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Laboratory of Neuroendocrinology (I.M.A., M.G.T., A.E.H.), Babraham Institute, Cambridge CB2 4AT, United Kingdom; Neurobiology Research Group (I.M.A.), Hungarian Academy of Sciences, Eötvös Loránd University, H-1117 Budapest, Hungary; Receptor Biology Section (K.S.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and Centre for Neuroendocrinology and Department of Physiology (A.E.H.), University of Otago School of Medical Sciences, Dunedin, New Zealand
Address all correspondence and requests for reprints to: Allan E. Herbison, Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand. E-mail: allan.herbison{at}stonebow.otago.ac.nz.
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Abstract |
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and ß) are unclear. We examined here the in vivo role of classical ERs in rapid estrogen actions by evaluating the estrogen-induced effects on two major signaling pathways within the brains of ER-, ßER-, and double ßER-knockout (ERKO) ovariectomized female mice. Estrogen significantly (P < 0.05) increased the numbers of phospho-cAMP response element binding protein (phospho-CREB)-immunoreactive cells in specific brain regions of wild-type mice in a time-dependent manner beginning within 15 min. In brain areas that express predominantly ERß, this response was absent in ßERKO mice, whereas brain regions that express mostly ER displayed no change in ERKO mice. In the medial preoptic nucleus (MPN), an area that expresses both ERs, the estrogen-induced phosphorylation of CREB was normal in both ERKO and ßERKO mice. However, estrogen had no effect on CREB phosphorylation in the MPN, or any other brain region, in double ßERKO animals. Estrogen was also found to increase MAPK phosphorylation levels in a rapid (<15 min) manner within the MPN. In contrast to CREB signaling, this effect was lost in either ERKO or ßERKO mice. These data show that ER and ERß play region- and pathway-specific roles in rapid estrogen actions throughout the brain. They further indicate an indispensable role for classical ERs in rapid estrogen actions in vivo and highlight the importance of ERs in coordinating both classical and rapid actions of estrogen. |
Introduction |
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and ERß, rapid nongenomic effects of estrogen are now also recognized (1, 3). The mechanisms underlying these rapid effects of estrogen are not clear, and considerable controversy exists regarding the location and identity of the receptors responsible for these responses.
Evidence for a critical role for classical ERs in the rapid effects of estrogen on the MAPK/ERK signaling pathway has been found in multiple cell types (4, 5, 6, 7, 8). Furthermore, recent studies have reported that only the ligand binding region of ER is required for estrogen activation of the Src/Shc/ERK signaling pathway in bone (9). However, estrogen modulates the activity of multiple intracellular signaling pathways, and in vitro studies have suggested that the rapid actions of estrogen on calcium (10, 11), protein kinase A/cAMP (12, 13), protein kinase C (14, 15), and neocortical MAPK (16) pathways may require a novel estrogen-binding receptor. In specific instances, estrogen has been shown to allosterically modulate known ion channels (17) or neurotransmitter receptors (18, 19), but, for the most part, the molecular mechanisms underlying rapid estrogen actions on the brain are unclear.
In the present study, we have used the ER- and ERß-knockout (ERKO) mice to examine in a definitive manner the relationship between the classical ERs and rapid estrogen actions on intracellular signaling cascades within the brain in vivo. The phosphorylation of cAMP response element binding protein (CREB) represents a major site of intracellular signal integration (20) and is influenced by all of the signaling cascades so far implicated in rapid estrogen actions. Accordingly, estrogen has been shown to alter CREB phosphorylation rapidly within many regions of the brain (21, 22, 23). As such, we have used the phosphorylation of CREB as a marker of activity in diverse intracellular signaling pathways to examine the impact of deletion of ER or ERß or both ERs on rapid estrogen actions in the brain in vivo. For comparison, we also evaluated the rapid effects of estrogen on MAPK/ERK1/2 phosphorylation. We report here that all rapid effects of estrogen on CREB and MAPK activation were found to be dependent on the presence of ER or ERß or both in a brain region-specific and signaling pathway-specific manner.
