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Endocrin’os group (E.B., J.M.V., A.B., V.L.), CNRS UMR 319 Mécanismes du développement et de la Cancérisation Institut de Biologie de Lille, 59021 Lille Cedex France, Novartis Pharma AG (T.D., B.F.), K125 9–17, P11002 Basel, Switzerland Department of Biological Sciences (D.T.D.), Rutgers University, Piscataway, New Jersey 08855, Department of Anatomy and Cell Biology (J.E.A.), University of Toronto, Toronto, M5S 1A8 Canada Centre de Biologie Cellulaire du Développement (X.D.) Université des Sciences et Techniques de Lille Villeneuve d’Ascq, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Two orphan receptors, estrogen-related receptor-1 (ERR-1) and ERR-2 (5), were identified by low-stringency screening of cDNA libraries with a probe encompassing the DNA-binding domain of the human estrogen receptor (ER). Sequence alignment of ERR-1, ERR-2, and ER reveals an high similarity (68%) in the 66 amino acids of the DNA-binding domain. The putative ligand-binding domain, positioned between amino acids 295 and 521 of ERR-1, shows 63% identity when compared with ERR-2 and 36% to the ER. Analysis of the tissue distribution of these two orphan receptors in adult mice showed that ERR-2 is expressed at lower levels and in a more restricted pattern than ERR-1. Recently, it was shown that ERR-2 is expressed during the early stages of mouse chorion formation (6). In contrast, ERR-1 appears to be widely distributed although more abundant in the central nervous system (5). ERR-1 has been identified as a regulator of the SV40 major late promoter during the early-to-late switch of expression (7). Yang et al. (8) also recently showed that ERR-1 modulates the activating effect of estrogens on the lactoferrin promoter and suggested that ERR-1 may interact with ER through protein-protein interactions.
To search for a possible physiological role for ERR-1, we analyzed its expression during mouse embryonic development by in situ hybridization. Among complex expression patterns that will be published elsewhere (Bonnelye E., Vanacker J.-M., Spruyt N., Alric S., Fournier B., Desbiens X., and Laudet V., submitted), a striking relationship was noted between ERR-1 and skeleton formation. In this paper, we report our findings that ERR-1 mRNA is detected in ossification sites of the developing mouse embryo. In parallel, we show that ERR-1 is highly expressed in both human primary osteoblasic cells and osteosarcoma cell lines. Because little is known about the mechanisms of action of ERR-1, we have examined its transactivation functions. Our data demonstrate that ERR-1 binds to the SFRE (SF1-responsive element; TCAAGGTCA; Refs. 9 and 10) motif as a monomer and acts through this sequence as a transcriptional activator. The latter property is cell-type specific and occurs in osteoblastic cells among other cell lines. Seven SFRE-like sequences are present in the promoter of the gene encoding mouse osteopontin (OPN), a noncollagenous protein released in the bone matrix by osteoblasts and believed to play an important role in the formation and remodeling of bone tissues (11). By cotransfection experiments in rat osteosarcoma cells, we show that the OPN promoter is positively regulated by ERR-1. Taken together, our data suggest an important transcriptional regulatory role of the orphan receptor ERR-1 in bone metabolism.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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With respect to bones formed by endochondral ossification, ERR-1 was
detected by in situ hybridization in forelimb bones such as
the ulna, radius, and humerus at E17.5 (u, r, and h, respectively, in
Fig. 1A
). This expression is specific
since no signal was seen with the sense probe (Fig. 1F). As show by
picro-indigo-carmine labeling, which stains the ossification centers in
brown and the cartilage in blue, ERR-1 expression is restricted to the
bone in the midshaft and is not found in any zone of cartilage
including the hypertrophic zone (compare Fig. 1A and Fig. 1B). At
higher magnification of the ulna, the specificity of ERR-1 for the bone
[ossification zone (oz) in Fig. 1, C, D, and E] but not hypertrophic
cartilage, is clear.
