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Physiol Rev
82: 923–944, 2002; 10.1152/physrev.00014.2002.
Estrogen and Thyroid Hormone Receptor Interactions:
Physiological Flexibility by Molecular Specificity
NANDINI VASUDEVAN, SONOKO OGAWA, AND DONALD PFAFF
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, New York
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I. Introduction
II. Hormonal Induction of Genes in the Central Nervous System and in Cell Lines
A. Estrogen induction of genes in the brain
B. Isoforms from genes for ER and TR: distinct and overlapping functions
C. Molecular interactions between the ER and TR isoforms: cell culture studies
III. Physiological Data and Their Implications
A. Lordosis behavior
B. Differences in isoforms from nuclear receptor genes: use of knock-out models
C. Patterns of behavior
D. Physiological implications of thyroid hormone modulation of estrogen action
IV. Role of Promoter and Cell Specificity in Distinct Transcriptional Results
V. Questions Unanswered
A. Gene duplication and splice variants
B. Rapid versus slow effects of estrogen: two separate opportunities for thyroid
hormone modulation?
C. Thyroid hormone elevation: does it signal cold temperatures?
VI. Summary
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Vasudevan, Nandini, Sonoko Ogawa, and Donald Pfaff. Estrogen and Thyroid Hormone Receptor Interactions:
Physiological Flexibility by Molecular Specificity. Physiol Rev 82: 923–944, 2002; 10.1152/physrev.00014.2002.—The
influence of thyroid hormone on estrogen actions has been demonstrated both in vivo and in vitro. In transient
transfection assays, the effects of liganded thyroid hormone receptors (TR) on transcriptional facilitation by
estrogens bound to estrogen receptors (ER) display specificity according to the following: 1) ER isoform, 2) TR
isoform, 3) the promoter through which transcriptional facilitation occurs, and 4) cell type. Some of these molecular
phenomena may be related to thyroid hormone signaling of seasonal limitations upon reproduction. The various
combinations of these molecular interactions provide multiple and flexible opportunities for relations between two
major hormonal systems important for neuroendocrine feedbacks and reproductive behaviors.
I. INTRODUCTION
Cross-talk between members of the nuclear receptor
superfamily theoretically can multiply the possible modes
of gene regulation, leading to a greater and more flexible
array of transcriptional responses to environmental
changes. In the central nervous system (CNS), such gene
regulation conceivably can help to coordinate behavioral
responses of the organism to climatic and social stimuli
(217). Such cross-talk can also underlie metastatic processes. The activation of the estrogen-dependent growth
responses by a nonestrogen such as the growth factor,
insulin growth factor (IGF), may promote the growth of
various cell types. Cross-talk between IGF and estrogens,
for example, can lead to cell proliferation in breast carwww.prv.org
cinoma (41 and references therein) and hence is of considerable interest as a target for adjunct therapy.
Estrogen (ER) and thyroid hormone receptors (TR)
are members of the nuclear receptor superfamily that
bind the low-molecular-weight ligands, estrogens and thyroid hormones, respectively. They transduce these signals
into gene regulation events. These receptors have a modular protein structure with high homology in the central
DNA binding domain. They are ligand-activated transcription factors that influence transcription from target genes
(43, 105). Nuclear receptors bind enhancer elements on
DNA called hormone response elements to regulate transcription from genes (43, 105).
How do nuclear receptors regulate gene transcription? Gene activation events require the recruitment of
0031-9333/02 $15.00 Copyright © 2002 the American Physiological Society
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VASUDEVAN, OGAWA, AND PFAFF
II. HORMONAL INDUCTION OF GENES
IN THE CENTRAL NERVOUS SYSTEM
AND IN CELL LINES
A. Estrogen Induction of Genes in the Brain
Estrogens are necessary for the induction of the primary female-typical sexual behavior lordosis (91) in several species. Estrogens regulate the expression of several
genes in the brain, some of which are responsible for the
facilitation of lordosis (reviewed in Ref. 145). For example, the nonapeptide oxytocin (OT) and its receptor, the
oxytocin receptor (OTR), are expressed in the uterus
Physiol Rev • VOL
during pregnancy (96) and are thought to be important for
gestation, parturition, and lactation. Mice that do not have
OT (OT knock-out mice) cannot lactate and therefore
cannot nurse pups (123). The expression of OT and OTR
in the CNS is believed to be important for the facilitation
of affiliative (24, 44) and sexual behaviors (7, 8, 22) that
are, in turn, required for optimal reproduction.
Estrogen administration to ovariectomized female
rats increases OTR mRNA in the ventromedial hypothalamus (VMH), a brain region critical for lordosis (153).
Estrogens also upregulate OTR mRNA in the medial
amygdala, hippocampus, and anterior pituitary but do not
change the concentration of OTR mRNA in the caudate
putamen or arcuate nucleus of the rat (153). Concomitantly, estrogen treatment increases oxytocin binding in
the bed nucleus of the stria terminalis, lateral ventral
septum, amygdala, and VMH (20, 59, 188). In situ hybridization studies show that OTR mRNA is highest in the rat
VMH at proestrous, showing a correlation with the estrogen surge that occurs during this part of the estrous cycle
(12). When antisense oligonucleotides are infused into the
VMH of estrogen-primed female rats, the rats show significantly higher rejection behavior and lower lordosis,
thus demonstrating the need for an intact OT-OTR system
for reproductive success (107).
In a similar manner, estrogen treatment also upregulates preproenkephalin (PPE) mRNA in the rodent VMH
(97, 168, 169). The importance of the expression of this
gene is underscored by the ability of antisense oligonucleotides against PPE in the hypothalamus to reduce lordosis behavior (121).
B. Isoforms From Genes for ER and TR:
Distinct and Overlapping Functions
1. Two ER genes: ␣ and ␤
Among vertebrates, the ER exists in two isoforms, ␣
and ␤, which are products of different genes (186). The
newly discovered ER␤ isoform was cloned from rat prostate and the ovary. The isoforms exhibit considerable
homology in the DNA binding domain and COOH-terminal
AF2 domain but high divergence in the NH2-terminal
transactivation AF-1 domain (65). Both isoforms can bind
several ligands with similar affinities (92); they also bind
the consensus the estrogen response element (ERE) with
similar affinities (31). The dissociation of ER␣ and ER␤
from such a consensus ERE is similarly affected in the
presence and absence of ligand at elevated temperature
(136). They also bind many EREs (72) derived from estrogen-regulated genes that have deviations from the consensus ERE sequence. Both receptors contain a functionally conserved AF-2 domain, which can be stimulated by
binding the steroid receptor coactivator (SRC1) (31, 186).
Despite limited homology in the NH2-terminal AF-1 do-
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specific coactivators by ligand-bound nuclear receptors
(33, 116, 122). This leads to the remodeling of chromatin,
since many coactivators possess histone acetyltransferase (HAT) activity (27, 178). The remodeling and
“opening” up of chromatin leads to gene activation (27).
Unlike the ER, the TR can regulate transcription even in
the absence of ligand (213). Two well-characterized corepressors termed nuclear corepressor (NCoR) and SMRT
exist for the TRs and the retinoic acid receptors (RAR)␣
(71, 93). In the absence of ligands, TR and RARs recruit
corepressors, which have histone deacetylase activity and
antagonize HAT coactivators. This, in turn, represses gene
transcription (68).
Estrogens are critical in the control of reproduction
in both male and female mammals (88). The deletion of
the ER␣ isoform causes infertility in both male and female
mice (104, 128). The nonreproductive functions of estrogens include maintenance of bone mass (64 and references therein) and cardioprotective effects (170). The
central role of estrogens in mammalian reproduction is
reflected in the neuroendocrine control of gonadotrophin
production from the anterior pituitary and feedback regulation of gonadotropin releasing hormone (GnRH) in the
hypothalamus (88, 89). Recently, neuroprotective effects
as well as effects on mood and cognition have also been
described (99, 147, 204).
Unlike estrogens, which have a more focused role,
the thyroid hormones triiodothyronine (T3) and thyroxine
(T4) exhibit a large range of actions (135, 208). In the adult
homeothermic animal, they exert control over lipogenesis, lipolysis, and thermogenesis. They are critical for
growth, development, and differentiation (134, 172). In
humans, neonatal hypothyroidism results in cretinism, a
disorder characterized by mental retardation and skeletal
defects (35). The effects of thyroid hormone on the brain
are especially well illustrated by thyroid hormone control of
myelin basic protein and the consequent myelination of
axons in the brain (45). This article attempts to review the
relevant information on estrogen and thyroid hormone interactions with a perspective on neuroendocrine functions.
PATTERNS OF ER AND TR ACTIONS IN CNS
2. Differences between ER␣ and ER␤
At AP-1 sites, classical estrogens such as diethylstilbestrol and 17␤-estradiol activated transcription when
bound to ER␣ but were antiestrogens when bound to ER␤
(137). On the human RAR␣-1 promoter, ER␣ activates
transcription in response to estrogens through nonclassical ERE and not by direct DNA-receptor binding. However, in response to estrogens, ER␤ does not activate this
promoter; it activates it in response to tamoxifen, raloxifene, and ICI-164,384 (220). Therefore, the ER isoforms
show considerable promoter site specificity. In vivo and
in vitro, heterodimerization between ER␣ and ER␤ has
been shown (129, 143), and tissues that coexpress both
isoforms are thought, therefore, to respond differently to
various ER ligands compared with tissues that express
predominantly one isoform (65, 66). Therefore, there is
likely a considerable contribution of ER␤ to the pharmacology of estrogens and antiestrogens.