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Materials and Methods |
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ßERKO mice were transferred to the Neurobiology Research Group, Hungarian Academy of Sciences and cared for according to regulations of the Local Animal Care Committee at the Eötvös Loránd University. All mice were maintained under 12-h light, 12-h dark cycle lighting conditions (lights on 0700 h) with food and water available ad libitum. Female homozygous ERKO, ßERKO, and double ßERKO mice and wild-type siblings were identified by PCR analysis using the protocol of Couse et al. (26).
Experimental design and protocol
Young adult female wild-type mice (C57BL6/J x CBA/Ca) were ovariectomized (OVX) at 40–54 d of age under Avertin anesthesia and used for experiments 3 wk later. Between 1000 and 1100 h, mice were administered 1 or 10 µg 17-ß-estradiol (E2; Sigma, Poole, UK; in 0.1 ml ethyl oleate vehicle, sc) or vehicle alone and killed 15 min, 1 h, or 4 h later by an overdose of Avertin (0.3 ml/20 g body weight) followed by perfusion through the heart with ice-cold 4% paraformaldehyde in phosphate buffer (pH 7.6) (n = 5–6 per group). Brains were removed, post-fixed for 2 h, and placed into 30% sucrose Tris-buffered saline solution overnight at 4 C. The next day, 1:4 series of 30-µm-thick frozen sections were cut in the frontal plane on a sliding microtome.
Homozygous ERKO, ßERKO, and ßERKO female mice and their wild-type siblings (C57BL6/J; n = 5–6 per group) were treated in the same manner detailed above with the exception that they were only treated with the lower 1-µg E2 dose or vehicle and killed 1 h later.
For estrogen time- and dose-dependent studies in wild-type mice, estrogen- and vehicle-treated mice were perfused alternatively. At each estrogen dose and time point, brain sections from pairs of estrogen- and vehicle-treated mice were processed together in the same wells to ensure identical immunostaining conditions. The raw data were then analyzed using ANOVA with Student-Newman-Keuls post hoc tests, and, for simplicity, data were presented as percentage of vehicle control. For ERKO mice, experiments were undertaken by alternate perfusion of estrogen- and vehicle-treated mice (n = 5–6) from ERKO, ßERKO, and wild-type littermates as three individual experiments. As before, brain sections from pairs of estrogen- and vehicle-treated mice were processed together in the same wells. The experiment with double ßERKO mice involved alternate perfusion of estrogen- and vehicle-treated wild-type mice and then ßERKO mice, and the paired processing of sections as above. Data from ERKO mice were analyzed with two-way ANOVA with Student-Newman-Keuls post hoc, and this smaller amount of data presented as direct cell counts. All statistical analyses were performed using Statistica for Windows 5.1 software (StatSoft; Statistica, Tulsa, OK).
Immunocytochemistry and analysis
Free-floating, peroxidase-based immunocytochemistry was undertaken in the same manner as reported previously (27). In brief, after a 0.1% H2O2/40% methanol/Tris-buffered saline wash, one set of sections was incubated in each of the three polyclonal rabbit primary antibodies [phospho-CREB (pCREB), 1:100; CREB, 1:100; pMAPK/ERK1/2, 1:1000; Cell Signaling Technology, New England Biolabs, Beverly, MA] for 48 h at 4 C. This was followed by biotinylated goat antirabbit IgGs (1:200; Vector Laboratories, Peterborough, UK) for 2 h and the Vector Elite avidin-biotin-horseradish peroxidase complex (1:200) for 2 h. Labeling was then visualized with nickel-diaminobenzidine tetrahydrochloride.
