Regulation of expression of the retinoic acid-synthesising enzymes retinaldehyde dehydrogenases in the uteri of ovariectomised mice after treatment with oestrogen, gestagen and their combination
Ralph Rühl A B F , Britta Fritzsche A C , Julien Vermot D , Karen Niederreither D E , Ulrike Neumann A , Anja Schmidt C , Florian J. Schweigert A and Pascal Dollé DA Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany.
B Department of Biochemistry and Molecular Biology, Medical Health and Science Center, University of Debrecen, 4012 Debrecen, Hungary.
C Gynecology and Andrology Research, Female Health Care, Schering AG, 13342 Berlin, Germany.
D Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, 67404 Illkirch Cedex, France.
E Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77230, USA.
F Corresponding author. Email: rruehl@indi.biochem.dote.hu
Reproduction, Fertility and Development 18(3) 339-345 https://doi.org/10.1071/RD05056
Submitted: 13 May 2005 Accepted: 15 November 2005 Published: 27 January 2006
Abstract
The active metabolite of vitamin A, retinoic acid (RA), plays an important role in the female reproductive system. The synthesis of RA is tightly regulated by the activity of retinaldehyde dehydrogenases (Raldh). Among these, Raldh1 and Raldh2 exhibit specific temporal and spatial expression patterns in the mouse uterus, both during the oestrous cycle and early pregnancy. In the present study, we have assessed whether oestradiol and progesterone directly influence the uterine expression of Raldh1 and Raldh2 in ovariectomised mice. We investigated the effect of gestagen (promegestone 0.3 mg kg−1 bodyweight), oestrogen (oestradiol 3 µg kg−1 bodyweight) and their combination on the uterine expression of Raldh2. Expression was analysed using in situ hybridisation and quantified using real-time detection reverse transcription–polymerase chain reaction. The results show that the expression of Raldh2 is rapidly (within 1–4 h) induced in stromal cells by oestrogen, but not by gestagen, treatment, whereas combined oestrogen + gestagen treatment leads to a more prolonged (48 h) response. In contrast, oestrogen, but not progesterone, treatment downregulates (within 4–24 h) Raldh1 expression in the uterine glandular epithelium. We conclude that the uterine RA concentrations are regulated by oestrogens via an effect on the expression of the Raldh synthesising enzymes. Such a regulation is consistent with the natural fluctuations of Raldh expression during the oestrous cycle, early pregnancy and blastocyst implantation.
Acknowledgments
The authors thank Natascha Manovski and Alexander Walter for excellent technical assistance, Valerie Fraulob for help with in situ hybridisation and Karl-Heinrich Fritzemeier for valuable scientific discussion. This work was supported by funds from the CNRS, INSERM, the Association pour la Recherche sur le Cancer and the Institut Universitaire de France. RR was supported by the funds from the European Comission RT EU-NUC-REC-NET.
Bo, W. J. , and Smith, M. S. (1966). The effect of retinol and retinoic acid on the morphology of the rat uterus. Anat. Rec. 156, 5–9.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Boehm, N. , Chateau, D. , and Rochette-Egly, C. (1997). Retinoid receptors in rat vaginal and uterine epithelia: changes with ovarian steroids. Mol. Cell. Endocrinol. 132, 101–108.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Boettger-Tong, H. L. , and Stancel, G. M. (1995). Retinoic acid inhibits estrogen-induced uterine stromal and myometrial cell proliferation. Endocrinology 136, 2975–2983.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bucco, R. A. , Zheng, W. L. , Wardlaw, S. A. , Davis, J. T. , Sierra-Rivera, E. , Osteen, K. G. , Melner, M. H. , Kakkad, B. P. , and Ong, D. E. (1996). Regulation and localization of cellular retinol-binding protein, retinol-binding protein, cellular retinoic acid-binding protein (CRABP), and CRABP II in the uterus of the pseudopregnant rat. Endocrinology 137, 3111–3122.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bucco, R. A. , Zheng, W. L. , Davis, J. T. , Sierra-Rivera, E. , Osteen, K. G. , Chaudhary, A. K. , and Ong, D. E. (1997). Cellular retinoic acid-binding protein (II) presence in rat uterine epithelial cells correlates with their synthesis of retinoic acid. Biochemistry 36, 4009–4014.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Cain, J. M. , Zaino, R. , Shearer, D. , Bennett, R. A. , Olt, G. , and Weisz, J. (2002). Expression of a retinol dehydrogenase (hRoDH-4), a member of the retinol/steroid dehydrogenase family implicated in retinoic acid biosynthesis, in normal and neoplastic endometria. Am. J. Obstet. Gynecol. 186, 675–683.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Carter, C. A. , Pogribny, M. , Davidson, A. , Jackson, C. D. , McGarrity, L. J. , and Morris, S. M. (1996). Effects of retinoic acid on cell differentiation and reversion toward normal in human endometrial adenocarcinoma (RL95–2) cells. Anticancer Res. 16, 17–24.
