few PR cells expressed neither coactivator. In addition, compared to control animals, 17β-estradiol benzoate (EB) treatment increased SRC-1 levels in the arcuate nucleus, but not the medial preoptic area or the ventromedial nucleus of the hypothalamus. EB did not alter SRC-2 expression in any of the three brain regions analyzed. Conclusions: Taken together, the present findings identify a population of cells in which steroid receptors and nuclear receptor coactivators may interact to modulate steroid sensitivity in brain and regulate hormone-dependent behaviors in female mice. Given that cell culture studies reveal that SRC-1 and SRC-2 can mediate distinct steroid-signaling pathways, the present findings suggest that steroids can produce a variety of complex responses in these specialized brain cells.

© 2011 S. Karger AG, Basel


  

Key Words

  • Estrogen receptor
  • Hypothalamus
  • Progestin receptor
  • Sexual behavior
  • Steroid receptor coactivator
  • Steroid receptor coactivator-1

 Introduction

The ovarian hormones estradiol (E) and progesterone regulate growth, proliferation and differentiation in a variety of tissues. In addition, these hormones play an important role in hormone-dependent cancers of the reproductive systems, including breast cancer [1]. E and progesterone act in specific brain regions to influence a variety of functions, including cognition and female reproductive behavior and physiology [2,3].

Estrogens and progestins bind to their respective steroid receptors, ER and PR, which are members of a superfamily of ligand-dependent transcription factors. Intracellular ER exist as two subtypes, α and β, which are transcribed from different genes [4,5,6]. In primates and rodents, PR are expressed in two forms; the full-length PR-B and the N-terminal truncated PR-A, which are encoded by the same gene but are regulated by different promoters [7]. In the traditional genomic mechanism of action, these steroid receptors bind hormones and undergo a conformational change that causes the dissociation of heat shock proteins and other immunophilins [8]. Activated receptors dimerize and bind preferentially to specific hormone response elements in the promoter regions of target genes to increase or decrease gene transcription [9,10]. In addition, ER and PR have been found to function in the absence of ligand and at the membrane to rapidly activate cytoplasmic signaling pathways [11,12,13,14,15].

A classic example of a steroid-induced gene is the induction of the PR gene by E in a variety of tissues, including brain. This ER-mediated induction of PR is thought to occur via an estrogen response element in the promoter region of the PR gene [16,17,18]. While PR are present in low levels in the brains of ovariectomized rodents, E priming dramatically increases the expression of PR in the medial preoptic area (MPA), arcuate nucleus (ARC) and ventromedial nucleus of the hypothalamus (VMN) [19,20,21,22,23,24,25,26,27,28]. Based on studies in ER knockout mice, E induction of PR in brain appears to be predominantly, while not solely [29], dependent on ERα [30,31,32]. In support of this ERα-mediated event, virtually all E-induced PR cells in the hypothalamus also express ERα [26,33]. These E-induced PR in the hypothalamus are important for progesterone-facilitated reproductive behavior [34]. In addition, studies using PR-A- and PR-B-specific knockouts reveal that while both receptors are important, PR-A appears to have a larger role in the full display of progesterone-facilitated lordosis [35].

Nuclear receptor coregulators consist of coactivators and corepressors that are required for efficient transcriptional regulation by nuclear receptors [36,37,38,39]. There is mounting evidence that coregulators are involved in human disease, including metabolic disorders and cancers [40]. Nuclear receptor coactivators dramatically enhance the transcriptional activity of nuclear receptors, including PR and ER, through a variety of mechanisms, including acetylation, methylation, phosphorylation and chromatin remodeling [36,37]. In vitro, these coactivators are often rate limiting for steroid receptor activation and act as bridging proteins between the receptor and the basal transcriptional machinery [36,37].

The p160 steroid receptor coactivator (SRC) family includes SRC-1/NcoA-1 [41], SRC-2/TIF2/GRIP1/NcoA2 [42,43], and SRC-3/p/CIP/ACTR/AIB1/TRAM-1/RAC3 [44,45]. Recent work reveals that two members of this p160 family of coactivators, SRC-1 and SRC-2, are important for hormone action in brain and behavior [46,47]. SRC-1 [48,49,50,51,52,53,54,55,56,57] and SRC-2 [58,59,60] are expressed at high levels in the cortex, hypothalamus and hippocampus of rodents. Our laboratory and others have found that SRC-1 and SRC-2 are important for hormone-dependent sexual differentiation of the brain [53], gene expression in brain [54,61,62,63] and sexual behavior [54,61,62,63,64]. Finally, SRC-1 and SRC-2 from rodent brain physically interact with ER and PR in a receptor subtype- and brain region-specific manner [58,65].

In order for coactivators to function with steroid receptors in hormone action in brain, both the coactivators and receptors must be expressed in the same cells. Our previous work in female rats reveals that the majority of E-induced PR cells in the hypothalamus also express SRC-1 [48]. In support, SRC-1 and SRC-2 expression is significantly related to PR expression in hormone-responsive meningiomas [66]. In contrast, SRC-1 was not detected in mouse mammary epithelial cells expressing E-induced PR [67], suggesting that SRC-1 functions in a cell-type- and tissue-specific manner. However, it is not known if SRC-1 or SRC-2 are expressed in PR-containing cells in mouse brain. Therefore, we used a triple-label immunofluorescent technique to ask if E-induced PR cells expressed SRC-1, SRC-2 or both coactivators in reproductively relevant brain regions of female mice.

 

 Materials and Methods


 Animals

Female C57 mice, 5–6 weeks old, were obtained from Taconic (Germantown, N.Y., USA) and group-housed for 1 week under a 12:12-hour light/dark cycle with food and water freely available. One week after arrival, the animals were ovariectomized under 1.5% isoflurane. One week following ovariectomy, the mice were injected subcutaneously with either 17β-estradiol benzoate (EB, 1 µg in sesame oil) or vehicle 48 h prior to sacrifice. Ovariectomized mice treated with EB (n = 8) or vehicle (n = 7) were anesthetized with Fatal Plus (sodium pentobarbital 0.1 ml, 390 mg/ml) and perfused with 4% paraformaldehyde. Five thousand units of sodium heparin dissolved in saline were injected into the left ventricle. Saline (0.15 M, 8 ml) preceded the flow of 4% paraformaldehyde in 0.1 M sodium phosphate buffer (pH = 7.2) at a flow rate of 8 ml/min for 8 min. Brains were removed from the cranium, blocked and stored in 0.1 M sodium phosphate buffer (pH = 7.2) containing 20% sucrose at 4°C for 48 h. Coronal sections were cut on a freezing rotary microtome at 40 µm from the MPA through the hypothalamus following the mouse brain atlas [68]. The sections were stored in cryoprotectant at –20°C until processing. All animal procedures were approved by the Institutional Animal Care and Use Committees of Wellesley College.

 Immunohistochemistry

A triple-label immunohistochemistry technique was used to identify cells expressing PR, SRC-1 and SRC-2 in the VMN, ARC and MPA. The brain sections were incubated in 0.05 M Tris-buffered saline (TBS) and incubated in donkey anti-mouse IgG to occupy the endogenous mouse antibodies. The sections were washed again in TBS and incubated in 20% donkey serum to reduce nonspecific binding. To detect PR, SRC-1 and SRC-2, the sections were incubated for 24 h at 4°C in a cocktail containing a PR mouse monoclonal antibody directed against amino acids 922–933 of the C-terminus of human PR (1:6,000, MAB 462, Millipore), an SRC-1 goat polyclonal antibody directed against the C-terminus (aa 1355–1405) mouse SRC-1 (1:250, M-20, sc-6098, Santa Cruz Biotechnology), and an SRC-2 rabbit polyclonal antibody directed against the C-terminus (aa 1400–1464) of human SRC-2 (1:1,000, NB100-1756, Novus Biologicals). The specificities of the PR and SRC-1 antibodies have been established previously in rodent brain [48,69,70]. Analysis of homogenates of mouse hypothalamus by Western blot using NB100-1756 revealed a distinct immunoreactive band for SRC-2 (see online supplementary figure 1, www.karger.com/doi/10.1159/000323780) at the expected molecular mass of 160 kDa [41,42]. The sections were washed with TBS and incubated in a cocktail of fluorescently labeled secondary antisera containing donkey anti-mouse serum (1:300, Alexa 594, Invitrogen) for detection of PR, donkey anti-goat (1:100, Alexa 488) for detection of SRC-1, and donkey anti-rabbit (1:100, Alexa 647) for detection of SRC-2. The sections were then washed with TBS and mounted on gel-coated glass slides, coverslipped with Fluoro-Gel (EMS) and stored at 4°C.