The specificities of the CREB and MAPK antibodies have been reported previously in multiple rodent species (28) (Cell Signaling Technology data) including the mouse (29, 30). The pCREB antibody detects CREB only when phosphorylated at Ser133 as well as phosphorylated forms of the CREB-related proteins activating transcription factor-1 and cAMP response element modulator. The pMAPK antibody is dual phosphospecific, detecting ERK1 only when phosphorylated at Thr202 and Tyr204 and ERK2 when phosphorylated at Thr183 and Tyr185. The omission of primary antibodies in this study resulted in a complete absence of immunoreactivity.
Sections were viewed under a Leica (Nussloch, Germany) DM-RB microscope, and a quantitative evaluation of the numbers of pCREB- and CREB-positive nuclei was undertaken by a blinded investigator using a computer-based imaging system (AIS 6.0, Rel. 1.3; Imaging Research, Inc., St. Catherines, Ontario, Canada) with the images digitized using a Sony (Tokyo, Japan) charge-coupled device (DXC 950P) camera. Five regions were selected for evaluation, depending on their known ER expression pattern in adult mice (31, 32). This consisted of the ventrolateral aspect of the hypothalamic ventromedial nucleus (vlVMN; predominantly ER), the medial septum (exclusively ERß), the medial preoptic nucleus (MPN; both ER and ERß), the retrosplenial granulate cortex (gCTX; minimal ERß), and the caudate-putamen (no ER or ERß). The pMAPK immunoreactivity was restricted to a small number of brain regions and analyzed in the MPN and gCTX by the manual counting of immunoreactive cell numbers.
For each region, two sections were selected at the appropriate level (see below) in each mouse (n = 5–6 per group), and bilateral cell counts were undertaken by counting all immunoreactive cell nuclei (CREB and pCREB) or cells exhibiting cytoplasmic staining (pMAPK) within a specified rectangle defined as follows: vlVMN, rectangle size 0.04 mm2, anterior-posterior level in plate 43 of Franklin and Paxinos atlas (33); medial septum, 0.48 mm2, plate 26; gCTX, 0.27 mm2, plate 50; MPN, 0.43 mm2, plate 31; and caudate-putamen, 1.92 mm2, plate 26.
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Results |
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). The administration of E2 to OVX wild-type C57BL6/J x CBA/Ca mice increased the numbers of cells expressing pCREB by up to 2-fold (P < 0.05) in the MPN (Figs. 1B and 2A), medial septum (Fig. 2B), and vlVMN (Fig. 2C), but had no effect in the gCTX (data not shown) and caudate-putamen (Fig. 2D). This occurred in the MPN and medial septum within 15 min and persisted at 1 and 4 h. Significantly increased numbers of pCREB-immunoreactive cells were only detected at 1 and 4 h in the vlVMN (Fig. 2). The 1- and 10-µg doses of E2 had the same effects on the magnitude of pCREB induction in all brain areas (Fig. 2). In all cases, the numbers of CREB-immunoreactive cells were not changed by E2 (data not shown).
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) as those observed above in C57BL6/J x CBA/Ca mice (Fig. 2
). In the MPN, E2 treatment resulted in a similar increase (P < 0.05) in pCREB cell numbers in wild-type, ERKO, and ßERKO mice (Figs. 1C and 3A). However, in the medial septum, the E2-induced increase in pCREB expression was found in wild-type and ERKO mice but was absent in ßERKO mice (Fig. 3B). In contrast, in the vlVMN, the estrogen-induced increase in pCREB was found in wild-type and ßERKO mice, but not ERKO animals (Fig. 3C). Basal pCREB levels, but not CREB itself, were significantly elevated in vehicle-treated ERKO mice compared with vehicle-treated wild-type controls in the vlVMN (Fig. 3C).
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ßERKO mice. We found that the E2-induced increase in pCREB within the MPN was completely absent in double ßERKO animals (Figs. 1D and 3A). In fact, as predicted by the ER- and ERß-dependent responses in the vlVMN and medial septum, respectively, estrogen had no effect on pCREB levels in any of the brain regions in double ßERKO mice (Fig. 3). Basal levels of CREB were not different in vehicle-treated wild-type, ERKO, ßERKO, or ßERKO mice and were not altered by estrogen treatment (data not shown).