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, K and L), in the hindlimb (femur; Fig. 1, G,
H, and I), and in the vertebrae (see va in Fig. 1, M and N).
Restriction of ERR-1 transcripts to areas of bone is clear when the
in situ hybridization is compared with the
picro-indigo-carmine histochemistry (oz in Fig. 1, G-J). ERR-1
hybridization is exclusively localized to bone in the midshaft
(diaphyses) and is not present in the cartilaginous epiphyses. Notably,
ERR-1 transcripts are also detected in the ossification centers of the
ribs at the same stage (not shown). To confirm that ERR-1 is not
expressed in cartilage cells, E11 limb bud cells were cultured for 24
or 96 h and then analyzed by in situ hybridization.
ERR-1 expression was not observed at either time point, although
cartilage nodules were clearly present by 96 h.
Notably, ERR-1 was also expressed in bones formed by intramembraneous
ossification, e.g. strong signal was seen in the maxillary
bones of the face (see ma in Fig. 1, O and P). Thus, ERR-1 mRNA levels
are high in all ossification centers during both intramembranous and
endochondral bone formation.
ERR-1 Is Expressed in Human Osteoblastic Cells
The expression of ERR-1 during in vivo bone development
led us to investigate the presence of its mRNA in cultured bone-derived
cells. Since the process of ossification involves many cell populations
that cannot be easily distinguished by in situ
hybridization, such an experiment may also provide a first
discrimination of the cell type displaying ERR-1 expression. We
performed RT-PCR experiments with primers designed to amplify
separately the three ER-related mRNAs: ERR-1, ERR-2, and ER itself
(Fig. 2A). Figure 2B shows that ER is expressed in
osteoblastic cell lines SaOs, TE85, and primary human osteoblastic
populations (NHB), but not in DAMI platelet cells, as expected. To
address further the specificity of ERR-1 for osteoblastic cells, we
screened other nonosteoblastic cells using TFIID as a positive control.
Consistent with our observation that ERR-1 is expressed in the
developing mammary gland (Bonnelye et al., submitted), T47D
(a mammary carcinoma cell line) cells contain ERR-1 and a weak amount
of ER (Fig. 2C). On the contrary, HeLa- and FLG 29.1 cells [a human
leukemic line that exhibits osteoclastic differentiation markers upon
TPA treatment (12)]) are devoid of ERR-1 mRNA.
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). In agreement with the data published by Petersson et
al. (6), we found that these cells express ERR-2. ERR-1 is also
present in ES cells, suggesting an early onset of its expression in the
developing embryo. Taken together, the detection of ERR-1 mRNA in
cultured cells is consistent with its expression in vivo, in
particular in bone-derived populations where it appears to be
restricted to osteoblastic cells.
ERR-1 binds to DNA as a Monomer on the SFRE Element
As a first step toward understanding the molecular effects of the
ERR-1 gene, we determined the DNA target of its product. ERR-1, like
all members of the nuclear receptor superfamily, can be expected to
bind to specific DNA sequences that contain the general core responsive
element (AGGTCA). Electrophoretic mobility shift analyses (EMSAs) were
performed using in vitro translated ERR-1 product and
various synthetic oligonucleotides containing the core element as
probes. These included palindromic sequences (HREpal, see Fig. 3A, and estrogen responsive element), direct repeats
motifs [response elements to the thyroid hormone-, the vitamin
D3- or the retinoic acid receptor; see Glass (13) for a
review], or monomeric half- sites (response elements to Rev-erb, SF-1,
or NGF1B) in the presence or absence of unlabeled oligonucleotides as
competitors (Fig. 3 and data not shown). We found that ERR-1
specifically binds to the SFRE probe (SF1/FTZ-F1 responsive element;
TCAAGGTCA; Refs. 9 and 10), as illustrated in Fig. 3B. ERR-1-programmed
reticulocyte lysate (lane 2) but not unprogrammed lysate (lane 1) forms
a single retarded complex with a SFRE probe. The recognition was
specific since complex formation was inhibited by an excess of
unlabeled homologous- (SFRE; lanes 3 and 4), but not of related but
distinct oligonucleotides (lanes 5 to 10; sequences in Fig. 3A). Other
receptors have been described to bind to a single element
(e.g. SF-1/FTZ-F1, NGF1B, Rev-erb ... ; see Refs. 13 and
14 and references therein). The sequence immediately 5' of the core
element is, in this case, assumed to mediate the specificity of binding
of each type of receptor (9, 13). We therefore assayed the requirement
of ERR-1 toward the nucleotides present upstream of the core element
(Fig. 3b). Addition of excesses of NGRE (NGF1B responsive element; Ref.