3. TRs: two genes and four isoforms
The four TR isoforms are protooncogene products
derived by differential splicing of two different genes:
Physiol Rev • VOL
TR␣1 and TR␣2 are from the TR␣ gene, while TR␤1 and
TR␤2 are from a separate TR␤ gene. In chicken, a shorter
TR␣1 transcript lacking the NH2-terminal A/B domain is
also present. Also, two TR␤1 transcripts, which possess
very short A/B domains, are also present in the chicken.
Xenopus laevis has several transcripts with homology to
TR␤1 but none similar to TR␤2 (98). Again, although there
is considerable homology in the central DNA binding
domain among the isoforms, significant dissimilarity exists in the NH2-terminal A/B domain. Not all TR isoforms
can bind ligand; the TR␣2 isoforms lacks the ability to
bind ligand due to a loss of 40 amino acids in the COOHterminal hormone-binding domain. The role of TR␣2 in
physiology is unclear; ex vivo studies in cell culture implicate it as a dominant negative inhibitor of TR action.
However, the potency of dominant negative action is
lower than the unliganded TR isoforms, possibly due to
deficient interactions with corepressors (182).
4. Transcriptional properties of TR isoforms
The transcriptional properties of different TR isoforms have been poorly studied, but there do exist some
differences. The differences in the TR isoforms could
allow for differential interactions with other proteins,
thereby regulating transcription. For example, unliganded
TR␤2 can bind SRC-1, unlike TR␣1 and TR␤1 (125). The
TR␤2 is a more potent mediator of ligand-independent
activation than TR␣1 or TR␤1 of T3 target genes such as
the thyroid stimulating hormone (TSH) subunit gene and
the TRH gene (70, 94, 171). This ability is independent of
NCoR and may be due to differential binding of coactivators. The TR␤2 isoform also is unable to mediate ligandindependent repression on the growth hormone promoter, unlike the TR␤1 and TR␣1 isoforms, due to lack of
NCoR binding ability (70). Zhu et al. (215) have noted an
increased ability of TR␤1 to transactivate from a F2 thyroid hormone response element (TRE) compared with
TR␣1 (215). Differential interaction with other proteins,
including other nuclear receptors, may therefore play a
role in thyroid hormone physiology.
Since the consensus DNA sequences bound by ER
and TR share a common half site, it is possible that
competition between the two receptors may lead to antagonism of the other’s effect. Indeed, this was first demonstrated for the vitellogenin ERE by Glass et al. (60); the
thyroid hormone receptor could decrease ER␣-mediated
transactivation.
Steroid hormone receptors have been shown to decrease ligand-dependent TR transactivation from a TRE
(210). Estrogens were also shown to suppress the T3
effect on the ␣-glycoprotein hormone subunit promoter
(207). In both pituitary-derived GH3 cells and JEG-3 choriocarcinoma cells, T3 mediates suppression of the ␣-glycoprotein hormone subunit promoter. 17␤-Estradiol sup-
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main, both ER␣ and ER␤ contain a mitogen-activated
protein kinase (MAPK) phosphorylation site that results
in enhanced transcription (186). Hall and McDonnell (66)
show that despite similar binding affinities for several
ligands, activation of transcription from simple target promoters containing EREs by ER␤ is dependent on pure
agonists. On the other hand, ER␣ can activate transcription when bound to agonists and partial agonists. If a
chimeric ER␤ receptor containing the A/B domain of the
ER␣ is tested for transcriptional activation, antiestrogens
such as tamoxifen, which showed no transcriptional activation with ER␤, could now show some degree of transactivation (110). Jones et al. (76) investigated the ability
of ER␣ and ER␤ to activate transcription from a number
of different promoters that are estrogen responsive but
lack classical EREs in human breast, bone, and uterine
cell lines. These included a collagenase promoter containing an AP-1 element important in estrogen induction, a
nonconsensus ERE containing complement C3 promoter,
and a transforming growth factor (TGF)-␣ promoter containing both ERE and Sp1 elements. All antiestrogens
studied were agonistic on the collagenase reporter in the
uterine cell lines when ER␤ was transfected, but tamoxifen alone was agonistic when ER␣ was transfected (76).
Also, the ability of ER␤ to repress transactivation of
NF␬B in osteoblasts occurs only in the presence of 17␤estradiol, whereas ER␣ can repress NF␬B transactivation
in the absence or presence of ligand (152). This suggests
important mechanistic differences, possibly arising from
differences in amino acid sequence in the AF-1 domain
(66, 195).
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VASUDEVAN, OGAWA, AND PFAFF
pressed this inhibition. In vitro synthesized ER␣ could
bind to the TRE present in this promoter, thereby suggesting competition between these two nuclear receptor
systems as a distinct possibility (207). However, in both
these studies, pure TR and ER isoforms were not used.
Hence, the investigation of possible differential interactions between distinct ER and TR isoforms is of interest.
C. Molecular Interactions Between the ER and TR
Isoforms: Cell Culture Studies
1. Modulation of ER␣ transcriptional activity by the
ligand-binding TR isoforms
The interaction of ER␣, the classical ER isoform, and
the ligand-binding TR isoforms has been observed on a
consensus vitellogenin ERE linked to a minimal thymidine kinase promoter in kidney fibroblast, CV-1, cells
(190, 218). CV-1 cells were chosen since they have low
endogenous ER and TR isoforms (215). On cotransfection
of ER␣ and TR␣1 expression vectors, the T3-liganded
TR␣1 isoform could interfere with the ER␣ induction of
this simple promoter (Fig. 1A) (190, 218). However, the
TR␤1 or TR␤2 isoforms did not have any effect on the
ER␣ induction of this promoter (190, 218) (Fig. 1, B and
C). This demonstrates that on a simple consensus ERE,
there is considerable difference in the modulation of transcriptional activity of ER␣ by the ligand-binding TR isoforms.
2. Interactions of ER␤ with the ligand binding TR
isoforms on the consensus ERE
ER␤ could also induce this promoter in CV-1 cells,
albeit at a lower level than the ER␣ isoform (Fig. 2). When
the ligand binding TR isoforms were cotransfected with
ER␤ in CV-1 cells, the TR isoforms showed differential
effects on ER␤-mediated induction from the consensus
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3. ER␣ versus ER␤: TR␣1 modulation of induction
of the PPE promoter in CV-1 cells
Similar to the inhibitory effect by the TR␣1 on ER␣mediated transcription from the consensus ERE, the
TR␣1 inhibited ER␣ induction from the PPE promoter
(Fig. 3A). In contrast, the TR␣1 isoform stimulated ER␤mediated transcription (Fig. 3B), demonstrating differences in the interaction of a given TR isoform with an ER
isoform. In the CV-1 cell line, the TR␤ isoforms had no
effect on ER␣ or ER␤-mediated induction of the PPE
promoter (192). Again, similar to the consensus ERE, the
ability of the TR␣1 isoform to inhibit or stimulate ERmediated transcription of the PPE depends on the ER
isoform present in the cell (192).
4. TR isoform modulation of ER␣-mediated induction
of the OTR promoter
To test the interactions between the TR and ER
isoforms in a cell line with neuronal properties and to
compare these interactions with those occurring in a
nonneuronal cell line, the OTR promoter containing the
distal ERE was investigated in both CV-1 and SK-N-BE2C
cell lines (189). Again, the TR␣1 isoform was capable of
inhibiting the ER␣-mediated induction from the OTR promoter in both CV-1 and SK-N-BE2C cell lines. However, a
complex pattern of interactions emerged when the TR␤
isoforms were expressed in conjunction with the ER␣
isoform. Although the TR␤2 isoforms were inhibitory to
ER␣-mediated induction of this OTR promoter in either
cell line, the TR␤1 effect on ER␣ induction depends on
the cell line. In the CV-1 cell line, this isoform stimulated
the ER␣ induction while inhibiting it in the neuronal cell
line (189). A neuronal specific cofactor, NIX1, which can
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Two different promoters were initially used to examine the interactions between the ER and the TR. The
consensus ERE derived from the vitellogenin gene promoters has long been used as a model system to explain
molecular mechanisms by which estrogen regulates
genes. In CV-1 kidney fibroblast cells, the consensus ERE
linked to a CAT reporter has been shown previously to be
transcriptionally upregulated by estrogen-liganded ER␣
(218). Transiently transfected TR␣1 was able to inhibit
this ER␣-mediated induction, but TR␤1 and TR␤2 had no
effect (218). Contrasting to another promoter, when three
tandem copies of the estrogen response EREs from the
progesterone receptor promoter are used in the CV-1 cell
line, no TR isoform could inhibit the ER␣-mediated induction (173). This suggested that the interactions between
TR and ER isoform were different on different promoters.
ERE. In contrast to the inhibitory effect of the TR␣1
isoform on the consensus ERE, the TR␣1 isoform stimulated ER␤-mediated transcription (Fig. 2A). The TR␤1
isoform also stimulated ER␤-mediated transcription (Fig.
2B), while the TR␤2 isoform inhibited ER␤-mediated transcription (Fig. 2C). However, neither TR␤1 nor TR␤2 had
any effect on ER␣-mediated transcription. This shows
that a single TR isoform can lead to differential transcriptional outcomes depending on the ER isoform present in
the cell.
Are the interactions between the various TR and ER
isoforms different on a physiologically relevant promoter? To address this question, the estrogen-responsive,
behaviorally relevant PPE and OTR promoters cloned
upstream of reporter genes were transfected into CV-1
cell lines and neuronal (SK-N-BE2C) cell lines. The PPE
promoter has two EREs located within 450 bp of the
transcription start site (77), whereas the OTR promoter
has a distal ERE located ⬃4 kb from the transcription
start site (11).
