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Endocrinology Vol. 144, No. 10 4272-4275
Copyright © 2003 by The Endocrine Society

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Inhibition of Oxytocin Receptor and Estrogen Receptor-{alpha} Expression, But Not Relaxin Receptors (LGR7), in the Myometrium of Late Pregnant Relaxin Gene Knockout Mice

Andrew L. Siebel, Helen M. Gehring, Irna Grace T. Reytomas and Laura J. Parry

Department of Zoology and Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3010, Australia

Address all correspondence and requests for reprints to: A. L. Siebel, Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: a.siebel{at}hfi.unimelb.edu.au.

Abstract

This study used relaxin (RLX) gene knockout mice (Rlx-/-) to investigate the effects of RLX on myometrial oxytocin receptor (OTR) and estrogen receptor (ER)-{alpha} gene expression in late gestation. We also characterized the temporal expression of the RLX receptor (LGR7) and demonstrated gene transcripts in the myometrium of Rlx+/+ and Rlx-/- mice. There was a significant (P < 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 post coitum (pc) compared with earlier stages of gestation, but no differences between Rlx+/+ and Rlx-/- mice. Myometrial OTR mRNA levels increased at the end of gestation in Rlx+/+ but not Rlx-/- mice. ER{alpha} gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation. In contrast, ER{alpha} mRNA levels were significantly lower in Rlx-/- mice on d 14.5 and 18.5 pc. These data show that the increases in myometrial OTR and ER{alpha} expression in late pregnant Rlx+/+ mice were attenuated in Rlx-/- mice. The effects of RLX on OTRs are probably mediated via activation of ER{alpha}. Finally, RLX receptor expression in the myometrium of Rlx-/- mice did not differ from wild-type mice, implying that RLX does not influence expression of its receptor.

THE OXYTOCIN RECEPTOR (OTR) is an important contractile-associated protein that is highly up-regulated in the myometrium at term in many species. Activation of this receptor after ligand binding induces uterine contractions and leads to delivery of the young (1). In rodents, the characteristic increase in myometrial OTRs at the end of gestation is primarily influenced by estrogen (2). Treatment of late pregnant rats with tamoxifen, a specific estrogen receptor antagonist, delays the increase in uterine OTRs (3). The increase in OTRs is preceded by an up-regulation in estrogen receptors (ERs), which is also mediated by estrogen (4). The predominant ER transcript in the rodent uterus is ER{alpha}, although transcripts for both splice forms of the ERß are expressed at a very low level (5, 6). Studies in the ER{alpha} gene knockout mouse demonstrated that ER{alpha} is essential for the induction of OTR binding in the brain (7) and suggests an important association between these two receptors.

Recent evidence suggests that the peptide hormone relaxin (RLX) may interact with OTRs. RLX is primarily synthesized by the corpus luteum or placenta, with highest plasma concentrations observed during the second half of gestation in most species (8). RLX decreases oxytocin-stimulated myometrial contractions by inhibiting phosphatidyl-inositolphosphate turnover and suppressing phospholipase-C (9). An inhibitory effect of RLX on oxytocin binding to the OTR has also been demonstrated in human uterine smooth muscle cells (10).

RLX is capable of ligand-independent activation of ERs in the rat uterus (11). A specific ER antagonist, ICI 182,780, blocks the uterotrophic effects of RLX in immature ovariectomized rats. Pillai et al. (11) suggested that RLX initiates signal transduction pathways that lead to the activation of nuclear ERs. Thus, an alternative regulatory effect of RLX on uterine OTRs may be stimulatory via activation of the ER{alpha}.

Studies in RLX gene knockout mice (Rlx-/-) demonstrated that although females give birth to live young without any apparent sign of dystocia, they have abnormal cervical and vaginal morphology, no elongation of the pubic symphysis, and poor mammary gland and nipple development (12). This study used the Rlx-/- mouse to investigate the effects of RLX on myometrial OTR and ER{alpha} expression in late pregnancy. A second aim was to characterize the temporal expression of the recently discovered RLX receptor (13), a leucine-rich repeat G protein-coupled receptor (LGR7), in the myometrium of pregnant mice and assess whether or not LGR7 expression is modified in Rlx-/- mice.

Materials and Methods

Animals
All experiments were conducted with approval from the Animal Experimentation and Ethics Committee at the Howard Florey Institute (University of Melbourne, Melbourne, Australia). Tissues were obtained from time-mated C57/Blk6J Rlx+/+ mice (Howard Florey Institute) at five stages of gestation [d 7.5, 10.5, 14.5, 17.5, and 18.5 post coitum (pc)] and Rlx-/- littermates on d 14.5 and 18.5 pc (n = 5–6 per stage). The uterus was dissected immediately after anesthetic overdose; the myometrium was separated from the endometrium and placenta and snap-frozen. Total RNA was isolated from approximately 100 mg myometrium using RNAWiz (Ambion, Adelaide, South Australia). After isopropanol precipitation, the RNA pellet was resuspended in H2O treated with RNA Secure (Ambion) and stored at -80 C.