Controls for this triple-label technique included the omission of the primary or secondary antibodies. In addition, primary antibodies were preadsorbed with 20-fold molar excess of SRC-1 peptide of the C-terminus (SRC-1 M-20 P, Santa Cruz Biotechnology), a fragment of GST-tagged recombinant human SRC-2 protein consisting of aa 1365–1465 (H00010499-Q01, Novus Biologicals) or full-length human PR-B protein. Recombinant human PR-B proteins were expressed in Spodoptera frugiperda (Sf9) insect cells from the Baculovirus/Monoclonal Antibody Facility at the Baylor College of Medicine, as described previously [71,72].

 Imaging by Confocal Microscopy and Analysis

The MPA (fig. 33 of [68]), VMN (fig. 46 of [68]) and ARC (fig. 46 of [68]), which are rich in E-induced PR, were analyzed with the experimenter blind to treatment groups. Images of immunofluorescence from one section per brain region were captured at 200× with a Leica TCS SP laser scanning confocal microscope (equipped with an argon laser 488, diode laser 561 and helium-neon laser 633) using imaging software (LCS 1347a, Leica). For each brain region, a two-dimensional 1-µm optical section (512 × 512) was captured and analyzed. One side of a representative section of each animal was analyzed using a uniform region of interest for the MPA (total area of the region of interest = 44,981 µm2), VMN (total area = 40,373 µm2) and ARC (total area = 59,809 µm2). For each brain region, the region of interest was placed over the highest concentration of PR-immunoreactive (IR) cells in EB-treated animals and the corresponding area for vehicle animals. Laser output (mV) was measured using a FieldMaster (Coherent) and kept constant between animals and imaging sessions. Triple-labeled images (8-bit) were analyzed using NIS Elements (Nikon). The threshold for detection of specific immunoreactivity was determined as a function of background. For each brain region, the threshold was established as the mean maximum pixel intensity (ranging from 0 to 256) of 10 random samples of background for 3 randomly selected animals in each group. Within each optical section, cells were considered immunopositive if above the threshold value and the total area was greater than 8.0 µm2. To insure unbiased data collection for each optical section of a brain region, all objects that met the established criteria were counted in a uniform region of interest. In each brain region, the number of immunoreactive cells and the average optical density were collected for PR immunoreactivity, SRC-1 immunoreactivity and SRC-2 immunoreactivity.

 Statistical Analysis

To determine if EB influenced the expression of SRC-1 or SRC-2, images of matched sections from EB-treated and control animals were analyzed for total cell counts and relative optical density for coactivator immunoreactivity using NIS Elements (Nikon). Because the data were not normally distributed, differences in coactivator immunoreactivity between the EB and control groups were compared using a Kruskal-Wallis one-way analysis of variance by rank test (Statistica). Differences were considered statistically significant at a probability <0.05.

 

 Results


 Coexpression of E-Induced PR, SRC-1 and SRC-2

Consistent with previous studies in mice and rats, many E-induced PR-IR cells were detected in EB-treated mice, while little to no PR were observed in control animals [20,21,23,25,30,31,34,73,74,75,76,77,78] in the VMN (EB = 35.0 ± 2.0 cells vs. oil = 0.3 ± 0.2; p < 0.001), ARC (109.3 ± 23.7 vs. 1.6 ± 1.4; p < 0.01) and MPA (139.0 ± 25.9 vs. 31.1 ± 17.1; p < 0.01) (fig. 1a, b, 2a). Similar differences in the average optical density of PR immunoreactivity were found between EB and control animals (data not shown).

FIG01
Fig. 1. E-induced PR cells coexpress SRC-1 and SRC-2 in the VMN of female mice. The VMN of animals treated with EB (a–d) or vehicle (e–h) were immunostained for PR (a, e), SRC-1 (b, f), or SRC-2 (c, g). d, h Overlaid image shows cells expressing PR, SRC-1 and SRC-2 (yellow circles), shown in inset at higher magnification. Red circles indicate a cell expressing PR only, green circles indicate a cell expressing SRC-1 only and blue circles indicate a cell expressing SRC-2 only. Bar = 50 µm.

FIG02
Fig. 2. Expression of PR, SRC-1 and SRC-2 in the ARC of female mice treated with EB or vehicle. The ARC of animals treated with EB (a–d) or vehicle (e–h) were immunostained for PR (a, e), SRC-1 (b, f), or SRC-2 (c, g). Red circles indicate a cell expressing PR only and yellow circles indicate a cell expressing PR, SRC-1 and SRC-2. Bar = 50 µm.

SRC1-IR cells were observed throughout the hippocampus, amygdala (data not shown) and hypothalamus, including the VMN, ARC and MPA (fig. 1b, f, 2b), which is consistent with other limited studies of SRC-1 mRNA in mice [59,79]. In addition, the present findings of SRC-1 expression in mouse brain are consistent with previous studies in rats [48,49,50,51,52,53,54,70,80] and birds [57,81]. SRC2-IR cells were detected throughout the mouse hippocampus, amygdala (data not shown) and hypothalamus, including the VMN, ARC and MPA (fig. 1c, g, 2c). While the pattern of SRC-2 expression in brain has been studied much less, these results are consistent with other findings in mice and rats [59,60,61].

We found that a large majority of cells containing E-induced PR in the VMN coexpressed both SRC-1 and SRC-2 (table 1; fig. 1d). In addition, most of the E-induced PR cells in the MPA and ARC coexpressed both SRC-1 and SRC-2 (table 1; fig. 2d). A smaller proportion of E-induced PR cells in these three brain regions contained only SRC-1. Interestingly, in all three brain regions, fewer PR cells expressed SRC-2 only than SRC-1 only (table 1). A relatively small population of E-induced PR-IR cells expressed neither of the coactivators. In the VMN, the majority of coactivator-expressing cells also expressed PR (table 1;fig. 1d). However, in contrast to the VMN, the majority of SRC1-IR and SRC2-IR cells in the ARC and MPA did not express E-induced PR (table 1).

TAB01
Table 1. Cells immunostained for PR, SRC-1 and SRC-2 in the mouse VMN, ARC and MPA

 Regulation of Nuclear Receptor Coactivator Expression by Estradiol

To determine if EB alters the expression of SRC-1 or SRC-2 expression in the VMN, MPA or ARC, sections from EB- and vehicle-treated animals were compared. EB increased the number of SRC1-IR cells in the ARC, but not in the MPA or VMN (fig. 2b, f, 3a). No differences were detected in the number of SRC2-IR cells between EB and control animals in the three brain regions analyzed (fig. 3b). Similar effects were detected in the relative optical densities of SRC-1 and SRC-2 immunoreactivity between EB- and vehicle-treated animals (data not shown).

FIG03
Fig. 3. EB regulates SRC-1 expression in the ARC. Average number (±SEM) of cells immunoreactive for SRC-1 (a) or SRC-2 (b) per region of interest for the VMN, ARC and MPA from oil- (open bars) and EB- (grey bars) treated mice. * p < 0.02.

