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Liver receptor homolog-1 is essential for pregnancy

Nature Medicine volume 19, pages 1061–1066 (2013)Cite this article

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Abstract

Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis1. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents2 and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation3. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation4. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy.

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Figure 1: Reduction of Lrh-1 in the peri-ovulatory follicle by Pgr-Cre causes luteal insufficiency.
Figure 2: Implantation is compromised in cKO mice and gestation fails in progesterone-supplemented cKO mice.
Figure 3: Lrh-1 is present in the endometrium of the mouse, and its depletion results in failure of gestation.
Figure 4: LRH-1 is crucial for decidualization of both the mouse and human endometrial stroma.

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Acknowledgements

This study was funded by OPG 11018 from the Canadian Institutes of Health Research to B.D.M. C.Z. was supported by the National Natural Science Foundation of China (31172040) and Shangdong Natural Science Foundation (ZR2011CM047). K.S. was supported by grants from the École Polytechnique Fédérale de Lausanne, the Swiss National Science Foundation (SNF) and the Swiss Cancer League, J.P.L. by US National Institutes of Health (NIH) R01CA77530 and F.J.D. by NIH U54 HD07495-31. M.J.L. is supported by NIH 5T32HD007165. We are grateful to V. Roussel for preparation of the figures, M. Dobias for hormone analyses, S. Ruiz Orduna for human endometrial stromal cell line experiments, J. Fenelon and K. Bertolin for aid with transcript studies, L. Lian for aid with oviduct transfer, X. Tang for statistical analyses, L. Giudice for coordinating acquisition of human endometrium from the NIH–University of California at San Francisco (UCSF) Endometrium Tissue Bank and J. Auwerx for Nr5a2 floxed (Nr5a2fl/fl) mice.

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Authors and Affiliations

  1. Centre de recherche en reproduction animale, Université de Montréal, Saint-Hyacinthe, Québec, Canada

    Cong Zhang & Bruce D Murphy

  2. Key Laboratory of Animal Resistance Research, College of Life Science, Shandong Normal University, Ji'nan, Shandong, China

    Cong Zhang

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

    Michael J Large, Francesco J DeMayo & John P Lydon

  4. Department of Animal Science, McGill University, Sainte-Anne-de-Bellevue, Québec, Canada

    Raj Duggavathi

  5. Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Kristina Schoonjans

  6. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA

    Ertug Kovanci

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  1. Cong Zhang
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Contributions

C.Z., R.D., F.J.D. and B.D.M. planned mouse experiments, which were carried out by C.Z. and B.D.M. C.Z., R.D. and B.D.M. wrote the manuscript. F.J.D., E.K. and M.J.L. planned and executed primary endometrial culture experiments and edited the manuscript. K.S. and J.P.L. provided mouse models and edited the manuscript.

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Correspondence to Bruce D Murphy.

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Zhang, C., Large, M., Duggavathi, R. et al. Liver receptor homolog-1 is essential for pregnancy. Nat Med 19, 1061–1066 (2013). https://doi.org/10.1038/nm.3192

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