RT-PCR
First-strand cDNA was synthesized from 5 µg total RNA, using 0.5 µg/µl random hexamers and 100 U Superscript II RNase H-reverse transcriptase (Invitrogen, Mulgrave, Victoria, Australia) in a total volume of 20 µl. Expression of murine LGR7 and ERß gene transcripts in the myometrium of both Rlx+/+ and Rlx-/- mice was then assessed by RT-PCR with gene-specific primers designed from the mouse ERß and LGR7 sequences. The latter was obtained from a basic local alignment search tool (BLAST) search using the human LGR7 sequence (13). Two microliters of the cDNA template were used in a touch-down PCR (annealing temperatures, 58–52 C) with 0.2 U Taq DNA polymerase (Promega, Annandale, New South Wales, Australia) and 100 ng/µl degenerate oligonucleotide primers (GeneWorks, Adelaide, Australia).

LGR7, OTR, and ER{alpha} mRNA expression
Real-time PCR was used to quantify LGR7, OTR, and ER{alpha} gene expression in the myometrium. For each sample, 1.5 µg total RNA was reverse transcribed in a 30-µl reaction containing 2 µM random hexamers and 1.25 U/µl Multi-Scribe reverse transcriptase (Applied Biosystems, Scoresby, Victoria, Australia). A separate reaction mix used 30 ng total RNA from each sample and a series of myometrium RNA dilutions (100–0.001 ng) for the endogenous reference 18S ribosomal RNA (18S) PCRs and to generate the 18S standard curves, respectively. First-strand cDNA synthesis for all samples was carried out simultaneously at 42 C for 45 min. All PCRs were carried out in triplicate using 96-well optical reaction plates, in 25-µl volumes consisting of 1xTaqMan Universal PCR Master Mix (Applied Biosystems), 0.8 µM forward and reverse primers, 0.4 µM probe, and 2.5 µl cDNA template. Mouse-specific LGR7, OTR, and ER{alpha} primers and FAM (6-carboxy fluorescein)-labeled probes (Keystone Division, Biosource International, Foster City, CA) were designed using Primer Express and span introns to eliminate false positives from contaminating genomic DNA. Real-time PCR was carried out in an ABI PRISM 7700 Sequence Detector (Applied Biosystems, Victoria, Australia) using the relative CT standard curve method, where CT is the cycle number at which DNA amplification is first detected. Expression of the target genes is calculated by dividing target gene log CT by the 18S log CT values. The intraassay coefficient of variation was less than 1% using the same 18S standards in four separate assays and the interassay coefficient of variation was 2.4%. Data were log transformed before analysis by one-way ANOVA (SPSS 10.0, SPSS, Inc., Chicago, IL); the least squares difference method tested for significant differences at the 95% confidence level.

Results and Discussion

LGR7 expression in murine myometrium
A gene transcript for LGR7 was detected in the myometrium of both Rlx+/+ and Rlx-/- mice at all stages of gestation examined. Expression of the RLX receptor appears to be higher in the earlier stages of gestation (Fig. 1AGo).



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  		FIG. 1. Analysis of LGR7 and ERß gene transcripts in the myometrium of wild-type (+/+) and RLX deficient (-/-) mice at five stages of gestation by RT-PCR. A, Primers were designed to the full-length variant of the murine LGR7 sequence. B, Primers spanned the splice variant and hence, both the full-length (450-bp) and truncated (320-bp) variants of LGR7 are detected. C, Primers located upstream of the alternative splice site in the ERß sequence, yielding a single (250-bp) amplicon. D, Glyceraldehyde-3-phosphate dehydrogenase PCR as a control for quality of first-strand cDNA synthesis. *, No template control. MW, 100-bp marker.

 
Quantitative analysis confirmed that there was a significant (P < 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 pc compared with earlier stages of gestation (Fig. 2AGo). These data support the hypothesis that RLX binds to receptors in the myometrium and inhibits uterine contractions in the early stage of gestation. High affinity RLX binding sites have previously been localized to the myometrium of rats, pigs (8), and the marmoset monkey (14). RLX also inhibits spontaneous and oxytocin-stimulated uterine contractions (15, 16) and is thought to prevent premature birth in some species. In this study, we report a down-regulation in myometrial LGR7 gene expression at term in mice. This presumably leads to an increase in uterine responsiveness to contractile-associated proteins. Despite this potential role for RLX in the mouse myometrium, there is no evidence for the premature onset of parturition in RLX-deficient mice (12).



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  		FIG. 2. Myometrial LGR7 (A), OTR (B), and ER{alpha} (C) mRNA concentrations at five stages of gestation in wild-type mice. Values are the ratio of target gene/18S (mean ± SEM, n = 5). *, P < 0.01 vs. d 10.5 and d 14.5 pc; **, P < 0.05 vs. d 7.5 and 10.5 pc; ***, P < 0.025 vs. all other stages of gestation.

 
There was no significant (P = 0.37) difference in LGR7 mRNA levels between Rlx+/+ and Rlx-/- mice at the two stages examined (Fig. 3AGo). Earlier binding studies suggested RLX causes a down-regulation of its own receptor in the rat myometrium at term (17). However, relatively high doses of exogenous RLX were used in these studies. In the Rlx-/- mouse, a decrease in LGR7 mRNA levels occurs in late gestation, despite the absence of circulating RLX. Our data, therefore, do not support the hypothesis that RLX regulates its own receptor.



