PLACENTAL ABNORMALITIES IN MOUSE EMBRYOS LACKING THE ORPHAN NUCLEAR RECEPTOR ERR-BETA

Classical endocrine studies have shown that steroid hormones are requi red for the maintenance of pregnancy and placental viability. The oest rogen-receptor-related receptor beta (ERR-beta) is an orphan member of the superfamily of nuclear hormone receptors(1) Although ERR-beta is homologous to the oestrogen receptor and binds the oestrogen response element(2), it is not activated by oestrogens'. Expression of ERR-beta during embryogenesis defines a subset of extra-embryonic ectoderm tha t subsequently forms the dome of the chorion, suggesting that ERR-beta may be involved in early placental development. Homozygous mutant emb ryos generated by targeted disruption of the Estrrb gene have severely impaired placental formation, and die at 10.5 days post-coitum. The m utants display abnormal chorion development associated with an overabu ndance of trophoblast giant cells and a severe deficiency of diploid t rophoblast. The phenotype can be rescued by aggregation of Estrrb muta nt embryos with tetraploid wildtype cells, which contribute exclusivel y to extra-embryonic tissues. Our results indicate that ERR-beta has a n important role in early placentation, and suggest that an inductive signal originating from or modified by the chorion is required for nor mal trophoblast proliferation and differentiation.