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 beta (ERR-beta) is an orphan member of the superfamily of nuclear hormone receptors. Although ERR-beta is homologous to the oestrogen receptor and binds the oestrogen response element, it is not activated by oestrogens. Expression of ERR-beta during embryogenesis defines a subset of extra-embryonic ectoderm that subsequently forms the dome of the chorion, suggesting that ERR-beta 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-beta 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.

Nuclear receptors, mitochondria and lipid metabolism

“…Because ERRα is widely expressed in adult tissues, especially in tissues that utilize or can utilize fatty acid β-oxidation, many studies have addressed its role in cellular energetics (Luo et al 2003). Loss of ERRβ results in placental defects and mid-gestational death of embryos, despite relatively limited expression in adult (Luo et al 1997). ERRγ is highly expressed in tissues with high metabolic activity (e.g.…”

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…Early expression studies show that ERRb exhibits a specific and restricted expression pattern confined to extraembryonic and few adult tissues, as compared to the relatively broader expression spectra of ERRa and ERRg. By northern blot, ERRb mRNA is expressed at weak levels in rat heart, kidney, brain and prostate (Gigue`re et al, 1988), whereas in situ hybridization shows that ERRb transcripts are detected only during a narrow developmental window in mouse trophoblast progenitor cells, primordial and gonadal germ cells, and human placental tissue (Pettersson et al, 1996;Luo et al, 1997;Tanaka et al, 1998;Mitsunaga et al, 2004;Fujimoto et al, 2005). However, recent studies by reverse transcription-PCR (RT-PCR) show that ERRb transcripts are widely expressed in many human and mouse tissues and organs Zhou et al, 2006), suggesting that ERRb may participate in more diverse transcriptional and metabolic regulations than initially thought.…”

“…However, recent studies by reverse transcription-PCR (RT-PCR) show that ERRb transcripts are widely expressed in many human and mouse tissues and organs Zhou et al, 2006), suggesting that ERRb may participate in more diverse transcriptional and metabolic regulations than initially thought. Targeted disruption of ERRb in ERRb-knockout mice induces abnormal placenta development with the mutants dying prenatally, suggesting that ERRb plays a role in placental formation (Luo et al, 1997). Similar to ERa and other ERR subtypes, ERRb can bind to the classical palindromic estrogen response element (ERE; AGGTCAnnnTGA CCT) in vitro and some direct repeat elements with extended half-site sequence (ERRE/SFRE; TNAAGG TCA or TCAA/GGGTCA), including thyroid hormone response element (Pettersson et al, 1996;Vanacker et al, 1999;Xie et al, 1999).…”

From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

“…Conversely, the expression of other pluripotency factors seems to be dispensable for early development. Notably, Esrrb null embryos survive until 10.5 days post coitum (dpc) and die due to placental abnormalities [73]. Similarly, while Dppa4, Dppa5 and Utf1 are specifically expressed in pluripotent cells in vivo and in culture, the impact of their absence is only observed during late embryonic stages, though redundancy among these genes has not yet been investigated [74][75][76].…”

“…Targeted deletion experiments in embryos and trophoblast stem cells have together provided relevant data for inference of a TE regulatory network that includes genes such as Cdx2, Tead4, Eomes, Id2, Elf5, Tcfap2c, Esrrb, Sox2, Nanog and Oct4 (figure 4a) [20,73,[91][92][93][94][95]). Reciprocal inhibition between Oct4, Nanog and Cdx2 is perhaps the most central element of this network, as CDX2 and OCT4 form a functional repressor complex in the early embryo [96], while Cdx2 is required for downregulation of Oct4 and Nanog in the TE, resulting in restriction of their expression to the ICM [92].…”