9; lanes 5 and 6) or of the RevRE (Rev-erb responsive element; Refs. 15
and 16 and data not shown) to the binding reaction did not affect the
fixation of ERR-1 on the SFRE. Mutations inside the core element (as
present in competitor SFREm; lanes 7 and 8) impaired the ability to
compete. Finally, the palindromic hormone responsive element (HREpal;
lanes 9 and 10) did not interfere with ERR-1 binding. The formation of
the ERR-1-SFRE complex is thus strikingly dependent upon the integrity
of the TCA sequence located 5' of the core element.
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). The resulting construct (
96ERR-1) was (after sequencing)
in vitro translated and used in EMSA (Fig. 3C). 96ERR-1
forms a complex with SFRE that migrates faster than wild type (wt)
ERR-1-SFRE. Combination of wt ERR-1 and 96ERR-1 in the binding
reaction produces two distinct complexes and no intermediary one, which
would be expected in the case of dimer binding. ERR-1 is thus a new
example of monomer binding orphan receptor.
Transcriptional Activity of ERR-1
As the ERR-1 gene product binds to a specific DNA sequence, we
have tested its ability to regulate transcription. To this end, SFRE
oligonucleotides were cloned as pentamers in front of the
HSVtk promoter and a chloramphenicol acetyltransferase (CAT)
reporter gene. After sequencing, resulting constructs were
cotransfected in HeLa cells with varying amounts of pSGERR-1 plasmid
(Fig. 4A). Reporter gene expression from pSFREtk was
enhanced in a dose-dependent manner by cotransfection of ERR-1-encoding
plasmid. As a positive control, the FTZ-F1 group member xFF1r acts
through the same sequence. It should be noted that a high (10-fold)
reporter-effector ratio was required to reach a maximal effect.
Stimulation by ERR-1 requires the presence of SFRE sites in the
plasmid, since no transactivation was observed with the minimal
promoter supplemented with the nonbinding HREpal sequence (plasmid
pHREptk). We also tested the ability of several other cell lines to
support ERR-1-induced transactivation. As shown in Fig. 4B, ERR-1
exerts a pleiotropic activity, ranging from high (HeLa cells) to
low or no (simian COS1, human HepG2 cell) stimulation capacity. Human
NB-E and rat FREJ4 cell lines supported ERR-1 transactivation to an
intermediate level. This phenomenon cannot be interpreted in terms of
differences of expression of the transfected ERR-1 in the various cell
lines as verified by EMSA and examplified in Fig. 4C. Transfection of
ERR-1 in HeLa cells (lane 2) resulted in a SFRE-protein complex that
was undetectable in mock-transfected cells (lane 1). This complex arose
in comparable amounts when NB-E (lane 4) or COS cells (lane 6) were
transfected even though the latter cells already express endogenous
ERR-1 (see lane 5). We therefore conclude that the transcription
activation potential of ERR-1 exhibits strong cell type
specificity.
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).
Again, no effect of ERR-1 was observed on the pHREtk vector (data not
shown).