PATTERNS OF ER AND TR ACTIONS IN CNS
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bind liganded TR␤1 and downregulate transcription,
could be responsible for this phenomenon (63). The expression of the cofactor appears to be confined to dentate
gyrus, the amygdala, as well as thalamic and hypothalamic regions and may contribute to the differences in
transcriptional activation observed with the TR␤1 isoform in these cell lines. Therefore, cell-specific effects are
also important in the interactions between nuclear receptor isoforms. These data underscore the need to test
physiological promoters in different cell lines.
Table 1 summarizes the transcriptional pattern obtained using different promoters and various combinations of ER and TR isoforms. The different outcomes
show that the interaction between the ER and TR isoforms demonstrates considerable promoter specificity. It
is easy to visualize that different levels of TR and ER
Physiol Rev • VOL
isoforms in cells may, therefore, allow for flexible regulation of EREs depending on stimuli.
5. Mechanisms of TR␣1-mediated inhibition
A) COMPETITIVE DNA BINDING. What are the possible
mechanisms by which the TR isoforms interact with the
ER isoforms? Since the consensus DNA sequences, the
hormone response element (HRE), bound by both ER and
TR, are very similar, TR can interfere with ER-mediated
transcription by competing with the ER for binding to the
ERE on DNA (60). A TR␣1 mutant called the TR P-box
mutant has a mutation in the DNA binding region; this
disallows binding by this isoform to DNA (209). If DNA
binding were important in the inhibitory interaction between TR␣1 and the ER␣ isoform, then such a mutant
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FIG. 1. Effect of the ligand binding thyroid hormone receptor (TR) isoforms on estrogen receptor (ER)␣-mediated
induction of the consensus estrogen response element (ERE) in CV-1 cells. CV-1, a kidney fibroblast cell line, was grown
in DMEM supplemented with 10% fetal bovine serum. The reporter plasmid is the ERE-tk-CAT and has a single consensus
vitellogenin ERE upstream of a minimal thymidine kinase promoter linked to chloramphenicol acetyltransferase (CAT)
(218). The cells seeded in 6-well plates (Falcon) were transfected at 60% confluency. The expression plasmids used were
the pSG-hER␣ coding for the ER␣ protein and the pCDNAI-rTR␣1, -␤1, and -␤2 coding for the TR isoforms (218). The
pSV-␤-galactosidase (pSV␤gal) plasmid coding for the enzyme ␤-galactosidase was used as a normalization control for
transfection efficiency and lysate preparation. The reporter plasmid (200 ng), the expression plasmids for the nuclear
receptors (80 ng), and the pSV␤gal (80 ng) plasmids were cotransfected into CV-1 cells using the Effectene reagent
(Qiagen) according to the manufacturer’s instructions. Twenty-four hours after transfections, phenol red-free media
supplemented with hormone-free sera were added to the cells. Either 17␤ -estradiol (E) (10⫺7 M) or triiodothyronine (T)
(10⫺6 M) or both (E⫹T) were added to wells. A set of wells received the vehicle, ethanol, alone. Forty-eight hours after
hormone treatment, cells were lysed using Reporter lysis buffer (Promega) according to the manufacturer’s instructions,
and CAT and ␤-gal assays were performed on every sample. The CAT activity was normalized to the ␤-gal activity for
every sample. Results (fold over vehicle control) represent means ⫾ SE (n ⫽ 5/treatment group). Statistical comparisons
between treatment groups were done using ANOVA followed by Student-Newman-Keuls post hoc tests. A (TR␣1):
*P ⬍ 0.001 compared with the vehicle-treated group. #P ⬍ 0.001 compared with the estrogen-treated group. B (TR␤1):
*P ⬍ 0.05 compared with the vehicle-treated group. C (TR␤2): *P ⬍ 0.001 compared with the vehicle-treated group.
[Modified from Vasudevan et al. (190).]
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VASUDEVAN, OGAWA, AND PFAFF
should not be able to inhibit the ER␣ induction. With the
consensus ERE in CV-1 cells, inhibition by the TR␣1
isoform was lost when the TR P-box mutant is used (190,
218), implicating DNA binding and hence competition for
the ERE as important in this inhibition. In addition, the
TR␤1 and TR␣1 isoforms can bind to the consensus ERE,
thus making inhibition by competitive DNA binding possible (218). However, differences arise when “physiologi-
cal” promoters such as the OTR and PPE promoters are
used. Despite lack of DNA binding ability, the TR P-box
mutant could nonetheless inhibit the ER␣-mediated induction of both PPE (Fig. 4A) and OTR promoters, suggesting that DNA competition may not be a universal
mechanism in inhibition. Also, to check if the levels of ER
isoforms expressed in the CV-1 cell lines significantly
differ, binding of [3H]estradiol to extracts of cells trans-
FIG. 3. TR␣1 has opposing effects on ER␣-mediated (A) and ER␤-mediated (B) induction from the rat preproenkephalin (PPE) promoter in CV-1 cells. The protocol for transfection and the expression and normalization plasmids
used have been described in the legends to Figures 1 and 2 and in previous studies (137, 218). The rat PPE gene promoter
(⫺437 to ⫹53 bp) containing two putative EREs was inserted into pUTKAT1 (77, 218). The CAT activity was normalized
to the ␤-gal activity for every sample. Results (fold over vehicle control) represent means ⫾ SE. Statistical comparisons
between treatment groups were done using ANOVA followed by Student-Newman-Keuls post hoc tests. A (n ⫽ 8/
treatment group): *P ⬍ 0.001 compared with the vehicle-treated group. #P ⬍ 0.01 compared with the estrogen-treated
group but ⬎0.05 compared with vehicle-treated group. B (n ⫽ 5/treatment group): *P ⬍ 0.05 compared with the
vehicle-treated group. #P ⬍ 0.01 compared with estrogen-treated group. [Modified from Vasudevan et al. (192).]
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FIG. 2. Effect of the ligand binding TR
isoforms on the ER␤-mediated induction
from the consensus ERE in CV-1 cells.
The protocol for transfection as well as
the reporter and expression plasmids for
the TR isoforms has been detailed in the
legend to Figure 1. The ER␤ expression
plasmid used was the pCMV-ER␤ (137).
The CAT activity was normalized to the
␤-gal activity for every sample. Results
(fold over vehicle control) represent
means ⫾ SE (n ⫽ 8 or 9/treatment group).
Statistical comparisons between treatment groups were done using ANOVA followed by Student-Newman-Keuls post
hoc tests. A (TR␣1): *P ⬍ 0.01 compared
with the vehicle-treated group. #P ⬍ 0.001
compared with the vehicle-treated group.
⵩ P ⬍ 0.001 compared with the estrogentreated group. B (TR␤1): *P ⬍ 0.001 compared with the vehicle treated group.
#P ⬍ 0.001 compared with the estrogentreated group. C (TR␤2): *P ⬍ 0.01 compared with the vehicle-treated group.
#P ⬍ 0.001 compared with the vehicletreated group. ⵩ P ⬍ 0.01 compared with
the estrogen-treated group. [Modified
from Vasudevan et al. (190).]
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PATTERNS OF ER AND TR ACTIONS IN CNS
TABLE 1. ER␣ compared with ER␤ in the specificities of interactions with different TR isoforms: promoter and
cell type dependence
T4/ TR Interactions
ER Driving E-Facilitated
Transcription
I
II
III
ER␣
ER␤
ER␣
ER␤
ER␣
ER␤
ER␣
ER␤
cf
of
cf
cf
TR␣1
TR␤1
TR␤2
2
1
2
No E induction
2
No E induction
2
1
⬃
⬃
1
No E induction
2
No E induction
⬃
1
⬃
⬃
2
No E induction
2
No E induction
⬃
2
Promoter
PPE
PPE
OT receptor
Cell Type
CV1
OT receptor
cf
SK-N-BE2C
ERE consensus
CV1
fected with either ER␣ or ER␤ was done. There was no
difference in the levels of ER␣ or ER␤; this also correlates
well with the similar level of transcriptional activation
promoted by either isoform in response to 17␤-estradiol.
The nuclear corepressor NCoR mediates basal repression
by unliganded TR isoforms (30). However, because the
inhibition detailed in Table 1 is ligand dependent, this
must represent a novel, NCoR-independent mechanism.
B) RESCUE OF TR␣1 INHIBITION BY THE EXPRESSION OF A
COACTIVATOR. The p160 group of coactivators, of which
FIG. 4. Mechanisms of TR-mediated interference of ER-driven transcription. A: a TR␣1 mutant unable to bind DNA,
the TR P-box mutant, can still cause inhibition of the ER␣-mediated induction from the rat PPE promoter in CV-1 cells.
B: SRC-1 overexpression rescues TR␣1 inhibition of ER␣-mediated induction from the rat OTR in CV-1 cells. A: CV-1 cells
were cotransfected with PPE reporter plasmids and the expression plasmids for ER␣ and the TR P-box mutant (209) as
detailed in the legend to Figure 1. [Modified from Vasudevan et al. (192).] B: SRC-1, a general steroid receptor
coactivator, was overexpressed in CV-1 along with the TR␣1 and ER␣ isoforms as detailed in the legend to Figure 1. The
samples that were transfected with SRC-1 expression vector (4th, 5th, and 6th bar from left) were treated with
17␤-estradiol (E) (10⫺7 M) or both 17␤-estradiol and triiodothyronine (E ⫹ T). Corresponding hormone treatment was
given to a set of samples that received the empty control SRC-1 expression plasmid (first 3 bars from left). [Modified from
Vasudevan et al. (189).] Forty-eight hours after hormone treatment, cells were lysed, and each sample was assayed for
both ␤-gal and CAT activity. The reporter gene activity was normalized to the ␤-gal activity for every sample. Results
(fold over vehicle control) represent means ⫾ SE. Statistical comparisons between treatment groups were done using
ANOVA followed by Student-Newman-Keuls post hoc tests. A (n ⫽ 8/treatment group): *P ⬍ 0.01 compared with
vehicle-treated group. #P ⬍ 0.01 compared with estrogen treatment. B (n ⫽ 5/treatment group): *P ⬍ 0.05 compared with
the vehicle-treated group. #P ⬍ 0.05 compared with the vehicle-treated ⫺SRC-1 group. ƒP ⬍ 0.001 compared with the
estrogen-treated ⫺SRC-1 group.