| PubMed |
Deng, L. , Shipley, G. L. , Loose-Mitchell, D. S. , Stancel, G. M. , Broaddus, R. , Pickar, J. H. , and Davies, P. J. (2003). Coordinate regulation of the production and signaling of retinoic acid by estrogen in the human endometrium. J. Clin. Endocrinol. Metab. 88, 2157–2163.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Duester, G. (2000). Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur. J. Biochem. 267, 4315–4324.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Fukunaka, K. , Saito, T. , Wataba, K. , Ashihara, K. , Ito, E. , and Kudo, R. (2001). Changes in expression and subcellular localization of nuclear retinoic acid receptors in human endometrial epithelium during the menstrual cycle. Mol. Hum. Reprod. 7, 437–446.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Geisen, C. , Denk, C. , Gremm, B. , Baust, C. , Karger, A. , Bollag, W. , and Schwarz, E. (1997). High-level expression of the retinoic acid receptor beta gene in normal cells of the uterine cervix is regulated by the retinoic acid receptor alpha and is abnormally downregulated in cervical carcinoma cells. Cancer Res. 57, 1460–1467.
| PubMed |
Kim, S. H. , Park, T. K. , and Kwon, J. Y. (2003). 13-cis-Retinoic acid for chemoprevention after colpoconization for cervical intraepithelial neoplasia. Int. J. Gynaecol. Obstet. 81, 217–218.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Kumarendran, M. K. , Matthews, C. J. , Levasseur, M. D. , Prentice, A. , Thomas, E. J. , and Redfern, C. P. (1994). Oestrogen and progesterone do not regulate the expression of retinoic acid receptors and retinoid ‘X’ receptors in human endometrial stromal cells in vitro. Hum. Reprod. 9, 229–234.
| PubMed |
Kumarendran, M. K. , Loughney, A. D. , Prentice, A. , Thomas, E. J. , and Redfern, C. P. (1996). Nuclear retinoid receptor expression in normal human endometrium throughout the menstrual cycle. Mol. Hum. Reprod. 2, 123–129.
| PubMed |
Li, X. H. , and Ong, D. E. (2003). Cellular retinoic acid-binding protein II gene expression is directly induced by estrogen, but not retinoic acid, in rat uterus. J. Biol. Chem. 278, 35 819–35 825.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Li, X. H. , Kakkad, B. , and Ong, D. E. (2004). Estrogen directly induces expression of retinoic acid biosynthetic enzymes, compartmentalized between the epithelium and underlying stromal cells in rat uterus. Endocrinology 145, 4756–4762.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Loughney, A. D. , and Redfern, C. P. (1995). Menstrual cycle related differences in the proliferative responses of cultured human endometrial stromal cells to retinoic acid. J. Reprod. Fertil. 105, 153–159.
| PubMed |
Loughney, A. D. , Kumarendran, M. K. , Thomas, E. J. , and Redfern, C. P. (1995). Variation in the expression of cellular retinoid binding proteins in human endometrium throughout the menstrual cycle. Hum. Reprod. 10, 1297–1304.
| PubMed |
Mangelsdorf, D. J. , Thummel, C. , Beato, M. , Herrlich, P. , and Thummel, C. , et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83, 835–839.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Mowa, C. N. , and Iwanaga, T. (2000a). Developmental changes of the oestrogen receptor-alpha and -beta mRNAs in the female reproductive organ of the rat: an analysis by in situ hybridization. J. Endocrinol. 167, 363–369.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Mowa, C. N. , and Iwanaga, T. (2000b). Differential distribution of oestrogen receptor-alpha and -beta mRNAs in the female reproductive organ of rats as revealed by in situ hybridization. J. Endocrinol. 165, 59–66.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Napoli, J. L. (1999). Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim. Biophys. Acta 1440, 139–162.