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shows that ERR-1 positively regulates the OPN promoter
in a dose-dependent manner, thus suggesting a physiological relevance
of ERR-1 expression in bone cells. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Bone formation and turnover are known to be under the control of
many hormones and cytokines, among which estrogens play a critical
role, as exemplified by the accelerated bone loss leading to
osteoporosis at menopause. The low concentration of ER in osteoblasts
(200–1000 molecules per cell; Refs. 21–23) relative to reproductive
tissues (10000–100000 molecules per target cell) is consistent with
the hormone having a more limited number of direct actions on the
skeleton. It is rather commonly believed that most of the known effects
of estrogens in bone may be mediated by the action of specific growth
factors and cytokines (24, 25). It is also possible that ERR-1 plays a
role in this complex series of events by regulating estrogen response.
Interestingly, the level of mRNA expression of ERR-1 is much higher
than of ER, as determined both by RT-PCR (Fig. 2) and in
situ hybridization experiments (not shown). Whether this reflects
the amount of protein available inside the cells remains to be
established. A detailed study of the level of ER and ERR-1 mRNA and
proteins during bone differentiation is therefore of particular
importance in this context. Although highly related to the ER, ERR-1 is
unlikely to bind estrogen, since its transcriptional activity seems to
be ligand-independent (see below). In this respect, an indirect
regulatory pathway seems likely, consistent with the in
vitro demonstration of a physical interaction between ER and ERR-1
and the suggestion that, in given promoter contexts, ERR-1 may enhance
the transcriptional effects of ER (8). The two factors could thus
regulate overlapping gene networks. Whether such an effect takes place
in osteoblastic cells constitutes an interesting possibility that
remains to be addressed. This awaits the identification of common
target genes of ER and ERR-1, expressed during bone formation
(e.g. in osteoblasts).
Osteoblasts are very active cells that synthesize many different products as type I collagen (26), osteocalcin (27), osteopontin (28) and bone sialoprotein (29, 30). Any of these genes could be candidates for ERR-1 target genes. Indeed, we found that the osteopontin promoter, which contains seven SFRE-like elements, positively responds to ERR-1 in transient cotransfection experiments, suggesting an in vivo regulation of osteopontin by ERR-1. In support of this hypothesis, there is a temporal correlation between the onset of osteopontin expression (E16; 31 and ERR-1 (E15.5). Taken together with our expression data, these results suggest that ERR-1 may play a key role in bone development. This could be achieved through direct promoter regulation and/or by interference with the estrogen-controlled pathway, through interaction with ER.
Relations of ERR-1 with Other Nuclear Receptors
The SFRE motif was first described as the response element of the
members of the SF1/FTZ-F1 subfamily of nuclear receptors. These orphan
receptors bind to DNA as monomers, and it has been demonstrated that,
when they do so, the conserved T and A boxes (which lie downstream of
the Zn-fingers) play an important role in the recognition of the
5'-extension of the core motif (9). It is interesting to note that in
these critical regions, ERR-1 and SF1 harbor a high level of sequence
identity (adapted from Ref. 9 in our Fig. 6) that allow
to define a TCA consensus. In contrast, these T and A boxes are
divergent from those of NGF1B or Rev-erb
. This suggested that
SF-1/FTZ-F1 and ERR-1 could recognize common sequences, distinct from
the ones bound by NGF1B and Rev-erb. In agreement with this, we
indeed found that ERR-1 binds specifically to the SFRE motif, an
interaction that is not competed by NBRE or RevRE sequences. Analysis
of the T and A box sequences in the work mentioned above (9) also
predicted monomer binding for ERR-1, a feature confirmed in our
experiments. However, the behavior of ERR-1 in the presence of repeats
of SFRE has not been investigated, and it remains possible that, as
with Rev-erb on the RevDR2 elements (32), ERR-1 could homodimerize on
specific direct repeats or heterodimerize with RXR as is the case for
several other nuclear receptors.
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The behavior of ERR-1 is different from that described for its close relative ERR-2, which binds as a homodimer to the estrogen responsive element and appears to be transcriptionally inactive on this element (6). Although the result obtained for transactivation may be also explained by a cell-specific action of ERR-2, the difference in DNA binding specificities of these two strongly related factors appears provocative. ERR-1 and ERR-2 display high sequence identity in the C domain as well as the T box, whereas differences exist in the A box that might be responsible for preference toward their target DNA site. On the other hand, it is not excluded that, though binding to the ERE, ERR-2 might also recognize another sequence, such as the SFRE. Altogether, both ERRs may interconnect with ER-regulatory pathways, through DNA binding on ERE (i.e. ERR-2) or through protein interactions (i.e. ERR-1).