 Controls for Triple-Label Immunohistochemistry

Controls were performed to confirm specificity of the triple-label immunohistochemistry technique. Omission of each individual primary antibody resulted in no detectable immunoreactivity of the respective label (data not shown). In addition, omission of each individual secondary antibody resulted in no observable immunoreactivity of the respective label (data not shown). Preadsorption of (1) MAB-462 with a 20-fold excess of recombinant human PR-B protein resulted in no PR immunoreactivity, (2) M-20 with a 20-fold molar excess of SRC-1 peptide of the C-terminus resulted in no SRC-1 immunoreactivity, and (3) NB100-1756 (SRC-2) with a fragment of recombinant human SRC-2 protein resulted in no SRC- 2 immunoreactivity (data not shown). In further confirmation of the specificity of the triple-label technique, intensely labeled cells with only PR, SRC-1 or SRC-2 immunoreactivity were observed.

 

 Discussion

Our laboratory and others have shown that the nuclear receptor coactivators SRC-1 and SRC-2 are important for steroid action in the brain. These coactivators modulate ER-mediated transactivation of the PR gene in the brain and ER- and PR-dependent reproductive behaviors in female rodents [54,61,64]. In order for nuclear receptor coactivators to function with steroid receptors in brain, both coactivator and receptor must be expressed in the same cell. In the present study, triple-label immunofluorescence was used to investigate the coexpression of E-induced PR with SRC-1 or SRC-2 in individual cells in the female mouse brain.

SRC-1 and SRC-2 were expressed at high levels in the VMN, ARC and MPA, regions known to be involved in reproductive behavior. Interestingly, the majority of E-induced PR cells in the VMN, MPA and ARC coexpress both SRC-1 and SRC-2. Given that virtually all E-induced PR cells in the hypothalamus express ERα [26,33], the present data indicate that a distinct population of cells in the VMN, MPA and ARC coexpress steroid receptors (ER and PR) and two members of the p160 family of nuclear receptor coactivators (SRC-1 and SRC-2). A smaller population of E-induced PR cells in these three brain regions expressed only SRC-1, while less expressed only SRC-2. Finally, there was a small proportion of E-induced PR cells that expressed neither SRC-1 nor SRC-2. While it is possible that very low levels of SRC-1 and SRC-2 were not detected in PR cells by the immunofluorescent technique, it may be that ER and PR transcriptional activity in these cells is mediated by other coactivators in brain [46]. In future experiments it will be important to investigate other coregulatory proteins that interact with ER and PR, including SRC-3 and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) which have recently been shown to function together to coactivate ER transactivation of the PR gene in MCF-7 cells [82]. It is also possible that the ER and PR in some cells function through a coactivator-independent pathway [83,84]. It should be noted that not all coactivator-containing cells expressed PR, suggesting that these coactivators function with other steroid receptors such as glucocorticoid and androgen receptors [46].

There is evidence that SRC-1 and SRC-2 expression in rat brain is altered by steroids [60,80,85,86,87,88] and endocrine disruptors [89], while other studies have found no effects of steroids on coactivator expression [see [46] for a more thorough review; [48,49] ]. However, very little is known about hormonal regulation of coactivators in mouse brain. Therefore, the present study addressed the possibility of E regulation of SRC-1 or SRC-2 expression in mouse brain. EB treatment increased SRC-1 expression in the ARC compared with vehicle-treated control animals. In contrast, EB did not alter SRC-1 levels in the VMN or MPA, or SRC-2 expression in any of the three brain regions. It is possible that the present immunofluorescent technique was not sensitive enough to detect slight changes in SRC-1 or SRC-2 expression in these other brain regions. The present E-induced increase of SRC-1 in the ARC is consistent with other studies in rats that have found changes in SRC-1 protein over the estrous cycle [85] and E-induced increases in SRC-1 mRNA in the hypothalamus [86]. The present findings suggest that E regulates SRC-1, but not SRC-2, in a brain-region-specific manner.

The mechanisms by which individual cells modulate steroid responsiveness in a given brain region is a fundamental issue in steroid hormone action in brain. Taken together with previous findings, the present results identify putative sites of functional interaction of ovarian steroid receptors (ERα and PR) with nuclear receptor coactivators (SRC-1 and SRC-2) in reproductively relevant brain regions. These results support and extend our previous findings that the majority of E-induced PR cells in the rat hypothalamus express SRC-1 and CBP [48] and support the findings that SRC-1 and SRC-2 function in the hypothalamus to modulate hormone-dependent female sexual behavior [54,61,64]. In addition, these results provide neuroanatomical support for the concept that these coactivators are important in ER transactivation of the PR gene in brain [54,61]. However, the functional differences of these coactivators in ER-mediated activation of the PR gene in brain are not known. For example, it is not known if these two coactivators contribute differentially to the ER-mediated induction of the two PR isoforms. In support of this idea, ER and other steroid receptors have distinct affinities for nuclear receptor coactivators. For example, SRC-1 and SRC-2 from the rat hypothalamus and hippocampus physically associate with ER and PR in a receptor subtype- and brain region-specific manner [58,65]. Interestingly, SRC-1 from the hypothalamus interacts more with ERα than ERβ, while SRC-2 associates with ERα but shows virtually no interaction with ERβ [58,65]. In addition, receptor-coactivator interactions are influenced by different ligands and response elements on DNA [90,91,92,93]. In MCS80 Schwann cells, glucocorticoid receptors recruit SRC-1 or SRC-3, but not SRC-2, in the transactivation of a minimal glucocorticoid-sensitive reporter gene containing two GREs [94,95]. Studies in T47D cells reveal that SRC-1 preferentially recruits CBP resulting in acetylation of histone H4, while SRC-2 recruits pCAF leading to acetylation of histone H3 [96]. It has been suggested that this recruitment of differential histone acetyltransferases can modulate the transcription of various steroid-responsive genes. Moreover, ER (as well as androgen receptors) in the presence of classical hormone response elements, recruit distinct heterodimers of the SRC family members [97]. Interestingly, on non-hormone response element-containing genes (such as AP-1 sites of early genes), ER recruit SRC proteins as monomers. Taken together, the present findings that many E-induced PR cells coexpress both SRC-1 and SRC-2 provide neuroanatomical support for the concept that steroid responsiveness can be fine-tuned not only by the presence or absence of coactivators but also by the ratio of these coactivators present within individual neurons. Thus, these distinct populations of cells expressing SRC-1 and SRC-2 may allow alternate steroid receptor signaling pathways in the regulation of behavior. Furthermore, the E-induced upregulation of SRC-1 expression in a brain-region-specific manner provides another mechanism by which E can increase the sensitivity of individual cells to steroids. Thus, studying the order and timing of recruitment of different coregulator complexes to the promoter, which is likely to be cell- and region-specific, will be critical to understanding hormone action in the brain.

 

 Acknowledgement

This research was supported by the National Institutes of Health RO1 DK61935 and a Brachman-Hoffman Fellowship from Wellesley College (M.J.T.).