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Summary of the interaction between the ligand-binding thyroid hormone receptor (TR) isoforms and the estrogen receptor (ER)␣ and ER␤
isoforms in CV-1 (kidney fibroblast) and SK-N-BE2C (neuroblastoma) cells. All effects of thyroid hormone-liganded TR isoforms are tested only if
there is estrogen (E) induction via either ER␣ or ER␤ of the promoter. The promoters used were as follows: ppe-cat, physiological rat
preproenkephalin (PPE) gene promoter (⫺437 to ⫹53) linked to the chloramphenicol acetyltransferase reporter gene (77); otr-luc, physiological rat
oxytocin (OT) receptor gene promoter linked to the luciferase reporter gene (11); eretkcat, a single copy of the consensus (ERE) derived from the
vitellogenin gene linked to the chloramphenicol acetyltransferase reporter gene (218). 1, T4 through TR isoform increases E-induced transcription;
2, T4 through TR isoform decreases E-induced transcription; ⬃, T4 through TR isoform has no effect on E-induced transcription. I, data from
Vasudevan et al. (192); II, data from Vasudevan et al. (189); III, data from Vasudevan et al. (190).
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VASUDEVAN, OGAWA, AND PFAFF
6. PPE and OTR, “downstream genes,” providing
routes from estrogens/ERs to behavior
The PPE gene plays a role in analgesic responses
which can help the female to put up with somatosensory
stimuli during mating which otherwise would be treated
as noxious (17). Therefore, PPE gene induction represents a causal route which allows us to link a hormone’s
genomic effects with a specific behavior, lordosis. In the
rat VMH, PPE mRNA in the afternoon of proestrous was
significantly higher than diestrous (56). In the female ewe,
PPE mRNA increased in the VMH both during lactation
and with estrogen treatment (21). On a single dose of
Physiol Rev • VOL
17-estradiol-3-benzoate given to female ovariectomized
mice, PPE mRNA was upregulated in the VMH, medial
amygdala (MeAmyg), and arcuate nucleus (ARC) at 24
and 48 h (154). However, PPE is not regulated in the
caudate putamen or in the cortical amygdala by estrogens
(154). A single dose of estradiol benzoate to ovariectomized female rats resulted in a biphasic increase in PPE
mRNA producing cells both in the ARC and VMH with a
peak at 48 h (151). This biphasic response of PPE consists
of a primary peak at 1 h and a second peak between 24
and 48 h postinjection. The rapid first peak was stress
induced and could be blocked by adrenalectomy or constant low levels of corticosterone. A peak of plasma corticosterone also coincided with this peak. In the medial
amygdala, the antiestrogen tamoxifen blocked the second
peak of PPE mRNA expression. These data indicate that
both steroids and noxious mild somatosensory stimuli
interact to give increases in PPE expression (177). This is
consistent with a role for PPE in female reproductive
behavior. Acute, mild stress in the form of male approach
behavior may activate limbic and hypothalamic circuits
known to be important for the full display of reproductive
behavior (177).
The OTR gene is also critical for reproductive success. Infusion of oxytocin into the VMH increases sexual
behavior and maternal behavior. How does it do so? It is
thought that most laboratory tests for sexual behavior and
maternal behavior involve unfamiliar, novel and potentially threatening surroundings for rodents. Exposure to
such apparatuses or to an unfamiliar animal could trigger
inhibitory stress responses. In Swiss Webster mice pretreated with estrogens, peripherally administered OT increased entries into open arms in the elevated plus maze
(108). In mice given intracerebroventricular injections of
OT, entries into open arms were increased compared with
mice given arginine vasopressin (108). Therefore, estrogen upregulation of OT could be a vital component in
anxiolytic actions, decreasing stress and facilitating social
interactions (109).
Therefore, both PPE and OTR are downstream genes
with proven behavioral roles and are upregulated by a
primary reproductive effector, estrogen. These downstream gene products are expressed in behaviorally relevant neurons that possess ERs. Indeed, they can be visualized as systems that link a small hormonal signal with an
identifiable behavior.
III. PHYSIOLOGICAL DATA
AND THEIR IMPLICATIONS
A. Lordosis Behavior
Neuronal and genetic mechanisms for lordosis behavior have been worked out in such detail (reviewed in
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SRC-1 is a member, has been shown to bind both the ER
ligand binding domain and the TR (103). Therefore, SRC-1
appeared to be an attractive candidate that could be
tested for its ability to restore transcriptional activation
by ER␣ on the rat OTR and PPE promoters in the presence of the inhibitory TR␣1 isoform. To explore the idea
that coactivators are sequestered by the TR isoforms, we
overexpressed a general steroid coactivator, the SRC-1,
along with TR␣1 and ER␣. On both PPE and OTR (Fig.
4B), promoters as well as the minimal promoter containing the consensus ERE, SRC-1 overexpression could rescue TR␣1 inhibition, suggesting that squelching of common coactivators is an important mechanism of inhibition
by the TR isoforms. Recently, Auger et al. (10) have
shown that reduction in brain SRC-1 levels by antisense
oligonucleotide injection reduces the ability of the ER to
defeminize the brain during postnatal sexual differentiation in Sprague-Dawley rats. Inhibition of T3-dependent
transcriptional activation by other nuclear receptors such
as the glucocorticoid and estrogen receptor has been
reported to be due to titration of essential coactivators
(209). The ligand-bound TR␣ and TR␤ proteins could
interfere with progesterone receptor (PR)-mediated
transactivation from a progesterone responsive reporter
in the CV-1 cell line. Deletion of the DNA binding region
did not affect the inhibitory properties; however, deletion
of the six amino acids in the ligand binding domain
needed for binding coactivators abolished the interference (214). Therefore, squelching of proteins has important consequences for gene regulation. For example, the
coactivator proteins RIP140 and TIF2 compete for a common binding site on the glucocorticoid receptor (GR),
allowing TIF2 to relieve the inhibitory effect of RIP140 on
GR action (180). Although it is not clear if ER-containing
neurons also coexpress SRC-1, the widespread distribution of SRC-1 in the brain makes this likely (10). Also,
many ER containing VMH neurons coexpress SRC-1, thus
making such alleviation of inhibition possible in vivo (10).
Therefore, the ability of the TR␣1 isoform to bind DNA as
well to squelch coactivators such as SRC-1 provides a
rationale for the inhibition observed with this isoform.
PATTERNS OF ER AND TR ACTIONS IN CNS
B. Differences in Isoforms From Nuclear Receptor
Genes: Use of Knock-out Models
1. TR gene knock-out mice
Differences in the physiological roles of the different
isoforms have been explored using knock-out mice models. Despite similar ligand binding characteristics, the
differential distribution of the TR isoforms as well as data
obtained from knockout mice suggest a unique role for
the various TR isoforms. The TR␣1 and the TR␤ isoforms
have both common and specific roles in vivo. Predicated
on the high concentration of TR␤2 in the anterior pituitary
(69), the TR␤2 isoform plays a major role in the negativePhysiol Rev • VOL
feedback regulation of TSH by thyroid hormone. Lack of
TR␤2, therefore, causes hyperthyroidism in mice (2). On
the other hand, lack of the TR␣1 isoform results in a mild
hypothyroidism in mice (75). The distribution of the TR␤2
isoform in the developing retina of the mouse is also
indicative of an important developmental role for this
isoform. In rodents, cones contain different opsins sensitive to different wavelengths. The TR␤2 isoform is responsible for a commitment to M-cone (M, middle or green
wavelengths) identity. Deletion of this isoform results in a
lack of M cones and a concomitant increase in S-opsin (S,
short wavelength) immunoreactive cones (119). The inability for one isoform to substitute for another is also
exemplified by T3-controlled type 1 deiodinase expression
(6). Although both TR␣1 and TR␤ are present in both liver
and kidney, expression of the deiodinase was highly dependent on TR␤ in the liver and completely dependent on
TR␤ in the kidney (6). Another example, the TR␤1 isoform, is implicated in hearing loss, whereas the TR␣
knock-out mice remain unaffected (2).
The TR␣ and TR␤ isoforms also play distinct roles in
the facilitation of lordosis in female mice. Deletion of the
TR␣1 isoform resulted in decreased lordosis behavior in
female mice, whereas loss of the TR␤ isoforms resulted in
increased lordosis (36). OT immunoreactivity in the paraventricular nucleus (PVN) was elevated in TR␤ knock-out
female mice treated with estradiol compared with wildtype mice given the same treatment, implicating OT increase in the PVN as important in increased lordosis (36).
Both behavioral and molecular data on the cross-talk
between the ER␣ and TR isoforms on the PPE and OTR
promoters point to opposing effects of the TR␣ and TR␤
isoforms.
2. ER␣ knock-out mice versus ER␤ knock-out mice:
behavioral phenotypes
Reproductive and affiliative behaviors are differentially affected according to which of the ERs is deleted in
mice. ER␣ knock-out (ERKO) female mice show virtually
no lordosis (128, 132), whereas ER␤ knock-out mice
(BERKO) not only show normal lordosis behavior but
express this behavior during a larger portion of the estrous cycle than wild-type littermate controls (126).
ERKO females have striking deficits in maternal behavior.