Estrogen exerts rapid ER-dependent effects on MAPK phosphorylation in vivo
Immunoreactivity for pMAPK was localized throughout the cell (Fig. 4A), and a strong signal was detected in the preoptic area, hypothalamic paraventricular and supraoptic nuclei, and bed nucleus of stria terminalis, with smaller numbers of positive cells found in the piriform cortex, central amygdala, thalamus, and gCTX. Using the exact same areas employed for the CREB analysis, we evaluated pMAPK-immunoreactive cell numbers in the MPN and gCTX. Treatment of wild-type C57BL6/J x CBA/Ca (Fig. 5, A and B) and C57BL6/J (Fig. 5C) mice with E2 resulted in a significant 2.5-fold increase in the numbers of pMAPK-immunoreactive cells in the MPN, but had no effect in the gCTX (Fig. 5, E and F). The increase in the MPN was observed within 15 min (Fig. 5A) and showed dose dependency (Fig. 5B). The numbers of pMAPK-immunoreactive cells in the MPN were significantly reduced in vehicle-treated ßERKO mice compared with wild-type mice (Fig. 5C). In marked contrast to pCREB regulation, the E2-induced increase in pMAPK was not detected in any of the ERKO (Fig. 4B), ßERKO (Fig. 4C), or dual ßERKO genotypes (Fig. 5, C and D).
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Discussion |
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ßERKO mice, and the established differential expression patterns of ER and ERß in the mouse brain (31, 32) predicted the ER responsible for E2-dependent CREB phosphorylation in each brain region. The medial septum expresses ERß exclusively, and E2-induced CREB phosphorylation in this area was found to be dependent only on ERß. Conversely, the vlVMN expresses predominantly ER, and CREB phosphorylation in these cells was dependent only on ER. Both the caudate-putamen and gCTX of mice express little, if any, ER or ERß under normal circumstances (34), and accordingly, we found no evidence for rapid estrogen effects on CREB phosphorylation in these areas. Interestingly, the rapid pCREB response to estrogen in the CA1 hippocampus of mice is absent only in ßERKO mice (27). Taken together, these data suggest a tight correlation between classical ER expression and rapid estrogen signaling impacting on CREB within the brain. We suspect that this regional relationship also holds true for specific neuronal phenotypes within the brain. Specifically, the GnRH neurons of the hypothalamus express only ERß (35), and we have shown recently that estrogen exerts rapid and direct effects on CREB phosphorylation in these neurons through a selective ERß-mediated mechanism (27).
Neurons of the MPN are known to coexpress ER and ERß in the mouse (36) and rat (37), and we find here that either of these receptors can mediate the phosphorylation of CREB in the absence of the other within MPN cells. We initially observed that the E2-induced phosphorylation of CREB was unaltered in either ERKO or ßERKO mice. At first sight, this suggested that E2 was acting through a mechanism independent of ER and ERß to alter CREB phosphorylation. However, the possibility remained that each ER was compensating for the loss of the other, and, to address this issue, we generated double ßERKO mice. The complete lack of rapid estrogen actions on CREB phosphorylation in the MPN observed in double ßERKO mice confirmed the latter possibility. This result also indicated that any residual ER activity in the ERKO mice used here (38) was not functional in the context of rapid estrogen actions. The ability to switch between ERs is probably not a unique property of MPN cells because we have also observed the same pattern of ER dependence in the anteroventral periventricular area, another preoptic brain region where cells express both ERs. Although studies in endothelial cells have shown that only ER can mediate rapid estrogen actions on phosphatidylinositol 3-kinase/Akt signaling (39), other workers have suggested that ER and ERß may act in an interchangeable manner in vitro (4, 8, 40). The present data provide in vivo evidence that cells expressing both ERs can use either receptor to respond to E2 in a rapid manner.