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  		FIG. 3. Comparison of myometrial LGR7 (A), OTR (B), and ER{alpha} (C) mRNA concentrations between wild-type (Rlx+/+) and RLX-deficient (Rlx-/-) mice on d 14.5 and 18.5 pc. Values are the ratio of target gene/18S (mean ± SEM, n = 5/6 as indicated above each bar). *, P < 0.05 vs. Rlx+/+; **, P < 0.02 vs. Rlx+/+.

 
Recent studies identified a splice variant in the human LGR7 (18). This variant lacks 34 amino acids in the N terminus of the coding region and is not activated by RLX. In the present study, we used two combinations of LGR7 primers, one to include the putative murine splice variant and the other not. Figure 1BGo demonstrates a full-length LGR7 transcript (450-bp) and truncated splice variant (320-bp) in the murine myometrium. The second PCR was performed using the same conditions as the first (Fig. 1AGo) but was not as efficient. Therefore, gene transcripts were only detected in the earlier stages of gestation, with no differences between the Rlx+/+ and Rlx-/- mice. At present, no function has been attributed to the LGR7 splice variant, but it may form part of an inhibitory mechanism to reduce the effects of RLX in this tissue.

OTR and ER{alpha} mRNA expression
OTR mRNA expression in the myometrium of Rlx+/+ mice increased on d 14.5 pc and was significantly (P < 0.025) higher compared with all other stages of gestation on d 18.5 pc (Fig. 2BGo). This is similar to previous studies in the mouse (19) and is indicative of an increase in uterine responsiveness to oxytocin. In contrast, myometrial OTR mRNA concentrations were significantly (P < 0.02) lower in Rlx-/- mice on both d 14.5 and 18.5 pc compared with Rlx+/+ mice (Fig. 3BGo). On the basis of earlier reports in the literature (9, 10), we anticipated that myometrial OTR expression would increase earlier than d 17.5 pc in the RLX-deficient mice. However, this was not the case. In the absence of RLX, there was no marked increase in myometrial OTRs. Although an inhibitory effect of RLX on oxytocin-stimulated uterine contractions has been shown, this involves disruption at the level of the intracellular signaling pathway (9). As yet, there is no evidence of a direct interaction (stimulatory or inhibitory) between RLX and the OTR gene itself.

The present study also examined myometrial ER{alpha} gene expression, because there are links between ER activation and regulation of OTRs (7). Myometrial ER{alpha} gene expression increased significantly (P < 0.05) on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation (Fig. 2CGo). However, there was no increase in ER{alpha} gene expression in the myometrium of Rlx-/- mice on d 14.5 or 18.5 pc; ER{alpha} mRNA levels were significantly (P < 0.05) lower compared with Rlx+/+ mice (Fig. 3CGo).

A direct effect of RLX on uterine ERs was recently reported by Pillai et al. (20). Treatment of immature ovariectomized rats with porcine RLX caused a decrease in uterine ERß 1 and ERß 2 mRNA levels within 6 h. Interestingly, RLX had no effect on uterine ER{alpha} expression in these rats. The implication of these findings, as proposed by the authors (20), is that a RLX-induced down-regulation of ERß mRNA may be a prerequisite for estrogen and other ER activators to exert their effects on target tissues. Several groups have demonstrated that both ERß 1 and ERß 2 inhibit ER{alpha}-mediated transcriptional activity or signaling (21, 22). In the Rlx-/- mice, there is a reduction in ER{alpha} expression compared with the wild-type mice. This might be due to a RLX-induced down-regulation of ERß. However, preliminary PCR data do not support this view, showing no differences between Rlx+/+ and Rlx-/- mice (Fig. 1CGo).

In summary, this study demonstrated that the up-regulation in OTR and ER{alpha} expression observed in the myometrium of late pregnant Rlx+/+ mice was attenuated in Rlx-/- mice. We suggest that the effects of RLX on OTRs are probably mediated via activation of ERs but emphasize that this may be species and/or tissue specific. Our data also showed that RLX positively influences myometrial ER{alpha} expression in pregnant mice. Finally, we report the temporal expression of RLX receptors in the murine myometrium and show that a down-regulation in LGR7 mRNA levels occurs in late gestation. RLX receptor expression in the myometrium of Rlx-/- mice did not differ from wild-type mice, implying that endogenous RLX does not influence expression of its receptor.

Acknowledgments

We thank Gillian Bryant-Greenwood and Elaine Unemori for advice with this study. We also thank Geoff Tregear for providing laboratory facilities and the RLX knockout mice.

Footnotes

This work was supported by an Australian Research Council (ARC) Linkage Grant (LP0211545). L.J.P. received an ARC QEII Research Fellowship.

Abbreviations: ER, Estrogen receptor; OTR, oxytocin receptor; pc, post coitum; RLX, relaxin; 18S, 18S ribosomal RNA.

Received May 1, 2003.

Accepted for publication July 16, 2003.

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