The action of ERR-1 through the SFRE element emphasizes the promiscuous behavior of many members of the nuclear receptor superfamily. Indeed, our study demonstrates that several unrelated groups of orphan receptors are able to bind and regulate transcription through the SFRE site. Until now, the SFRE site has been demonstrated to be a target only for members of the SF1 group. These orphan receptors are expressed in steroidogenic tissues as well as in gonads and appear to be important for the regulation of the endocrine cascade that controls gonad differentiation and sex determination. Our study extends the number of orphan receptors and tissue types for which the SFRE element is a key determinant. The expression territories of SF1 and ERR-1 are partly overlapping, but no competition or synergy in transcriptional regulation by both proteins could be observed (discussed in Bonnelye et al., submitted). Nevertheless, we cannot exclude that in particular tissues or physiological situations, a cross-talk between SF1 and ERR-1-mediated transcriptional regulation may occur. Interestingly, the GCNF orphan receptor binds as a dimer to a DR0 element (38). This site harbors the TCAAGGTCA motif, and here again we cannot exclude a possible cross-talk between GCNF, ERR-1, and SF1 on given response elements.
Our results give the first hints as to the possible in vivo functions of the ERR-1 orphan receptor. Expression studies as well as in vitro experiments suggest that ERR-1 may play an important role in the formation of the skeleton. ERR-1 could act independently and/or intervene in regulation pathways controlled by other members of the nuclear receptor superfamily. These interconnections may be necessary for the differential regulation of a given set of target genes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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RT-PCR
Total RNA was extracted from confluent cells using the Quiagen
kit for total RNA preparation from cell cultures (Quiagen, Chatsworth,
CA). Samples of total cellular RNA (5 µg) were reverse-transcribed
using the first strand synthesis kit of Pharmacia Biotech (Uppsala,
Sweden).
PCR was performed to generate amplified fragments of ERR-1, ERR-2, and ER. The primers used, located in different exons, were as follow:
ER upstream: AGT ATG GCT ATG GAA TCT GCC A
ER downstream: TTT CAA CAT TCT CCC TCC TCT
ERR-1 upstream: TGG TCC AGC TCC CAC TCG CT
ERR-1 downstream: TGA GAC ACC AGT GCA TTC ACT G
ERR-2 upstream: TCA AGT GCG AGT ACA TGC TT
ERR-2 downstream: GAA ATC TGT AAG CTC AGG TA
TFIID upstream: ACA GGA GCC AAG AGT GAA GAA
TFIID downstream: CCA GAA ACA AAA ATA AGG AGA
The PCR reaction mixture contained cDNA (10 µl), 2 µl dNTP mix (10 mM), 1x PCR buffer with Mg++, 20 pmol primers and 5 U of Taq polymerase from Boehringer (Mannheim, Germany). Reactions were carried out in a PCR apparatus Master cycle 5330 plus from Eppendorf. One PCR cycle consisted of denaturation for 30 sec (94 C), annealing for 30 sec (60 C), and extension for 30 sec (72 C). Each PCR reaction consisted of 30 cycles.
In Situ Hybridization
E11, E15.5, and E17.5 mouse embryos were fixed at 4 C for
16 h in 4% paraformaldehyde in PBS containing 5 mM
MgCl2, dehydrated, and embedded in paraffin.