Dramatically, aggressive behaviors in young adult BERKO
males are heightened (124), whereas they are markedly
suppressed in ERKO males (131). Note that there appears
to be genotype/age interactions in aggressive behavior by
BERKO mice, in that the relatively inexperienced young
BERKO mice are more aggressive in resident-intruder
tests. Finally, the increase in locomotor activity in both
genetic females and genetic males, following estrogen
administration, depends absolutely on the patency of the
ER␣ gene but not the ER␤ gene (127).
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Ref. 145) that the behavior virtually stands as an expression system for ER transcriptional activation. In turn,
interactions between liganded TRs and ER function can
be charted thereby.
The neuroanatomy of estrogens liganded to ER␣ or
ER␤ has been charted in considerable detail (144, 146,
175). VMH neurons binding estrogens sit on top the lordosis behavior neuronal circuit (148). Hormone implant
experiments establish that it is the estrogenic sensitivity
of these neurons that accounts for hormonal facilitation
of lordosis. New RNA and protein synthesis are required
for the behavioral facilitation. Specific, hypothalamically
expressed genes have the following properties: they are
turned on by estrogens, and their products facilitate lordosis (150). Therefore, in the manner of a logical syllogism, their induction comprises part of the mechanisms
by which estrogenic hormones turn on the behavior.
These particular genes in no way exhaust the possibilities of hormone-stimulated messages, which are behaviorally relevant. New DNA-microarray experiments
have revealed hitherto unimagined genes that are hormone sensitive (113) which indicate linked glial/neuronal
and possible leptomeningeal/neuronal cooperation in
neuroendocrine function.
Normal gene expression for ER␣ is required for normal lordosis behavior (128, 132). In dramatic contrast,
active gene expression for ER␤ actually suppresses lordosis; ER␤ knock-out female mice show the behavior
during a larger portion of their estrous cycles than wildtype female littermate controls (126).
Therefore, estrogen-dependent lordosis behavior is
well suited to look for thyroid/estrogenic interactions.
Thyroid hormone administration, in fact, reduces lordosis
behavior performance both in female rats (38) and in
female mice (114). The molecular mechanisms involved
are not necessarily simple and require further investigation; that is, against all predictions, the contribution of the
TR␣ gene to the regulation of female reproductive behavior is diametrically opposite to that of the TR␤ gene (36).
931
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VASUDEVAN, OGAWA, AND PFAFF
3. Cross-talk between the ER␣ and ER␤ isoforms
It has been suggested that the inability of ERKO mice
to induce OTR in response to estradiol benzoate treatment (212) is a factor in their failure to promote social
interactions. Antagonistic effects of two ER isoforms expressed in the same cell have also been reported. On a
consensus ERE promoter in HeLa cells, Hall and McDonnell (66) have noted that coexpression of ER␤ along with
ER␣ reduces the transactivation seen with ER␣. We were
interested in investigating if there is a similar effect on a
physiological promoter in both the cell lines. However,
although ER␤ did not affect the transactivation observed
with the ER␣ isoform on the OTR promoter in response to
17␤-estradiol in the CV-1 cell line (Fig. 5), it decreased the
transcriptional activation observed on this promoter in
the SK-N-BE2C cell line (Fig. 5). Again, cell-specific effects such as the expression of tissue-specific cofactors
may play a role in this phenomenon. The inability of
estrogen-liganded ER␤ to activate transcription from a
physiological OTR promoter may also help explain a result obtained from ERKO mice. The OTR gene promoter is
upregulated by estrogens in several brain regions. Unlike
in the rat, estrogens do not induce OTR expression in the
mouse hippocampus but induce it in the cortex (212).
However, the ERKO mouse, which does not have ER␣ but
has ER␤, lacks estrogen induction of OTR in many brain
regions, such as the cortex, as monitored by OT binding
(212). This may be explained by the differential distribution of ER isoforms as well as the inability of the ER␤ to
induce the OTR. In the mouse hippocampus, ER␣ expresPhysiol Rev • VOL
sion is sparse, although ER␤ expression is intense (174).
It has been suggested that ER␤ distribution in the rat
brain results in overall “global” functions for ER␤ in estrogen action, augmenting cognitive processes and neuronal regeneration (176).
However, the cortex of the mouse expresses both
ER␣ and ER␤ isoforms. Although the ER␣ isoform consistently supported 17␤-estradiol induction of the rat OTR
promoter in both cell lines tested, the ER␤ isoform failed
to induce the OTR gene promoter under identical conditions. This would predict that brain regions rich in ER␤
but poor in ER␣ such as the hippocampus would fail to
support a significant induction of OTR gene expression in
wild-type mice. When the predominant ER isoform
present in brain areas is the noninducing ER␤ isoform,
this is precisely the case. The inability of ER␤ to induce
transcription in response to 17␤-estradiol has also been
reported in transiently transfected NG108 –15 neuroblastoma glioma cells using a neuropeptide Y-Y1 receptor
gene promoter (117). This receptor promoter has two
half-site ERE, and estrogen-mediated transcription is
strictly dependent on the presence of transfected ER␣.
Coexpression of both ER isoforms abolished the ER␣mediated transactivation, suggesting an antagonistic effect of ER␤ on this physiological promoter (117).
4. Mechanisms for ER␣ cross-talk with ER␤
Do relative amounts of ER␣ and ER␤ contribute to
this result? As monitored by [3H]estradiol binding, ER␣
and ER␤ appeared to be expressed equivalently to each
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FIG. 5. Effect of the coexpression of ER␣ and ER␤ on oxytocin receptor (OTR) gene transcription in CV-1 and
SK-N-BE2C cells. Both ER␣ and ER␤ expression plasmids were cotransfected into CV-1 and SK-N-BE2C cells at equal
concentrations along with the OTR-luciferase construct. A corresponding set of samples received the ER␣ or the ER␤
expression construct alone with the OTR-luciferase reporter construct. After treatment of each set with 10⫺7 M
17␤-estradiol or ethanol for 48 h (n ⫽ 6/treatment group), cells are lysed and assayed for ␤-gal and luciferase activity.
The results are analyzed using ANOVA followed by Student-Newman-Keuls post hoc test to compare between treatment
groups. CV-1 cells: *P ⬍ 0.001 compared with vehicle treatment of the ER␣ group. #P ⬍ 0.01 compared with vehicle
treatment of the ER␣ and ER␤ group. SK-N-BE2C cells: ‚P ⬍ 0.01 when compared with vehicle treatment of the same
group. ƒP ⬍ 0.01 when compared with estrogen treatment of the ER␣ group. [Modified from Vasudevan et al. (189).]
933
PATTERNS OF ER AND TR ACTIONS IN CNS
ucts. On the right side of Table 2 are summarized some of
the data gathered from genetic females and genetic male
mice on a number of behavioral and histochemical assays.
The variety of relations between ER␣ and ER␤ are reminiscent of the differences seen between ER␣ and ER␤ in
their molecular interactions, reviewed above, with a given
TR isoform in the cell culture model systems. For both the
molecular and the behavioral studies, the specificities of
interactions among ER gene products and TR gene product isoforms additionally provide us with internal
controls.
In the early 1940s, Beadle and Tatum (13), in their
famous genetic and biochemical studies on the fungus
Neurospora crassa, found that the loss of an enzyme led
to a specific biochemical defect. The underlying cause of
lack of enzyme activity was discovered to be a loss of a
gene, thus leading to the well-known “one gene-one enzyme” hypothesis (13, 158, 183). The data presented above
show us the combinatorial possibilities of nuclear receptor gene product interactions. These force us to redirect
our thinking into a new, more organismal framework
whereby patterns of gene expressions and interactions in
the central nervous system underlie patterns of behavior.
C. Patterns of Behavior
D. Physiological Implications of Thyroid Hormone
Modulation of Estrogen Action
The above data suggest that isoforms deriving from
closely related genes for nuclear receptors play unique
roles that are clearly not equivalent in whole animal studies. The ERKO mice do not exhibit the same behavioral
phenotype as the BERKO mice in several behavior tests,
especially those designed to elicit socially motivated responses. Similarly, the ␣TRKO females treated with estrogens do not display the same levels of sexual receptivity as the ␤TRKO females (36). Hence, the ␣KO are not
equivalent to the ␤KO mice in either ER or TR knock-out
models. Table 2 highlights theoretical scenarios for functional relations between ERKO and BERKO gene prod-
TABLE
1. Neuroendocrine data
The involvement of thyroid hormone in the neuroendocrine control of reproduction has been documented
especially well in starlings and sheep. In these species
inhabiting temperate latitudes, seasonal reproduction ensures the birth of young in conditions that maximize
survival. Therefore, the termination of the breeding season in sheep and the initiation of anestrous occur during
the long-day period (spring and summer). An endogenous
rhythm, which is entrained by such changes in day length,
2. Behavioral phenotypes shown by ␣ERKO and ␤ERKO mice
Necessary?
ER␣ and ER␤
Sufficient?
Neither ER␣
nor ER␤
Neither ER␣
nor ER␤
Either ER␣ or
ER␤
␣, ␤ each for its
own
␣,␤ each for its
own
ER␣ Absent
ER␤
Optimal ER␣/
ER␤ balance
ER␣ Absent
ER␤
Optimal ER␣/
ER␤ balance
Requirement
ER␣ and ER␤
must synergize
ER␣ and ER␤ can
substitute for
each other
ER␣ vs. ER␤
contributions
not related
ER␤ can reduce
ER␣ effect
ER␣ vs. ER␤
always opposed
Assays in the Male
Assays in the Female
None
None
E induction of PR (ICC) ER reduction of ER
(ICC)
E induction of PR ER
reduction of ER (ICC)
Maternal behavior (␣), suppression of
aggression (␣), food intake reduction (␣),
anxiety reduction (␣)
Lordosis behavior
Mounting behavior (␣), anxiety
response (␣)
None
Intromissions and ejaculation
Aggression
None
ER␣ knock out (␣ERKO) and ER␤ knock out (␤ERKO) male (124, 130, 131, 133) and female (126 –128, 132) mice were tested on a variety of
behavioral assays. The criteria for the requirement for either ER␣ or ER␤ are detailed in the table.