References

  1. Conzen SD: Minireview: nuclear receptors and breast cancer. Mol Endocrinol (Baltimore) 2008;22:2215–2228.
  2. Luine VN: Sex steroids and cognitive function. J Neuroendocrinol 2008;20:866–872.
  3. Pfaff DW, Tetel MJ, Schober JM: Neuroendocrinology: mechanisms by which hormones affect behaviors; in Bernston GG, Cacioppo JT (eds): Handbook of Neuroscience for the Behavioral Sciences. Chichester, Wiley, 2009.
  4. Jensen EV, Suzuki T, Kawasima T, Stumpf WE, Jungblut PW, de Sombre ER: A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA 1968;59:632–638.
  5. Shyamala G, Gorski J: Estrogen receptors in the rat uterus: studies on the interaction of cytosol and nuclear binding sites. J Biol Chem 1969;244:1097–1103.
  6. Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93:5925–5930.
  7. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms a and b. EMBO J 1990;9:1603–1614.
  8. Pratt WB, Galigniana MD, Morishima Y, Murphy PJ: Role of molecular chaperones in steroid receptor action. Essays Biochem 2004;40:41–58.
  9. Klein-Hitpass L, Tsai SY, Weigel NL, Allan GF, Riley D, Rodriguez R, Schrader WT, Tsai MJ, O’Malley BW: The progesterone receptor stimulates cell-free transcription by enhancing the formation of a stable preinitiation complex. Cell 1990;60:247–257.
  10. Kininis M, Chen BS, Diehl AG, Isaacs GD, Zhang T, Siepel AC, Clark AG, Kraus WL: Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol Cell Biol 2007;27:5090–5104.
  11. Tetel MJ, Lange CA: Molecular genomics of progestin actions; in Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds): Hormones, Brain and Behavior. San Diego, Academic Press, 2009, vol 3, pp 1439–1465.
  12. Mani SK, Portillo W, Reyna A: Steroid hormone action in the brain: cross-talk between signalling pathways. J Neuroendocrinol 2009;21:243–247.
  13. Micevych PE, Mermelstein PG: Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain. Mol Neurobiol 2008;38:66–77.
  14. Kelly MJ, Ronnekleiv OK: Membrane-initiated estrogen signaling in hypothalamic neurons. Mol Cell Endocrinol 2008;290: 14–23.
  15. Vasudevan N, Pfaff DW: Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 2008;29:238–257.
  16. Kraus WL, Montano MM, Katzenellenbogen BS: Cloning of the rat progesterone receptor gene 5′-region and identification of two functionally distinct promoters. Mol Endocrinol 1993;7:1603–1616.
  17. Kraus WL, Montano MM, Katzenellenbogen BS: Identification of multiple, widely spaced estrogen-responsive regions in the rat progesterone receptor gene. Mol Endocrinol 1994;8:952–969.
  18. Savouret JF, Bailly A, Misrahi M, Rauch C, Redeuilh G, Chauchereau A, Milgrom E: Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J 1991;10:1875–1883.
  19. MacLusky NJ, McEwen BS: Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others. Nature 1978;274:276–278.
  20. Warembourg M: Radioautographic study of the rat brain, uterus and vagina after [3H]r-5020 injection. Mol Cell Endocrinol 1978;12:67–79.
  21. MacLusky NJ, McEwen BS: Progestin receptors in rat brain: distribution and properties of cytoplasmic progestin-binding sites. Endocrinology 1980;106:192–202.
  22. Blaustein JD, Feder HH: Cytoplasmic progestin receptors in female guinea pig brain and their relationship to refractoriness in expression of female sexual behavior. Brain Res 1979;177:489–498.
  23. Lauber AH, Romano GJ, Pfaff DW: Sex difference in estradiol regulation of progestin receptor messenger RNA in rat mediobasal hypothalamus as demonstrated by in situ hybridization. Neuroendocrinology 1991;53:608–613.
  24. Ogawa S, Olazabal UE, Parhar IS, Pfaff DW: Effects of intrahypothalamic administration of antisense DNA for progesterone receptor mRNA on reproductive behavior and progesterone receptor immunoreactivity in female rat. J Neurosci 1994;14:1766–1774.
  25. Blaustein JD, King JC, Toft DO, Turcotte J: Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain. Brain Res 1988;474:1–15.
  26. Warembourg M, Jolivet A, Milgrom E: Immunohistochemical evidence of the presence of estrogen and progesterone receptors in the same neurons of the guinea pig hypothalamus and preoptic area. Brain Res 1989;480:1–15.
  27. Beyer C, Damm N, Brito V, Kuppers E: Developmental expression of progesterone receptor isoforms in the mouse midbrain. Neuroreport 2002;13:877–880.
  28. Scott REM, Wu-Peng XS, Pfaff DW: Regulation and expression of progesterone receptor mRNA isoforms A and B in the male and female rat hypothalamus and pituitary following estrogen treatment. J Neuroendocrinol 2002;14:175–183.
  29. Shughrue PJ, Lubahn DB, Negro-Vilar A, Korach KS, Merchenthaler I: Responses in the brain of estrogen receptor alpha-disrupted mice. Proc Natl Acad Sci USA 1997;94:11008–11012.
  30. Moffatt CA, Rissman EF, Shupnik MA, Blaustein JD: Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice. J Neurosci 1998;18:9556–9563.
  31. Kudwa AE, Rissman EF: Double oestrogen receptor alpha and beta knockout mice reveal differences in neural oestrogen-mediated progestin receptor induction and female sexual behaviour. J Neuroendocrinol 2003;15:978–983.
  32. Tetel MJ, Pfaff DW: Contributions of estrogen receptor-alpha and estrogen receptor-beta to the regulation of behavior. Biochim Biophys Acta 2010;1800:1084–1089.
  33. Blaustein JD, Turcotte JC: Estradiol-induced progestin receptor immunoreactivity is found only in estrogen receptor-immunoreactive cells in guinea pig brain. Neuroendocrinology 1989;49:454–461.
  34. Pleim ET, Brown TJ, MacLusky NJ, Etgen AM, Barfield RJ: Dilute estradiol implants and progestin receptor induction in the ventromedial nucleus of the hypothalamus: Correlation with receptive behavior in female rats. Endocrinology 1989;124:1807–1812.
  35. Mani SK, Reyna AM, Chen JZ, Mulac-Jericevic B, Conneely OM: Differential response of progesterone receptor isoforms in hormone-dependent and -independent facilitation of female sexual receptivity. Mol Endocrinol 2006;20:1322–1332.
  36. Lonard DM, O’Malley BW: The expanding cosmos of nuclear receptor coactivators. Cell 2006;125:411–414.
  37. Rosenfeld MG, Lunyak VV, Glass CK: Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 2006;20:1405–1428.
  38. O’Malley BW: Molecular biology: little molecules with big goals. Science 2006;313:1749–1750.
  39. Edwards DP: The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000;5:307–324.
  40. Lonard DM, Lanz RB, O’Malley BW: Nuclear receptor coregulators and human disease. Endocr Rev 2007;28:575–587.
  41. Oñate SA, Tsai SY, Tsai MJ, O’Malley BW: Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354–1357.
  42. Voegel JJ, Heine MJS, Zechel C, Chambon P, Gronemeyer H: Tif2, a 160 kDa transcriptional mediator for the ligand-dependent activation function Af-2 of nuclear receptors. EMBO J 1996;15:3667–3675.
  43. Hong H, Kohli K, Garabedian MJ, Stallcup MR: Grip1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 1997;17:2735–2744.
  44. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS: Aib1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997;277:965–968.
  45. Suen CS, Berrodin TJ, Mastroeni R, Cheskis BJ, Lyttle CR, Frail DE: A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity. J Biol Chem 1998;273:27645–27653.
  46. Tetel MJ, Auger AP, Charlier TD: Who’s in charge? Nuclear receptor coactivator and corepressor function in brain and behavior. Front Neuroendocrinol 2009;30:328–342.
  47. Tetel MJ: Modulation of steroid action in the central and peripheral nervous systems by nuclear receptor coactivators. Psychoneuroendocrinology 2009;34(suppl 1):S9–S19.