Five-micrometer-thick sections were transferred to
3-aminopropyltriethoxysilane (TESPA; Aldrich, Milwaukee, WI) coated
slides and dried at 42 C for 2 days. In situ hybridization
was performed as described (39) using 35S-labeled antisense
RNA probe synthesized from a full-length mouse ERR-1 cDNA cloned in
Bluescript II KS (Stratagene, La Jolla, CA). To avoid any
cross-hybridization with ERR-2 mRNA, hybridization was performed with
stringent conditions (60 C). As a negative control, adjacent sections
were hybridized with a 35S-labeled sense RNA probe
synthesized from the same template. At the end of the in
situ hybridization protocol, nuclei were stained with bisbenzimide
and appeared blue under fluorescent light.
Histological Staining
The sections were treated with toluene, hydrated, and stained
with Nuclear Red for 20 min. They were rinsed, stained with
picro-indigo-carmine for 15 min, and rinsed with 0.3% acetic acid.
Finally, the sections were dehydrated with ethanol and treated with
toluene before mounting under a coverslip.
Transfections
Transient transfections were performed according to the calcium
phosphate precipitation method (40), using plasmid pSG5 as a carrier up
to 6 µg of total DNA per sample. Cells were collected 48 h after
transfection. CAT activities were determined and normalized to the
total amount of protein present in the cell lysates.
ROS17/2.8 cells were plated at 50% confluency in Hams F12/Dulbecco MEM in 100-mm plates. At 80% confluence DNA-mediated gene transfer was performed using lipofectamine from GIBCO-BRL (Basel, Switzerland). Transfection time was 4 h and total DNA amount of 8 µg consisted of the reporter plasmid (pSFREtk) with respectively 4- and 10-fold ERR-1 expression vector. One microgram of pCMV ß-gal expression vector was used as an internal control for transfection efficiency. The cells were then cultured for another 48 h and harvested, and CAT activity was analyzed in cell extracts (prepared by three freeze-thaw cycles) using a procedure described previously (Gorman et al., 1982). Samples were run for 1 h on TLC plates (Merck, Darmstadt, Germany), and radioactivity was measured by a PhosphorImager (Molecular Dynamics, Sunnyvale, CA). ß-Galactosidase was determined in cell extracts using the Promega kit based on a technique described by Rosenthal (42). CAT enzyme results are normalized by ß-galactosidase activity.
Plasmid Constructions
Mouse ERR-1 cDNA (a generous gift of Vincent Giguère) was
subcloned in the EcoRI site of plasmid pSG5. To clone HRE
sequences upstream from the minimal tk promoter, synthetic
oligonucleotides containing SFRE or HREpal sites (see sequences on Fig. 3A) and flanked by BamHI and BglII sites were
phosphorylated and ligated. Pentamers were isolated in 5%
polyacrylamide gel and inserted into the BamHI site of
plasmid pBL Cat5 (43). For plasmid 96ERR-1, PCR was performed with
specific oligonucleotides. The resulting fragment was sequenced and
then reinserted in pSG5 plasmid.
Electrophoretic Mobility Shift Assays
Probes were labeled with T4 polynucleotide kinase in the
presence of [
-32P] ATP. In vitro
translations were performed using the TNT kit (Promega, Madison, WI)
and pSG5 either wild type (unprogrammed) or directing ERR-1 derivatives
expression. Binding reactions were performed as described (44), using 2
µl of translation reaction.
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ACKNOWLEDGMENTS |
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The authors are indebted to Katja Sucker for technical help. pOPN-Luc plasmid was constructed by Xiaojia Guo. We thank Dominique Stéhelin for support, Vincent Giguere for ERR-1 expression vector and sharing unpublished results, and Christine Dreyer for xFF1r expression vector. Nicole Devassine and Marie-Christine Bouchez performed excellent secretarial assistance.
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FOOTNOTES |
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This work was supported by Association pour la Re-cherche sur le Cancer (ARC), Centre Nationale Recherche Scientifique, and Institut Pasteur de Lille. E.B. is supported by a grant from ARC. J.E.A. is funded by MRC of Canada (Grant MT12380).
Received for publication July 8, 1996. Revision received February 28, 1997. Accepted for publication March 19, 1997.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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B Horard, A Castet, P-L Bardet, V Laudet, V Cavailles, and J-M Vanacker Dimerization is required for transacti |