Physiol Rev • VOL
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other in both CV-1 cells (190) and SK-N-BE2C (189) cell
lines. Although not statistically significant, ER␤ binding to
[3H]estradiol appeared to be slightly lower and may have
contributed to the noninducibility of the rat OTR promoter by ER␤. In contrast, in CV-1 kidney fibroblast cells
(Fig. 3B), ER␤ was capable of mediating the 17␤-estradiol
induction of the natural PPE gene promoter fragment.
Also, ER␤ is capable of promoting neurite elongation in
SK-N-BE2C human neuroblastoma cells in response to
added 17␤-estradiol, thus proving that both cell lines are
responsive to estrogens via both ER␣ and ER␤ (140).
Therefore, the nonresponsiveness of the OTR gene promoter on transfection of the ER␤ isoform in both the cell
lines tested is promoter and ER isoform specific. The
lower transcriptional efficiency of ER␤ has been noted
using the consensus ERE construct, ERE-tk-luc, in COS-1
and HepG2 cells. With the use of Gal4 DNA binding fusion
proteins fused to the AF-1 domains of either ER␣ or ER␤,
it was determined that the AF-1 activity of ER␤ was
negligible compared with ER␣ (32). On promoters and in
cell lines which require both AF-1 and AF-2 activity, ER␤
appears to be a poorer transcriptional activator than
ER␣ (32).
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VASUDEVAN, OGAWA, AND PFAFF
2. Mechanisms of thyroid hormone-induced
anestrous in sheep
The mechanisms of thyroid hormone-induced
anestrous in sheep have centered mainly on the gonadal
hypothalamic-pituitary axis. There is no effect of THX in
female ewes on the ability of a rise in estrogens to elicit
the LH surge or in the ability of progesterone to suppress
LH secretion (199). However, there is intensified estrogen-mediated negative feedback in control ewes compared with THX ewes (199). High-frequency pulses of
Physiol Rev • VOL
both GnRH and LH are observed in THX ewes that did not
make the transition to anestrous (198). Central infusion of
T4 to THX and ovarectomized ewes given Silastic implants
of estradiol benzoate restored anestrous to these ewes.
This demonstrated that thyroxine acts centrally in the
brain in ewes to promote changes in GnRH and LH that
signal anestrous (194). Also, TR␣ has been colocalized in
46% of GnRH neurons in sheep (74). In rats, hyperthyroid
rats had 25% less LH on proestrous, showing depression
of the LH surges. Also, the amount of estrogens required
to initiate a LH surge was greater in hyperthyroid animals
(53). Hyperthyroid animals could, however, respond to
GnRH, suggesting that the pituitary was not a site of
action for thyroid hormone. The hypothalamus is more
plausible, since stimulation of the arcuate nuclei-median
eminence area (ARC-ME) resulted in hyperthyroid rats
secreting less LH than control rats (53). In rats devoid of
the thyroid gland, the synthesis and metabolism of LH
was not affected, but the secretion of LH was higher (52).
Propylthiouracil (PTU), a goitrogen, given transiently to
neonatal rats dramatically increases sperm production
and testis size in the adult rat. However, it leads to a
significant drop in GnRH-stimulated LH production. Gonadal feedback is enhanced in PTU-treated males resulting in chronically reduced circulating levels of LH and
follicle stimulating hormone (86).
3. Thyroid hormone effects on reproductive behavior
in rodents
Thyroid hormone elevation has also been shown to
have an adverse effect of reproduction in rodents (38,
114). Concomitant administration of T4 to ovariectomized
rats (38) and mice (114) treated with estrogens has been
shown to reduce lordosis, compared with ovariectomized
rodents that received estrogens alone. TR knock-out female ovariectomized and estrogen-treated mice deleted
for TR␤ isoforms showed higher lordosis than the
␤TRWT, suggesting that TR␤ may exert an inhibitory
influence on ER-controlled reproduction (36).
Because reproductive behavior is controlled by estrogens via the ER, it is possible that a reduction in ER
target genes such as OT, OTR, and PPE could be responsible for TR-mediated inhibition (149, 217). Indeed, injections of thyroid hormone to estrogen-treated female rodents lead to a decrease of OT mRNA in the PVN (39). Ex
vivo studies indicate that thyroid hormone upregulates
the human OT promoter fivefold through the composite
element containing an imperfect ERE located at ⫺148/
⫺172 bp upstream of the transcriptional start site (4).
TR␣1 protein can bind to this composite element and
interfere with the transcriptional induction by estrogens
(4). Thyroid hormone elevation also reduces the expression of another estrogen-induced gene in the VMH, the
PPE gene, which facilitates lordosis behavior (37).
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controls the timing of seasonal reproduction (78, 166,
167). In starlings, thyroidectomy of starlings prevented
the start of photorefractoriness and allowed for continuation of the breeding season (201). Thyroxine rise during
long days in European starlings is permissive for the
neuroendocrine shift to the nonbreeding season, which is
primarily dictated by day length (15). In the thyroidectomized male American tree sparrow, administration of T4
given intracerebroventricularly could restore all components of seasonality. Therefore, T4 was capable of acting
centrally to program already photostimulated male American male sparrows (203).
However, in mammals, both retinal photoreceptors
and the pineal gland are required for reproductive responses to photoperiod (120). Long days induced a drop
in lutenizing hormone (LH) in thyroid-intact ewes, though
thyroidectomy blocked this effect (112). However, thyroidectomy had no effect on the circadian pattern of
circulating melatonin or prolactin and the change that
occurs with the photoperiod (34). Thyroid hormones may
play a permissive role to photoperiod; they need to be
present at the end of the breeding season for anestrous to
commence. This critical period of neuroendocrine responses to thyroid hormone is late in the breeding season.
The minimal effective duration of exposure to circulating
levels of thyroid hormone was 60 –90 days beginning in
late December such that anestrous could develop in
spring (184). Do thyroid hormones also play a role in the
maintenance of anestrous once it develops? In ewes thyroidectomized (THX) just as they entered anestrous, the
timing of the LH rise late in anestrous, indicative of the
next breeding season, was the same as non-THX controls.
Therefore, although thyroid hormones play a role in initiating anestrous, they do not have any role in the maintenance of the anestrous and the timing of the subsequent
breeding season (185) in sheep. However, in the male
American tree sparrow, T4, T3, and reverse T3 given intracerebroventricularly could allow for thyroid hormonedependent photoperiodic testicular growth. The order of
potency was T4 ⬎ T3 ⬎ reverse T3 (203). These data
demonstrate that thyroid hormone may play slightly different roles in the maintenance of nonreproductive conditions in mammals and birds.
PATTERNS OF ER AND TR ACTIONS IN CNS
4. Modulation of estrogen action by thyroid hormone
in other species
5. Estrogen and thyroid hormone influence each
other’s nonreproductive functions
One of the most prominent effects of estrogens is to
promote mitosis in the uterine luminal epithelium,
stroma, and myometrium. The ability of hypothyroid rats
to increase the mitotic index in these uterine regions is
reduced compared with the euthyroid controls (87). This
diminished uterine response is not due to a shift in the
dose-response curve of the estrogen; rather, it is possible
that thyroid hormones have a direct effect on the uterus
such that it lowers its responsiveness to estrogens (57). In
pregnancy, despite lower levels of free T4 and free T3,
there is no rise in serum TSH (50). A similar absence of
TSH rise is seen in postmenopausal women receiving
estrogen replacement therapy (1). Although estrogen
treatment did not augment the serum concentrations of
TSH in euthyroid or untreated hypothyroid rats, it increased the suppressive T3 effect on serum TSH in hypothyroid animals. An increase in the number of pituitary
nuclear receptors for T3 was seen after estrogen treatment in rats, suggesting that the augmentation of the T3
effect may be due to increase in thyroid hormone receptors (51). In bone tissue, where estrogens promote bone
mineral density, hyperthyroidism has been shown to increase bone turnover and decrease bone density (49). In
the pituitary, there was a significant increase in weight
and total cellular RNA when ovariectomized rats were
given estrogens. This increase was inhibited by concomitant administration of T3 (216). Estrogen produces an
anorectic effect in rats, presumably by acting on the
hypothalamus. T4 given daily subcutaneously could antagonize the estrogen-mediated anorectic effect. It has been
proposed that this antagonism could be related to thyroxPhysiol Rev • VOL
ine’s reductive effect on blood glucose level and subsequent decrease in satiety (211).
In the gonadectomized rat, there is a subset of estrogen-driven physiological responses that require thyroid
hormonal interplay. These include the estrogen suppression of somatic growth and the effects of estrogens on
serum triglycerides. It also includes estrogenic suppression of LH secretion (negative feedback control) (48).
Surprisingly, this subset of T3-dependent estrogen responses also can be promoted by tamoxifen acting as an
estrogen agonist. Because T3 regulates growth and energy
metabolism, this may provide an interactive mechanism
for relating metabolic state to reproductive biology (48).