    External Resources

  48. Tetel MJ, Siegal NK, Murphy SD: Cells in behaviourally relevant brain regions coexpress nuclear receptor coactivators and ovarian steroid receptors. J Neuroendocrinol 2007;19:262–271.
  49. Misiti S, Schomburg L, Yen PM, Chin WW: Expression and hormonal regulation of coactivator and corepressor genes. Endocrinology 1998;139:2493–2500.
  50. Shearman LP, Zylka MJ, Reppert SM, Weaver DR: Expression of basic helix-loop-helix/pas genes in the mouse suprachiasmatic nucleus. Neuroscience 1999;89:387–397.
  51. Martinez de Arrieta C, Koibuchi N, Chin WW: Coactivator and corepressor gene expression in rat cerebellum during postnatal development and the effect of altered thyroid status. Endocrinology 2000;141:1693–1698.
  52. Meijer OC, Steenbergen PJ, de Kloet ER: Differential expression and regional distribution of steroid receptor coactivators Src-1 and Src-2 in brain and pituitary. Endocrinology 2000;141:2192–2199.
  53. Auger AP, Tetel MJ, McCarthy MM: Steroid receptor coactivator-1 mediates the development of sex specific brain morphology and behavior. Proc Natl Acad Sci USA 2000;97:7551–7555.
  54. Molenda HA, Griffin AL, Auger AP, McCarthy MM, Tetel MJ: Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats. Endocrinology 2002;143:436–444.
  55. Ogawa H, Nishi M, Kawata M: Localization of nuclear coactivators p300 and steroid receptor coactivator 1 in the rat hippocampus. Brain Res 2001;890:197–202.
  56. Yousefi B, Jingu H, Ohta M, Umezu M, Koibuchi N: Postnatal changes of steroid receptor coactivator-1 immunoreactivity in rat cerebellar cortex. Thyroid 2005;15:314–319.
  57. Charlier TD, Lakaye B, Ball GF, Balthazart J: Steroid receptor coactivator src-1 exhibits high expression in steroid-sensitive brain areas regulating reproductive behaviors in the quail brain. Neuroendocrinology 2002;76:297–315.
  58. Yore MA, Im D, Webb LK, Zhao Y, Chadwick JG, Molenda-Figueira HA, Haidacher SJ, Denner L, Tetel MJ: Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors. Neuroscience 2010;169:1017–1028.
  59. Nishihara E, Yoshida-Kimoya H, Chan C, Liao L, Davis RL, O’Malley BW, Xu J: Src-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells. J Neurosci 2003;23:213–222.
  60. McGinnis MY, Lumia AR, Tetel MJ, Molenda-Figuiera HA, Possidente B: Effects of anabolic androgenic steroids on the development and expression of running wheel activity and circadian rhythms in male rats. Physiol Behav 2007;92:1010–1018.
  61. Apostolakis EM, Ramamurphy M, Zhou D, Onate S, O’Malley B: Acute disruption of select steroid receptor coactivators prevents reproductive behavior in rats and unmasks genetic adaptation in knockout mice. Mol Endocrinol 2002;16:1511–1523.
  62. Charlier TD, Ball GF, Balthazart J: Inhibition of steroid receptor coactivator-1 blocks estrogen and androgen action on male sex behavior and associated brain plasticity. J Neurosci 2005;25:906–913.
  63. Charlier TD, Harada N, Ball GF, Balthazart J: Targeting steroid receptor coactivator-1 expression with locked nucleic acids antisense reveals different thresholds for the hormonal regulation of male sexual behavior in relation to aromatase activity and protein expression. Behav Brain Res 2006;172:333–343.
  64. Molenda-Figueira HA, Williams CA, Griffin AL, Rutledge EM, Blaustein JD, Tetel MJ: Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Horm Behav 2006;50:383–392.
  65. Molenda-Figueira HA, Murphy SD, Shea KL, Siegal NK, Zhao Y, Chadwick JG, Denner LA, Tetel MJ: Steroid receptor coactivator-1 from brain physically interacts differentially with steroid receptor subtypes. Endocrinology 2008;149:5272–5279.
  66. Carroll RS, Brown M, Zhang J, DiRenzo J, De Mora JF, Black PM: Expression of a subset of steroid receptor cofactors is associated with progesterone receptor expression in meningiomas. Clin Cancer Res 2000;6:3570–3575.
  67. Shim WS, DiRenzo J, DeCaprio JA, Santen RJ, Brown M, Jeng MH: Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium. Proc Natl Acad Sci USA 1999;96:208–213.
  68. Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates, ed 2. Amsterdam, Elsevier Academic Press, 2004.
  69. Flanagan-Cato LM, Lee BJ, Calizo LH: Co-localization of midbrain projections, progestin receptors, and mating-induced fos in the hypothalamic ventromedial nucleus of the female rat. Horm Behav 2006;50:52–60.
  70. Bousios S, Karandrea D, Kittas C, Kitraki E: Effects of gender and stress on the regulation of steroid receptor coactivator-1 expression in the rat brain and pituitary. J Steroid Biochem Mol Biol 2001;78:401–407.
  71. Tetel MJ, Jung S, Carbajo P, Ladtkow T, Skafar DF, Edwards DP: Hinge and amino-terminal sequences contribute to solution dimerization of human progesterone receptor. Mol Endocrinol 1997;11:1114–1128.
  72. Tetel MJ, Giangrande PH, Leonhardt SA, McDonnell DP, Edwards DP: Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol Endocrinol 1999;13:910–924.
  73. Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J: Progesterone receptors: form and function in brain. Front Neuroendocrinol 2008;29:313–339.
  74. Chung WC, Pak TR, Weiser MJ, Hinds LR, Andersen ME, Handa RJ: Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor alpha and not estrogen receptor beta. Brain Res 2006;1082:50–60.
  75. Fenelon VS, Herbison AE: Progesterone regulation of Gaba(a) receptor plasticity in adult rat supraoptic nucleus. Eur J Neurosci 2000;12:1617–1623.
  76. Parsons B, MacLusky NJ, Krey L, Pfaff DW, McEwen BS: The temporal relationship between estrogen-inducible progestin receptors in the female rat brain and the time course of estrogen activation of mating behavior. Endocrinology 1980;107:774–779.
  77. Simerly RB, Seil FJ: Distribution and regulation of steroid hormone receptor gene expression in the central nervous system. Adv Neurol 1993;59:207–226.
  78. Turcotte JC, Blaustein JD: Immunocytochemical localization of midbrain estrogen receptor-containing and progestin receptor-containing cells in female guinea pigs. J Comp Neurol 1993;328:76–87.
  79. Schmidt MV, Oitzl M, Steenbergen P, Lachize S, Wurst W, Muller MB, de Kloet ER, Meijer OC: Ontogeny of steroid receptor coactivators in the hippocampus and their role in regulating postnatal HPA axis function. Brain Res 2007;1174:1–6.
  80. Iannacone EA, Yan AW, Gauger KJ, Dowling ALS, Zoeller RT: Thyroid hormone exerts site-specific effects on Src-1 and NCoR expression selectively in the neonatal rat brain. Mol Cell Endocrinol 2002;186:49–59.
  81. Charlier TD, Balthazart J, Ball GF: Sex differences in the distribution of the steroid coactivator Src-1 in the song control nuclei of male and female canaries. Brain Res 2003;959:263–274.
  82. Karmakar S, Gao T, Pace MC, Oesterreich S, Smith CL: Cooperative activation of cyclin D1 and progesterone receptor gene expression by the Src-3 coactivator and Smrt corepressor. Mol Endocrinol 2010;24:1187–1202.
  83. Lange CA, Gioeli D, Hammes SR, Marker PC: Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annu Rev Physiol 2007;69:171–199.
  84. Vasudevan N, Pfaff DW: Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 2007;28:1–19.
  85. Camacho-Arroyo I, Neri-Gomez T, Gonzalez-Arenas A, Guerra-Araiza C: Changes in the content of steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid hormone receptors in the rat brain during the estrous cycle. J Steroid Biochem Mol Biol 2005;94:267–272.
  86. Mitev YA, Wolf SS, Almeida OF, Patchev VK: Developmental expression profiles and distinct regional estrogen responsiveness suggest a novel role for the steroid receptor coactivator Src-l as a discriminative amplifier of estrogen signaling in the rat brain. FASEB J 2003;17:518–519.
  87. Ramos HE, Weiss RE: Regulation of nuclear coactivator and corepressor expression in mouse cerebellum by thyroid hormone. Thyroid 2006;16:211–216.
  88. Kurihara I, Shibata H, Suzuki T, Ando T, Kobayashi S, Hayashi M, Saito I, Saruta T: Expression and regulation of nuclear receptor coactivators in glucocorticoid action. Mol Cell Endocrinol 2002;189:181–189.
  89. Maerkel K, Durrer S, Henseler M, Schlumpf M, Lichtensteiger W: Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: developmental exposure of rats to 4-methylbenzylidene camphor. Toxicol Appl Pharmacol 2007;218:152–165.
  90. Wong C, Komm B, Cheskis BJ: Structure-function evaluation of ER alpha and beta interplay with Src family coactivators: ER selective ligands. Biochemistry 2001;40:6756–6765.
  91. Zhou G, Cummings R, Li Y, Mitra S, Wilkinson HA, Elbrecht A, Hermes JD, Schaeffer JM, Smith RG, Moller DE: Nuclear receptors have distinct affinities for coactivators: characterization by fluorescence resonance energy transfer. Mol Endocrinol 1998;12:1594–1604.
  92. Klinge CM, Jernigan SC, Mattingly KA, Risinger KE, Zhang J: Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. J Mol Endocrinol 2004;33:387–410.
  93. Heneghan AF, Connaghan-Jones KD, Miura MT, Bain DL: Coactivator assembly at the promoter: efficient recruitment of Src2 is coupled to cooperative DNA binding by the progesterone receptor. Biochemistry 2007;46:11023–11032.
  94. Grenier J, Trousson A, Chauchereau A, Amazit L, Lamirand A, Leclerc P, Guiochon-Mantel A, Schumacher M, Massaad C: Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol 2004;18:2866–2879.
  95. Grenier J, Trousson A, Chauchereau A, Cartaud J, Schumacher M, Massaad C: Differential recruitment of p160 coactivators by glucocorticoid receptor between Schwann cells and astrocytes. Mol Endocrinol 2006;20:254–267.
  96. Li X, Wong J, Tsai MJ, O’Malley B: Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. Mol Cell Biol 2003;23:3763–3773.
  97. Zhang H, Yi X, Sun X, Yin N, Shi B, Wu H, Wang D, Wu G, Shang Y: Differential gene regulation by the Src family of coactivators. Genes Dev 2004;18:1753–1765.

