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Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β

Abstract

Classical endocrine studies have shown that steroid hormones are required for the maintenance of pregnancy and placental viability. The oestrogen-receptor-related receptor β (ERR-β) is an orphan member of the superfamily of nuclear hormone receptors1. Although ERR-β is homologous to the oestrogen receptor and binds the oestrogen response element2, it is not activated by oestrogens1. Expression of ERR-β during embryogenesis defines a subset of extra-embryonic ectoderm that subsequently forms the dome of the chorion, suggesting that ERR-β may be involved in early placental development. Homozygous mutant embryos generated by targeted disruption of the Estrrb gene have severely impaired placental formation, and die at 10.5 days post-coitum. The mutants display abnormal chorion development associated with an overabundance of trophoblast giant cells and a severe deficiency of diploid trophoblast. The phenotype can be rescued by aggregation of Estrrb mutant embryos with tetraploid wild-type cells, which contribute exclusively to extra-embryonic tissues. Our results indicate that ERR-β has an important role in early placentation, and suggest that an inductive signal originating from or modified by the chorion is required for normal trophoblast proliferation and differentiation.

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Figure 1: Expression of Estrrb in trophoblast tissues.
Figure 2: Targeted disruption of the Estrrb gene and heterozygote inbreeding analysis.
Figure 3: Morphology of homozygous mutant embryos and trophoblast tissues.
Figure 4: Morphology of homozygous mutant embryos and trophoblast tissues.
Figure 5: Expression of cell-type-specific markers in trophoblast tissues.

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Acknowledgements

We thank M. Tremblay for injection of ES cells; M. Ratcliffe for the anti-BrdU antibody; and K. Kemball for technical advice. J.L. was supported by a fellowship from the MRC of Canada, and R.S. was supported by an NCIC Terry Fox clinician-scientist fellowship. This work was supported by grants from the MRC of Canada (C.G., J.R.). J.R. is an international scholar of the Howard Hughes Medical Institute and a Terry Fox research scientist of the NCIC. V.G. is an MRC scientist.

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Correspondence to Vincent Giguère.

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Luo, J., Sladek, R., Bader, JA. et al. Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β. Nature 388, 778–782 (1997). https://doi.org/10.1038/42022

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