Thyroid hormone may also affect the clearance rate
of estrogen, although there are conflicting studies on this
theme. Hypothyroidism lowers the clearance rate of estrogen in women (102). In another study in women, hyperthyroidism increased the clearance rate of estrogen
(164). This is also predicted by data in the male Japanese
quail (165). Also, in hyperthyroid rabbits, the clearance
rate of estrogen is increased (187). In female Japanese
quail, thyroidectomy actually increased the clearance rate
of estrogen, contrary to the data in males (141). However,
in male cytomegalous monkeys, there was no change in
the clearance rate of estrogen on thyroid hormone treatment (18).
IV. ROLE OF PROMOTER AND CELL
SPECIFICITY IN DISTINCT
TRANSCRIPTIONAL RESULTS
How do differences in sequences bound by the ER
and TR isoforms explain their transcriptional differences
in the context of cell lines and promoters? Different hormone response elements are allosteric mediators of
receptor conformation. Therefore, hormone response
elements not only position receptors close to basal
transcription complexes but also serve to direct the mode
of regulation of the target gene (100). Studies with the
consensus vitellogenin A2 ERE, or the imperfect pS2,
vitellogenin B1 or oxytocin (OT) ERE show that the A2
was the most potent activator of transcription followed by
the OT ERE (205). DNase footprinting revealed that
MCF-7 proteins protected the OT and A2 EREs to a
greater extent than the pS2 or B1 EREs. Although the
receptor-interacting domains of the glucocorticoid receptor interacting protein 1 (GRIP) and SRC-1 bound effectively to ER␣, TIF2 was bound less by B1-bound ER␣ than
A2-bound ER␣, suggesting that allosteric modulation of
ER␣ conformation by different EREs influences coactivator recruitment (205).
Different isoform conformations within the cell
could also have an effect in the recruitment of coactivators. The TR␤2 isoform, for example, can bind p160 class
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In other species, thyroid hormone has also been
shown to modulate estrogen action. In the fish tilapia,
Oreochromis neoloticus, three distinct populations of
GnRH exist: the terminal nerve neurons in the forebrain,
the preoptic neurons, and the midbrain neurons. In castrated male tilapia, terminal nerve neurons express
GnRH, which is lowered by exogenous T4 treatment (138).
Interestingly, in the tilapia, the ontogeny of terminal nerve
neuron GnRH is concomitant with a decrease in T4 levels.
Sexually mature tilapia have low levels of thyroid hormones but high levels of terminal nerve GnRH (197). In
oviparous species such as the clawed toad, Xenopus laevis, metamorphosis is dependent on thyroid hormone
while vitellogenesis is strongly dependent on estrogens
(155). T3 could enhance ER␣ production and autoinduction and thereby enhance the estrogenic activation of
vitellogenin genes (156).
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Physiol Rev • VOL
of functions is indeed unique to a certain isoform and
cannot be substituted by the other isoforms. The experiments suggest that a variety of transcriptional outcomes
are possible depending on the combination of isoforms
present in the cell. These represent different flexible outputs, presumably to ensure homeostasis, in response to
the same external stimulus, i.e., presence of ligand. We
suggest that the isoforms have evolved to allow for different cell responses to the same signal, possibly by differential cross-talk between isoforms, to achieve neuroendocrine integration.
V. QUESTIONS UNANSWERED
A. Gene Duplication and Splice Variants
Gene duplication events and splice variations comprise likely origins for a number of hormone receptor
isoforms. Those isoforms, which are gene duplication
products, provide fascinating opportunities to compare
their physiological roles. Some current examples from
molecular endocrinology and neuronal biophysics suggest that diametrically opposite functions represent an
interesting possibility.
Gustafsson and colleagues’ (122) have made the case
that in peripheral organs ER␤ can oppose the actions of
ER␣. Neurobiological results both with behavioral end
points (126, 131–133) and during transfection studies
(189, 190, 192) support this point of view. With respect to
the CNS, both transcriptional end points in cell lines (189,
192) and behavioral results (36) offer the possibility of
markedly different TR␣ and TR␤ actions.
Among nuclear hormone receptors, PRs show the
wide diversity of actions of PR splice variants; that is,
under circumstances where PR␤ can act as a transcriptional activator, the smaller splice variant PR␣ can have
the opposite transcriptional effect (58, 193, 200). The
same can be illustrated for neuropeptides. OT and vasopressin are extremely similar nonapeptides, which almost
certainly represent gene duplication products. OT is well
known to promote affiliative behaviors (23, 142). In contrast, vasopressin promotes aggressive and territory-defensive behaviors (5, 46, 47). The electrophysiological
actions of neurotransmitter receptors make the same
case. For the transmitter norepinephrine (␣1 vs. ␣2 receptors), dopamine (D1 vs. D2 receptors), serotonin (5-HT1
vs. 5-HT2 receptors) and acetylcholine (M1 vs M2) receptors, markedly different and even opposing actions of
likely gene duplication products are the rule rather than
the exception. All of these examples constitute new opportunities for the fine-grained analysis of gene domains
governing specific neuroendocrine functions.
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of coactivators in the absence of the hormone and, therefore, mediate ligand-independent activation of target
genes. This is mediated by contacts in the unique NH2
terminus of TR␤2 and an internal interaction domain of
SRC-1 and GRIP-1 coactivators. These contacts are different from the LXXLL motifs that mediate hormone-dependent coactivator contacts and hence hormone-dependent
transcriptional activation (206). The NH2-terminal region
in the human PR (hPR) also modulates differential coactivator and repressor binding. The hPR exists as two
different isoforms: hPRA, which is a strong ligand-dependent repressor of transcription, and the hPRB, which is a
transcriptional activator in most cell and promoter contexts. An inhibitory domain (ID) present in the hPRA and
B is active only in the hPRA isoform, facilitating the
interaction between this isoform and the transrepressor
SMRT. This and the inability of the hPRA isoform to
engage coactivators could provide an explanation of the
differential activities of the isoforms (58). Also, the specificity of NCoR interactions with TR␤1 could be because
of the ability of this TR isoform to interact with a novel
NCoR interacting domain, called N3 which is specific for
TR and interacts very poorly with other nuclear receptors,
such as the RAR␣ (29). Possible differences in isoform
conformation may allow for tissue-specific expression.
For example, although a ERE oligonucleotide derived
from the rat 3-hydroxy-3-methylglutaryl CoA (HMG CoA)
reductase promoter confers estrogen responsiveness to a
heterologous promoter in several cell lines, the “natural”
HMG CoA promoter containing the ERE shows estrogen
induction in MCF-7 breast carcinoma cells but not in
hepatic cell lines (40).
Within the mammalian CNS, the physiological results
of hormones liganding to specific nuclear receptor gene
products, as well as the consequences of their interactions, may often depend on the details of neuronal or glial
localization; that is, the neuroanatomical pattern of expression of ER␣ is much different from that for ER␤
(175), and the TR␣ and TR␤ gene products likewise are
distributed differently both inside and outside the CNS
(19, 90, 101, 111). Most importantly, differential distributions that depended on promoter sequences active during
certain developmental stages may well underlie functional differences between nuclear receptor isoforms. In
turn, what about the requirement that for direct TR/ER
interactions they must be expressed in the same neuron?
Kia and colleagues (83– 85), using a sensitive double in
situ hybridization methodology, showed that a high percentage of forebrain neurons expressing ER also expressed TRs.
Why are isoforms of the nuclear receptors such as ER
and TR maintained in organisms? The differential colocalization of the isoforms is a clue that they have distinct
nonoverlapping functions. The phenotypes of the isoformspecific knock-outs also appear to indicate that a subset
PATTERNS OF ER AND TR ACTIONS IN CNS
B. Rapid Versus Slow Effects of Estrogen:
Two Separate Opportunities For Thyroid
Hormone Modulation?
Physiol Rev • VOL
greater transcription than either pulse alone (Fig. 6). Reversal of the order of addition, 17␤-estradiol in the first
pulse and E-BSA in the second pulse, did not have any
effect on transcription, showing that primary membrane
effects of estrogens are important to the nuclear effects of
estrogens. Addition of inhibitors to the signal transduction cascade in the first 2-h pulse along with E-BSA could
inhibit this synergism, demonstrating that activation of
protein kinases A and C plays a role in facilitation of
transcription by the nuclear 17␤-estradiol-bound ER. In
contrast, addition of these inhibitors in the second 2-h
pulse along with 17␤-estradiol did not reduce synergism.
This synergistic transcription could be blocked by concomitant addition of the nuclear ER antagonist ICI in
either the 20-min first or 2-h second pulse, demonstrating
⫺9
FIG. 6. E-BSA (10
M), given for only 20 min in the first pulse, can
potentiate transcription mediated by 17␤-estradiol (10⫺9 M) in the second pulse. SK-N-BE2C, a human neuroblastoma cell line, was cotransfected with ERE-luciferase, pSG-hER␣, and pSV␤gal plasmids, 48 h after
plating, using the Effectene reagent (Qiagen), according to the manufacturer’s protocol. The day after the transfection, 17␤-estradiol was
added using a two-pulse paradigm. Briefly, 17␤-estradiol (10⫺9 M) was
added to the media twice in a first pulse of 20 min and a second pulse of
2 h with these two pulses separated by an interval of 4 h. At the end of
the second 2-h pulse of 17␤-estradiol, the cells were washed free of
hormones, fresh media were added, and incubation continued for a
further 16 h. Cell lysates were then prepared using the Reporter lysis
buffer as per the manufacturer’s instructions (Promega), and the luciferase activity normalized to the ␤-galactosidase (␤-gal) activity for every
sample. The results (fold over control) are expressed as fold induction
over that achieved by the vehicle ethanol alone. Control condition:
17␤-estradiol (10⫺9 M) in the first pulse was followed by E-BSA (10⫺9 M)
in the second pulse (4th bar from left). Test of “potentiation” hypothesis:
E-BSA given in the first pulse was followed by 17␤-estradiol in the
second pulse (far right bar). Results (n ⫽ 4/treatment group) are represented as means ⫾ SE. Statistical analysis was done using one-way
ANOVA using Student-Newman-Keuls post hoc test to compare between
treatment groups. *P ⬍ 0.05 compared with all other treatment groups.