  

Author Contacts

Marc J. Tetel
Neuroscience Program, Wellesley College
106 Central St.
Wellesley, MA 02481 (USA)
Tel. +1 781 283 3003, E-Mail mtetel@wellesley.edu

  

Article Information

Received: September 1, 2010
Accepted after revision: December 18, 2010
Published online: February 9, 2011
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 1, Number of References : 97
Additional supplementary material is available online - Number of Parts : 1

  

Publication Details

Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships)

Vol. 94, No. 1, Year 2011 (Cover Date: July 2011)

Journal Editor: Millar R.P. (Edinburgh)
ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aims: The steroid hormones, including estradiol (E) and progesterone, act in the brain to regulate female reproductive behavior and physiology. These hormones mediate many of their biological effects by binding to their respective intracellular receptors. The receptors for estrogens (ER) and progestins (PR) interact with nuclear receptor coactivators to initiate transcription of steroid-responsive genes. Work from our laboratory and others reveals that nuclear receptor coactivators, including steroid receptor coactivator-1 (SRC-1) and SRC-2, function in brain to modulate ER-mediated induction of the PR gene and hormone-dependent behaviors. In order for steroid receptors and coactivators to function together, both must be expressed in the same cells. Methods: Triple-label immunofluorescence was used to determine if E-induced PR cells also express SRC-1 or SRC-2 in reproductively relevant brain regions of the female mouse. Results: The majority of E-induced PR cells in the medial preoptic area (61%), ventromedial nucleus of the hypothalamus (63%) and arcuate nucleus (76%) coexpressed both SRC-1 and SRC-2. A smaller proportion of PR cells expressed either SRC-1 or SRC-2, while a few PR cells expressed neither coactivator. In addition, compared to control animals, 17β-estradiol benzoate (EB) treatment increased SRC-1 levels in the arcuate nucleus, but not the medial preoptic area or the ventromedial nucleus of the hypothalamus. EB did not alter SRC-2 expression in any of the three brain regions analyzed. Conclusions: Taken together, the present findings identify a population of cells in which steroid receptors and nuclear receptor coactivators may interact to modulate steroid sensitivity in brain and regulate hormone-dependent behaviors in female mice. Given that cell culture studies reveal that SRC-1 and SRC-2 can mediate distinct steroid-signaling pathways, the present findings suggest that steroids can produce a variety of complex responses in these specialized brain cells.

© 2011 S. Karger AG, Basel


  

Author Contacts

Marc J. Tetel
Neuroscience Program, Wellesley College
106 Central St.
Wellesley, MA 02481 (USA)
Tel. +1 781 283 3003, E-Mail mtetel@wellesley.edu

  

Article Information

Received: September 1, 2010
Accepted after revision: December 18, 2010
Published online: February 9, 2011
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 1, Number of References : 97
Additional supplementary material is available online - Number of Parts : 1

  

Publication Details

Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships)

Vol. 94, No. 1, Year 2011 (Cover Date: July 2011)

Journal Editor: Millar R.P. (Edinburgh)
ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 9/1/2010
Accepted: 12/18/2010
Published online: 2/9/2011
Issue release date: July 2011