| PubMed |
Niederreither, K. , and Dolle, P. (1998). In situ hybridization with 35S-labeled probes for retinoid receptors. Methods Mol. Biol. 89, 247–267.
| PubMed |
Niederreither, K. , Fraulob, V. , Garnier, J. M. , Chambon, P. , and Dolle, P. (2002). Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech. Dev. 110, 165–171.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Prentice, A. , Matthews, C. J. , Thomas, E. J. , and Redfern, C. P. (1992). The expression of retinoic acid receptors in cultured human endometrial stromal cells and effects of retinoic acid. Hum. Reprod. 7, 692–700.
| PubMed |
Schindler, A. E. , Campagnoli, C. , Druckmann, R. , Huber, J. , Pasqualini, J. R. , Schweppe, K. W. , and Thijssen, J. H. (2003). Classification and pharmacology of progestins. Maturitas 46(Suppl. 1), S7–S16.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Siddiqui, N. A. , Loughney, A. , Thomas, E. J. , Dunlop, W. , and Redfern, C. P. (1994). Cellular retinoid binding proteins and nuclear retinoic acid receptors in endometrial epithelial cells. Hum. Reprod. 9, 1410–1416.
| PubMed |
Siddiqui, N. A. , Thomas, E. J. , Dunlop, W. , and Redfern, C. P. (1995). Retinoic acid receptors and retinoid binding proteins in endometrial adenocarcinoma: differential expression of cellular retinoid binding proteins in endometrioid tumours. Int. J. Cancer 64, 253–263.
| PubMed |
Tarrade, A. , Rochette-Egly, C. , Guibourdenche, J. , and Evain-Brion, D. (2000). The expression of nuclear retinoid receptors in human implantation. Placenta 21, 703–710.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Toma, S. , Isnardi, L. , Raffo, P. , Dastoli, G. , De Francisci, E. , Riccardi, L. , Palumbo, R. , and Bollag, W. (1997). Effects of ALL-trans-retinoic acid and 13-cis-retinoic acid on breast-cancer cell lines: growth inhibition and apoptosis induction. Int. J. Cancer 70, 619–627.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Vermot, J. , Fraulob, V. , Dolle, P. , and Niederreither, K. (2000). Expression of enzymes synthesizing (aldehyde dehydrogenase 1 and reinaldehyde dehydrogenase 2) and metabolizaing (Cyp26) retinoic acid in the mouse female reproductive system. Endocrinology 141, 3638–3645.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wang, X. , Sperkova, Z. , and Napoli, J. L. (2001). Analysis of mouse retinal dehydrogenase type 2 promoter and expression. Genomics 74, 245–250.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wardlaw, S. A. , Bucco, R. A. , Zheng, W. L. , and Ong, D. E. (1997). Variable expression of cellular retinol- and cellular retinoic acid-binding proteins in the rat uterus and ovary during the estrous cycle. Biol. Reprod. 56, 125–132.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wellik, D. M. , and DeLuca, H. F. (1995). Retinol in addition to retinoic acid is required for successful gestation in vitamin A-deficient rats. Biol. Reprod. 53, 1392–1397.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wolbach, S. B. , and Howe, P. R. (1978). Nutrition Classics. The Journal of Experimental Medicine 42: 753–77, 1925. Tissue changes following deprivation of fat-soluble A vitamin. S. Burt Wolbach and Percy R. Howe. Nutr. Rev. 36, 16–19.
| PubMed |
Zhao, D. , McCaffery, P. , Ivins, K. J. , Neve, R. L. , Hogan, P. , Chin, W. W. , and Drager, U. C. (1996). Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur. J. Biochem. 240, 15–22.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zheng, W. L. , and Ong, D. E. (1998). Spatial and temporal patterns of expression of cellular retinol-binding protein and cellular retinoic acid-binding proteins in rat uterus during early pregnancy. Biol. Reprod. 58, 963–970.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zheng, W. L. , Sierra-Rivera, E. , Luan, J. , Osteen, K. G. , and Ong, D. E. (2000). Retinoic acid synthesis and expression of cellular retinol-binding protein and cellular retinoic acid-binding protein type II are concurrent with decidualization of rat uterine stromal cells. Endocrinology 141, 802–808.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zhuang, Y. H. , Ylikomi, T. , Lindfors, M. , Piippo, S. , and Tuohimaa, P. (1994). Immunolocalization of retinoic acid receptors in rat, mouse and human ovary and uterus. J. Steroid Biochem. Mol. Biol. 48, 61–68.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