Surprisingly, we found here that both of the classical ERs are required for rapid estrogen actions on pMAPK within MPN cells. The two ERs may act independently at different points in the MAPK pathway or, perhaps more intriguingly, only function as heterodimers in this context. Certainly, it is established that ER and ERß form heterodimers to regulate transcription (41). In contrast, we noted that basal levels of pMAPK were dependent on ERß alone in the MPN. Thus, any role of classical ERs in the maintenance of MAPK signaling may be different from those involved in their rapid estrogen-dependent activation. Although we have only been able to examine restricted brain regions, this is the first evaluation of rapid estrogen actions on the pMAPK/ERK1/2 pathway in vivo. These results show a previously unrecognized complexity in the mechanisms underlying rapid estrogen actions on the MAPK pathway but, overall, support the great majority of in vitro studies indicating a critical role for the classical ERs (4, 5, 6, 7, 8, 9).
The in vivo requirement for both ER and ERß in estrogen-induced MAPK phosphorylation reported here is not consistent with neuronal in vitro data. Studies by Dorsa and colleagues (5) have shown that either ER or ERß is sufficient for rapid E2-dependent MAPK phosphorylation in embryonic cortical neurons, whereas Toran-Allerand et al. (16) have suggested that a novel ER mediates the phosphorylation of MAPK by E2 in neonatal neocortical cells. We did not find robust pMAPK immunoreactivity in the precise cortical regions analyzed in those studies, so we are unable to make direct comparisons. The gCTX region, where we found no effects of estrogen on pMAPK, is reported to have very little, if any, ER expression (31, 32). However, it is important to note that our work was undertaken in vivo in adult mice as opposed to perinatal rats. Furthermore, our observations may relate especially to cells such as those in the MPN known for coexpression of both ERs. In this regard, it may be of importance that the phosphorylation of CREB within MPN cells requires the presence of either ER, whereas the phosphorylation of MAPK needs both ER and ERß. Although we do not know if these responses are occurring within the same cell type in the MPN, it is intriguing to speculate that ERs may be being used in a differential manner within the different signaling pathways in individual cells.
Estrogen exerts widespread effects on multiple neuronal networks, and it is agreed that both direct genomic and rapid nongenomic mechanisms of action exist (1). We have shown here that classical ERs are critical for all of the rapid estrogen actions we have observed on CREB and MAPK phosphorylation. The convergence of many intracellular signaling pathways to ultimately phosphorylate CREB and MAPK (20) suggests the strong likelihood that ER and ERß play critical roles in many, if not most, rapid estrogen effects in the brain. Because we observed many of these ER-dependent rapid estrogen actions in brain regions implicated in the control of reproduction, it seems likely that rapid estrogen actions are relevant for classical estrogen-receptive neural circuits in addition to the novel estrogen effects described elsewhere in the brain (1). More importantly, however, this work indicates a likely close relationship between the rapid and classical genomic actions of estrogen throughout the brain. A recent study by Vasudevan et al. (42) has demonstrated that the rapid effects of estrogen on a neuroblastoma cell line are required for the full expression of estrogen’s genomic influence. Equally, Kousteni et al. (9) have speculated that distinct conformational states of classical ERs may mediate the nongenomic or direct transcriptional actions of estrogen on bone cells. With our present data highlighting the importance of ER and ERß in rapid estrogen actions, these studies together demonstrate that the classical ER represents a critical coordination point for rapid and direct transcriptional actions of estrogen within cells in vivo.
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Acknowledgments |
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Footnotes |
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Abbreviations: CREB, cAMP response element binding protein; E2, 17-ß-estradiol; ER, estrogen receptor; ERKO, ER-knockout; gCTX, granulate cortex; MPN, medial preoptic nucleus; OVX, ovariectomized; pCREB, phospho-CREB; vlVMN, ventrolateral aspect of the hypothalamic ventromedial nucleus.
Received December 10, 2003.
Accepted for publication February 12, 2004.
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