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 1

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Conzen SD: Minireview: nuclear receptors and breast cancer. Mol Endocrinol (Baltimore) 2008;22:2215–2228.
  2. Luine VN: Sex steroids and cognitive function. J Neuroendocrinol 2008;20:866–872.
  3. Pfaff DW, Tetel MJ, Schober JM: Neuroendocrinology: mechanisms by which hormones affect behaviors; in Bernston GG, Cacioppo JT (eds): Handbook of Neuroscience for the Behavioral Sciences. Chichester, Wiley, 2009.
  4. Jensen EV, Suzuki T, Kawasima T, Stumpf WE, Jungblut PW, de Sombre ER: A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA 1968;59:632–638.
  5. Shyamala G, Gorski J: Estrogen receptors in the rat uterus: studies on the interaction of cytosol and nuclear binding sites. J Biol Chem 1969;244:1097–1103.
  6. Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93:5925–5930.
  7. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms a and b. EMBO J 1990;9:1603–1614.
  8. Pratt WB, Galigniana MD, Morishima Y, Murphy PJ: Role of molecular chaperones in steroid receptor action. Essays Biochem 2004;40:41–58.
  9. Klein-Hitpass L, Tsai SY, Weigel NL, Allan GF, Riley D, Rodriguez R, Schrader WT, Tsai MJ, O’Malley BW: The progesterone receptor stimulates cell-free transcription by enhancing the formation of a stable preinitiation complex. Cell 1990;60:247–257.
  10. Kininis M, Chen BS, Diehl AG, Isaacs GD, Zhang T, Siepel AC, Clark AG, Kraus WL: Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol Cell Biol 2007;27:5090–5104.
  11. Tetel MJ, Lange CA: Molecular genomics of progestin actions; in Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds): Hormones, Brain and Behavior. San Diego, Academic Press, 2009, vol 3, pp 1439–1465.
  12. Mani SK, Portillo W, Reyna A: Steroid hormone action in the brain: cross-talk between signalling pathways. J Neuroendocrinol 2009;21:243–247.
  13. Micevych PE, Mermelstein PG: Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain. Mol Neurobiol 2008;38:66–77.
  14. Kelly MJ, Ronnekleiv OK: Membrane-initiated estrogen signaling in hypothalamic neurons. Mol Cell Endocrinol 2008;290: 14–23.
  15. Vasudevan N, Pfaff DW: Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 2008;29:238–257.
  16. Kraus WL, Montano MM, Katzenellenbogen BS: Cloning of the rat progesterone receptor gene 5′-region and identification of two functionally distinct promoters. Mol Endocrinol 1993;7:1603–1616.
  17. Kraus WL, Montano MM, Katzenellenbogen BS: Identification of multiple, widely spaced estrogen-responsive regions in the rat progesterone receptor gene. Mol Endocrinol 1994;8:952–969.
  18. Savouret JF, Bailly A, Misrahi M, Rauch C, Redeuilh G, Chauchereau A, Milgrom E: Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J 1991;10:1875–1883.
  19. MacLusky NJ, McEwen BS: Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others. Nature 1978;274:276–278.
  20. Warembourg M: Radioautographic study of the rat brain, uterus and vagina after [3H]r-5020 injection. Mol Cell Endocrinol 1978;12:67–79.
  21. MacLusky NJ, McEwen BS: Progestin receptors in rat brain: distribution and properties of cytoplasmic progestin-binding sites. Endocrinology 1980;106:192–202.
  22. Blaustein JD, Feder HH: Cytoplasmic progestin receptors in female guinea pig brain and their relationship to refractoriness in expression of female sexual behavior. Brain Res 1979;177:489–498.
  23. Lauber AH, Romano GJ, Pfaff DW: Sex difference in estradiol regulation of progestin receptor messenger RNA in rat mediobasal hypothalamus as demonstrated by in situ hybridization. Neuroendocrinology 1991;53:608–613.
  24. Ogawa S, Olazabal UE, Parhar IS, Pfaff DW: Effects of intrahypothalamic administration of antisense DNA for progesterone receptor mRNA on reproductive behavior and progesterone receptor immunoreactivity in female rat. J Neurosci 1994;14:1766–1774.
  25. Blaustein JD, King JC, Toft DO, Turcotte J: Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain. Brain Res 1988;474:1–15.
  26. Warembourg M, Jolivet A, Milgrom E: Immunohistochemical evidence of the presence of estrogen and progesterone receptors in the same neurons of the guinea pig hypothalamus and preoptic area. Brain Res 1989;480:1–15.
  27. Beyer C, Damm N, Brito V, Kuppers E: Developmental expression of progesterone receptor isoforms in the mouse midbrain. Neuroreport 2002;13:877–880.
  28. Scott REM, Wu-Peng XS, Pfaff DW: Regulation and expression of progesterone receptor mRNA isoforms A and B in the male and female rat hypothalamus and pituitary following estrogen treatment. J Neuroendocrinol 2002;14:175–183.
  29. Shughrue PJ, Lubahn DB, Negro-Vilar A, Korach KS, Merchenthaler I: Responses in the brain of estrogen receptor alpha-disrupted mice. Proc Natl Acad Sci USA 1997;94:11008–11012.
  30. Moffatt CA, Rissman EF, Shupnik MA, Blaustein JD: Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice. J Neurosci 1998;18:9556–9563.
  31. Kudwa AE, Rissman EF: Double oestrogen receptor alpha and beta knockout mice reveal differences in neural oestrogen-mediated progestin receptor induction and female sexual behaviour. J Neuroendocrinol 2003;15:978–983.
  32. Tetel MJ, Pfaff DW: Contributions of estrogen receptor-alpha and estrogen receptor-beta to the regulation of behavior. Biochim Biophys Acta 2010;1800:1084–1089.
  33. Blaustein JD, Turcotte JC: Estradiol-induced progestin receptor immunoreactivity is found only in estrogen receptor-immunoreactive cells in guinea pig brain. Neuroendocrinology 1989;49:454–461.
  34. Pleim ET, Brown TJ, MacLusky NJ, Etgen AM, Barfield RJ: Dilute estradiol implants and progestin receptor induction in the ventromedial nucleus of the hypothalamus: Correlation with receptive behavior in female rats. Endocrinology 1989;124:1807–1812.
  35. Mani SK, Reyna AM, Chen JZ, Mulac-Jericevic B, Conneely OM: Differential response of progesterone receptor isoforms in hormone-dependent and -independent facilitation of female sexual receptivity. Mol Endocrinol 2006;20:1322–1332.
  36. Lonard DM, O’Malley BW: The expanding cosmos of nuclear receptor coactivators. Cell 2006;125:411–414.
  37. Rosenfeld MG, Lunyak VV, Glass CK: Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 2006;20:1405–1428.
  38. O’Malley BW: Molecular biology: little molecules with big goals. Science 2006;313:1749–1750.
  39. Edwards DP: The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000;5:307–324.
  40. Lonard DM, Lanz RB, O’Malley BW: Nuclear receptor coregulators and human disease. Endocr Rev 2007;28:575–587.
  41. Oñate SA, Tsai SY, Tsai MJ, O’Malley BW: Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354–1357.
  42. Voegel JJ, Heine MJS, Zechel C, Chambon P, Gronemeyer H: Tif2, a 160 kDa transcriptional mediator for the ligand-dependent activation function Af-2 of nuclear receptors. EMBO J 1996;15:3667–3675.
  43. Hong H, Kohli K, Garabedian MJ, Stallcup MR: Grip1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 1997;17:2735–2744.
  44. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS: Aib1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997;277:965–968.
  45. Suen CS, Berrodin TJ, Mastroeni R, Cheskis BJ, Lyttle CR, Frail DE: A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity. J Biol Chem 1998;273:27645–27653.
  46. Tetel MJ, Auger AP, Charlier TD: Who’s in charge? Nuclear receptor coactivator and corepressor function in brain and behavior. Front Neuroendocrinol 2009;30:328–342.
  47. Tetel MJ: Modulation of steroid action in the central and peripheral nervous systems by nuclear receptor coactivators. Psychoneuroendocrinology 2009;34(suppl 1):S9–S19.