#P ⬍ 0.05 compared with the vehicle group. The control condition was
also greater to groups where E-BSA in the first pulse followed vehicle in
the second pulse and where 17␤-estradiol in the first pulse was followed
by vehicle in the second pulse. The activity in the control group equaled
that of 17␤-estradiol given in both pulses (data not shown). [Modified
from Vasudevan et al. (191).]
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Although the classical mode of estrogen action is via
the nuclear ER and leads to the modulation of transcription rate of estrogen-target genes, nonnuclear ER-mediated effects exist and are certainly prominent in neurophysiological literature (14, 80 – 82). These nonnuclear ER
effects are typically rapid and are mediated by a putative
membrane receptor (mER) and involve several signal
transduction pathways (79 and references therein). Membrane-limited estradiol conjugates are used to investigate
the membrane effects of estrogens. The MAPK has been
implicated as a downstream effector molecule in estrogen’s rapid action at the membrane in a neuroblastoma
cell line, the SK-N-SH cell line (196). In a cell line with
endogenous ER␣ (the breast carcinoma MCF-7 line), nongenomic mechanisms have been shown to activate MAPK
(73). Protein kinase C activation in growth plate chrondocytes is seen on administration of both 17␤-estradiol
and E-BSA (181). The rapid rise in intracellular free Ca2⫹
has been thought to be mediated by mERs (9, 115, 179).
The identity of the putative mER has been explored in
several studies. In Chinese hamster ovary (CHO) cells,
ER␣ expressed in a transient transfection assay gave rise
to a single transcript and functional protein expression in
both nuclear and membrane fractions (159). Microscopy
on fetal rat hippocampal neurons reacted with affinitypurified anti-ER␣ revealed abundant staining at the neurites. Also, incubation with antisense oligonucleotides directed against ER␣ reduced the immunostaining (28).
Although work on the nuclear ER and membrane ER
has been ongoing for several years, they have usually
been presented as alternate modes of estrogen action.
However, this laboratory has recently shown that these
two modes of estrogen action can in fact synergize. Therefore, it is possible that an early, preliminary administration of estrogen leads to rapid activation of signal transduction cascades at the membrane, and this facilitates
transcription by a later administration of 17␤-estradiol (191).
The study utilized a two-pulse hormonal schedule in
an ex vivo neuroblastoma cell culture model system. Such
a pulse regimen was shown to be previously effective in
investigating estrogen’s effects on cell division (67). The
first pulse (of either 20-min or 2-h duration) utilized EBSA, a membrane-limited estrogen conjugate designed to
limit estrogen actions to the membrane and the second
2-h pulse utilized 17␤-estradiol to stimulate transcription.
Transcription from a transiently transfected reporter
gene, consisting of three tandem consensus EREs linked
to luciferase, was then measured. A 20-min first pulse
using E-BSA and a second 2-h pulse utilizing 17␤-estradiol, separated by a hormone free interval of 4 h, showed
937
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VASUDEVAN, OGAWA, AND PFAFF
that in this model system the mER is similar to the nuclear
ER (191).
Could thyroid hormone modulation of ER gene transcription affect either or both of these modes of estrogen
action? Discrete targets of modulation impart specificity
to thyroid hormone action. Also, the mechanisms of stimulatory cross-talk between the ER and TR remain currently unknown and would be an avenue of future research.
C. Thyroid Hormone Elevation: Does It Signal
Cold Temperatures?
Physiol Rev • VOL
VI. SUMMARY
Transcriptional influences of enhancer complexes on
gene promoters can depend on complex interplay among
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Impetus to the examination of TR and ER cross-talk
was provided by a series of studies investigating the nature of the mammalian response to cold temperatures and
its dependency on thyroid hormone. Cold temperatures
are also correlated with seasonal shifts in photoperiod
(short day length), which in turn signal anestrous in several mammalian species. Cold exposure increases the
blood levels of thyroid hormones and TSH. Despite elevated inhibitory levels of thyroid hormones, it also causes
an increase of TRH mRNA in the PVN, demonstrating the
ability of cold to override inhibition by T3 (219). Such cold
stress also transiently elevated corticotropin releasing
hormone (CRH) levels, cortisol, and ACTH levels in rats
(55). Acute stressors such as uncontrollable foot shock in
rats also elevated brain T3 levels in both male and female
rats (54). The role of brown adipose tissue (BAT) in
adaptive nonshivering thermogenesis in mammals has
been well studied. Intracellular conversion of T4 to T3 is
required for the optimal thermogenic function of BAT
(16). In thyroidectomized rats, the acute thermogenic response of BAT to cold exposure (measured by increase in
mitochondrial GDP binding) was decreased (139). The
5⬘-deiodinase present in BAT catalyzes the formation of
T3 from T4 and is elevated by cold temperatures (161).
Such activation of the deiodinase saturates the nuclear TR
in the BAT, and it plays a central role in thyroid hormonedependent thermogenic response (25). Uncoupling proteins, named UCP1, -2, and -3 (based on sequence homology), are inner mitochondrial membrane proteins that
generate heat by uncoupling oxidative phosphorylation
from the respiratory chain. UCP2 is ubiquitously expressed while UCP3 is predominant in skeletal muscle
(163). Such thermogenesis may be adaptive nonshivering
thermogenesis that occurs in newborns and small mammals (rodents) in response to cold or may be due to
metabolic substrate excess. Hence, the UCPs play a central role in energy balance and cold acclimitization (162).
At cold temperatures, thyroid hormone-stimulated production of uncoupling protein (UCP1) is the major mechanism by which T3 produces the thermogenic effect in
BAT. It transcriptionally upregulates the rat UCP gene via
two TREs located at around ⫺2,300 bp situated ⬃27 bp
apart in the rat promoter. These two TRE bind both TR
homodimers and the TR-RXR heterodimer and synergize
to give an increase in transcription (157). Increases in
stability of the UCP transcript have also been shown to be
dependent on thyroid hormone (160). Hypothyroidism
(16) and inhibitors to the 5⬘-deiodinase (161) result in
both lower basal levels of UCP1 and in lower response on
stimulation with cold than euthyroid controls. UCP1 levels are both positively correlated with decreased temperatures and with overfeeding and negatively correlated
with starvation and genetic obesity. UCP1-deleted mice
do not show adrenergic adaptive nonshivering thermogenesis in response to cold or thermogenesis in response
to fatty acid supply (diet-induced thermogenesis) (118),
arguing for a central role for UCP1 in thermogenesis. The
roles of UCP2 and UCP3 are more unclear. The human
UCP3 promoter has a TRE (3), which may explain the
upregulation of this protein by thyroid hormone (61).
However, the UCP3-deleted mice had no phenotypic abnormality and had normal body temperature responses to
thyroid hormone and cold exposure (62). UCP2 mRNA is
increased by T3 injections in the BAT, white adipose
tissue (106), and the heart, suggesting that the thyroid
hormone control on basal metabolic rate may be mediated by UCP2 (95). The TR␤-selective ligand GC-1 could
restore the UCP1 level in hypothyroid mice but could not
restore core body temperature, indicating that TR␣1 may
be important in maintaining core body temperature. In
accordance, mice with a TR␣1 ablation have reduced core
body temperature compared with wild type (202). Therefore, thyroid hormone upregulation of all three UCP
mRNAs demonstrates a major role for isoform-specific TR
in thermogenesis.
Ovariectomized Syrian hamsters exposed to cold
showed decreased lordosis behavior and ER immunoreactivity in the VMH when treated with estradiol benzoate
after cold exposure (42). To test the hypothesis that cold
exposure may decrease lordosis in rodents, mice were
exposed to cold and then tested both for locomotor activity using running wheels and lordosis behavior. The
main effect of cold temperature exposure was to reduce
female approaches to the stud male, perhaps as a consequence of markedly decreased locomotor activity (26). If
it could be shown that access of T3 to TRs in nerve cells
of the female mouse forebrain would be increased by this
cold exposure, then it would be possible that TRs which
mediate thermogenesis in response to cold also “transduce” this environmental signal to neuroendocrine systems mediating sexual behavior.
PATTERNS OF ER AND TR ACTIONS IN CNS
We thank Drs. Y. S. Zhu, Chris Krebs, and Kami Kia for
helpful discussions during preparation of this review.
This work was supported by National Institute of Child
Health and Human Development Grant HD-05751.
Current address of N. Vasudevan: 208 Mueller Labs, Pennsylvania State University, University Park, PA 16802.
Address for reprint requests and other correspondence: D.
Pfaff, Box 275, The Rockefeller University, 1230 York Ave., New
York, NY 10021 (E-mail: [email protected]).
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transcription factors. Here we reviewed evidence that two
classes of transcription factors, TRs and Ers, can interact
in several different modes, which depend on TR isoform,
ER isoform, gene promoter, and cell type.
The in vivo data utilizing gene knock-out mice also
point to different roles for different isoforms for both TRs
and ERs. This is evident from the behavioral data where
the deletion of one isoform does not lead to the same
phenotype as deletion of the other isoforms. For ER␣
compared with ER␤, enough behavioral assays have been
completed to show that different patterns of ER gene
expression are required for different patterns of neuronal
function and behavior. We note that nonredundancy of
isoforms could explain their continued maintenance in
the mammalian genome. In turn, different molecular patterns of TR-ER interactions may underlie alterations in
behavior. The genes for nuclear receptors represent scientifically accessible causal routes for effects of small,
circulating molecules on behaviors of considerable biological import.
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