    External Resources

  48. Tetel MJ, Siegal NK, Murphy SD: Cells in behaviourally relevant brain regions coexpress nuclear receptor coactivators and ovarian steroid receptors. J Neuroendocrinol 2007;19:262–271.
  49. Misiti S, Schomburg L, Yen PM, Chin WW: Expression and hormonal regulation of coactivator and corepressor genes. Endocrinology 1998;139:2493–2500.
  50. Shearman LP, Zylka MJ, Reppert SM, Weaver DR: Expression of basic helix-loop-helix/pas genes in the mouse suprachiasmatic nucleus. Neuroscience 1999;89:387–397.
  51. Martinez de Arrieta C, Koibuchi N, Chin WW: Coactivator and corepressor gene expression in rat cerebellum during postnatal development and the effect of altered thyroid status. Endocrinology 2000;141:1693–1698.
  52. Meijer OC, Steenbergen PJ, de Kloet ER: Differential expression and regional distribution of steroid receptor coactivators Src-1 and Src-2 in brain and pituitary. Endocrinology 2000;141:2192–2199.
  53. Auger AP, Tetel MJ, McCarthy MM: Steroid receptor coactivator-1 mediates the development of sex specific brain morphology and behavior. Proc Natl Acad Sci USA 2000;97:7551–7555.
  54. Molenda HA, Griffin AL, Auger AP, McCarthy MM, Tetel MJ: Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats. Endocrinology 2002;143:436–444.
  55. Ogawa H, Nishi M, Kawata M: Localization of nuclear coactivators p300 and steroid receptor coactivator 1 in the rat hippocampus. Brain Res 2001;890:197–202.
  56. Yousefi B, Jingu H, Ohta M, Umezu M, Koibuchi N: Postnatal changes of steroid receptor coactivator-1 immunoreactivity in rat cerebellar cortex. Thyroid 2005;15:314–319.
  57. Charlier TD, Lakaye B, Ball GF, Balthazart J: Steroid receptor coactivator src-1 exhibits high expression in steroid-sensitive brain areas regulating reproductive behaviors in the quail brain. Neuroendocrinology 2002;76:297–315.
  58. Yore MA, Im D, Webb LK, Zhao Y, Chadwick JG, Molenda-Figueira HA, Haidacher SJ, Denner L, Tetel MJ: Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors. Neuroscience 2010;169:1017–1028.
  59. Nishihara E, Yoshida-Kimoya H, Chan C, Liao L, Davis RL, O’Malley BW, Xu J: Src-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells. J Neurosci 2003;23:213–222.
  60. McGinnis MY, Lumia AR, Tetel MJ, Molenda-Figuiera HA, Possidente B: Effects of anabolic androgenic steroids on the development and expression of running wheel activity and circadian rhythms in male rats. Physiol Behav 2007;92:1010–1018.
  61. Apostolakis EM, Ramamurphy M, Zhou D, Onate S, O’Malley B: Acute disruption of select steroid receptor coactivators prevents reproductive behavior in rats and unmasks genetic adaptation in knockout mice. Mol Endocrinol 2002;16:1511–1523.
  62. Charlier TD, Ball GF, Balthazart J: Inhibition of steroid receptor coactivator-1 blocks estrogen and androgen action on male sex behavior and associated brain plasticity. J Neurosci 2005;25:906–913.
  63. Charlier TD, Harada N, Ball GF, Balthazart J: Targeting steroid receptor coactivator-1 expression with locked nucleic acids antisense reveals different thresholds for the hormonal regulation of male sexual behavior in relation to aromatase activity and protein expression. Behav Brain Res 2006;172:333–343.
  64. Molenda-Figueira HA, Williams CA, Griffin AL, Rutledge EM, Blaustein JD, Tetel MJ: Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Horm Behav 2006;50:383–392.
  65. Molenda-Figueira HA, Murphy SD, Shea KL, Siegal NK, Zhao Y, Chadwick JG, Denner LA, Tetel MJ: Steroid receptor coactivator-1 from brain physically interacts differentially with steroid receptor subtypes. Endocrinology 2008;149:5272–5279.
  66. Carroll RS, Brown M, Zhang J, DiRenzo J, De Mora JF, Black PM: Expression of a subset of steroid receptor cofactors is associated with progesterone receptor expression in meningiomas. Clin Cancer Res 2000;6:3570–3575.
  67. Shim WS, DiRenzo J, DeCaprio JA, Santen RJ, Brown M, Jeng MH: Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium. Proc Natl Acad Sci USA 1999;96:208–213.
  68. Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates, ed 2. Amsterdam, Elsevier Academic Press, 2004.
  69. Flanagan-Cato LM, Lee BJ, Calizo LH: Co-localization of midbrain projections, progestin receptors, and mating-induced fos in the hypothalamic ventromedial nucleus of the female rat. Horm Behav 2006;50:52–60.
  70. Bousios S, Karandrea D, Kittas C, Kitraki E: Effects of gender and stress on the regulation of steroid receptor coactivator-1 expression in the rat brain and pituitary. J Steroid Biochem Mol Biol 2001;78:401–407.
  71. Tetel MJ, Jung S, Carbajo P, Ladtkow T, Skafar DF, Edwards DP: Hinge and amino-terminal sequences contribute to solution dimerization of human progesterone receptor. Mol Endocrinol 1997;11:1114–1128.
  72. Tetel MJ, Giangrande PH, Leonhardt SA, McDonnell DP, Edwards DP: Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol Endocrinol 1999;13:910–924.
  73. Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J: Progesterone receptors: form and function in brain. Front Neuroendocrinol 2008;29:313–339.
  74. Chung WC, Pak TR, Weiser MJ, Hinds LR, Andersen ME, Handa RJ: Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor alpha and not estrogen receptor beta. Brain Res 2006;1082:50–60.
  75. Fenelon VS, Herbison AE: Progesterone regulation of Gaba(a) receptor plasticity in adult rat supraoptic nucleus. Eur J Neurosci 2000;12:1617–1623.
  76. Parsons B, MacLusky NJ, Krey L, Pfaff DW, McEwen BS: The temporal relationship between estrogen-inducible progestin receptors in the female rat brain and the time course of estrogen activation of mating behavior. Endocrinology 1980;107:774–779.
  77. Simerly RB, Seil FJ: Distribution and regulation of steroid hormone receptor gene expression in the central nervous system. Adv Neurol 1993;59:207–226.
  78. Turcotte JC, Blaustein JD: Immunocytochemical localization of midbrain estrogen receptor-containing and progestin receptor-containing cells in female guinea pigs. J Comp Neurol 1993;328:76–87.
  79. Schmidt MV, Oitzl M, Steenbergen P, Lachize S, Wurst W, Muller MB, de Kloet ER, Meijer OC: Ontogeny of steroid receptor coactivators in the hippocampus and their role in regulating postnatal HPA axis function. Brain Res 2007;1174:1–6.
  80. Iannacone EA, Yan AW, Gauger KJ, Dowling ALS, Zoeller RT: Thyroid hormone exerts site-specific effects on Src-1 and NCoR expression selectively in the neonatal rat brain. Mol Cell Endocrinol 2002;186:49–59.
  81. Charlier TD, Balthazart J, Ball GF: Sex differences in the distribution of the steroid coactivator Src-1 in the song control nuclei of male and female canaries. Brain Res 2003;959:263–274.
  82. Karmakar S, Gao T, Pace MC, Oesterreich S, Smith CL: Cooperative activation of cyclin D1 and progesterone receptor gene expression by the Src-3 coactivator and Smrt corepressor. Mol Endocrinol 2010;24:1187–1202.
  83. Lange CA, Gioeli D, Hammes SR, Marker PC: Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annu Rev Physiol 2007;69:171–199.
  84. Vasudevan N, Pfaff DW: Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 2007;28:1–19.
  85. Camacho-Arroyo I, Neri-Gomez T, Gonzalez-Arenas A, Guerra-Araiza C: Changes in the content of steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid hormone receptors in the rat brain during the estrous cycle. J Steroid Biochem Mol Biol 2005;94:267–272.
  86. Mitev YA, Wolf SS, Almeida OF, Patchev VK: Developmental expression profiles and distinct regional estrogen responsiveness suggest a novel role for the steroid receptor coactivator Src-l as a discriminative amplifier of estrogen signaling in the rat brain. FASEB J 2003;17:518–519.
  87. Ramos HE, Weiss RE: Regulation of nuclear coactivator and corepressor expression in mouse cerebellum by thyroid hormone. Thyroid 2006;16:211–216.
  88. Kurihara I, Shibata H, Suzuki T, Ando T, Kobayashi S, Hayashi M, Saito I, Saruta T: Expression and regulation of nuclear receptor coactivators in glucocorticoid action. Mol Cell Endocrinol 2002;189:181–189.
  89. Maerkel K, Durrer S, Henseler M, Schlumpf M, Lichtensteiger W: Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: developmental exposure of rats to 4-methylbenzylidene camphor. Toxicol Appl Pharmacol 2007;218:152–165.
  90. Wong C, Komm B, Cheskis BJ: Structure-function evaluation of ER alpha and beta interplay with Src family coactivators: ER selective ligands. Biochemistry 2001;40:6756–6765.
  91. Zhou G, Cummings R, Li Y, Mitra S, Wilkinson HA, Elbrecht A, Hermes JD, Schaeffer JM, Smith RG, Moller DE: Nuclear receptors have distinct affinities for coactivators: characterization by fluorescence resonance energy transfer. Mol Endocrinol 1998;12:1594–1604.
  92. Klinge CM, Jernigan SC, Mattingly KA, Risinger KE, Zhang J: Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. J Mol Endocrinol 2004;33:387–410.
  93. Heneghan AF, Connaghan-Jones KD, Miura MT, Bain DL: Coactivator assembly at the promoter: efficient recruitment of Src2 is coupled to cooperative DNA binding by the progesterone receptor. Biochemistry 2007;46:11023–11032.
  94. Grenier J, Trousson A, Chauchereau A, Amazit L, Lamirand A, Leclerc P, Guiochon-Mantel A, Schumacher M, Massaad C: Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol 2004;18:2866–2879.
  95. Grenier J, Trousson A, Chauchereau A, Cartaud J, Schumacher M, Massaad C: Differential recruitment of p160 coactivators by glucocorticoid receptor between Schwann cells and astrocytes. Mol Endocrinol 2006;20:254–267.
  96. Li X, Wong J, Tsai MJ, O’Malley B: Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. Mol Cell Biol 2003;23:3763–3773.
  97. Zhang H, Yi X, Sun X, Yin N, Shi B, Wu H, Wang D, Wu G, Shang Y: Differential gene regulation by the Src family of coactivators. Genes Dev 2004;18:1753–1765.