Expression of estrogen receptor alpha and beta during mouse embryogenesis

Lemmen, Josephine G.; Broekhof, J.L.M.; Kuiper, George G. J. M.; Gustafsson, Jan‐Åke; Saag, Paul T. van der; Burg, Bart van der

doi:10.1016/s0925-4773(98)00223-8

Cited by 135 publications

(105 citation statements)

References 8 publications

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“…Gene inactivation in mice surprisingly did not affect ovarian development and fertility but instead caused male infertility (28), a phenotype which intriguingly has been observed in mice lacking ER␣ (42). Moreover, developmental studies suggest coexpression of ERs and DAX-1 in testis and ovary during certain stages of embryogenesis (35,43). Possibly, DAX-1 serves as a tissue-or stage-specific ER coregulator involved in modulation of estrogen signaling.…”

Section: Discussionmentioning

confidence: 99%

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Zhang¹,

Thomsen

Johansson

et al. 2000

Journal of Biological Chemistry

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156

127

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We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ER␣ and ER␤. Interaction occurs with ligand-activated ERs in solution and on DNA and is mediated by the unique DAX-1 N-terminal repeat domain. Each of the three repeats contains a leucine-rich receptor-binding motif, known as the LXXLL motif, which is usually found in nuclear receptor coactivators. We have demonstrated that DAX-1 functions as an inhibitor of ER activation in mammalian cells and suggest a mechanism involving two sequential events, occupation of the ligand-induced coactivator-binding surface and subsequent recruitment of corepressors. Accordingly, we propose that DAX-1 itself acts as a corepressor for ERs. Because DAX-1 is coexpressed with ERs in reproductive tissues, these interactions could play significant roles by influencing estrogen signaling pathways. Our results point at functional similarities between DAX-1 and the orphan receptor SHP (NROB2) in that they have acquired features of transcriptional coregulators that are unique for members of the nuclear receptor family.To transduce hormone and metabolic signaling to target genes, nuclear receptors require transcriptional cofactors that are collectively referred to as coregulators (1). These proteins exist in multiple complexes, possess multiple enzymatic activities, and bridge receptors to chromatin components or to the basal transcription machinery or to both. Multiple candidate proteins exist that are believed to be critical for the proper function of nuclear receptor signaling (1-3). The majority of coregulators bind to the receptor ligand-binding domain (LBD), 1 which is able to adopt different conformations depending on the ligand status and thereby discriminate between coactivators and corepressors. Functional and structural studies in particular elucidated the precise mechanisms of coactivator interaction with the ligand-inducible activation domain (AF-2) via short leucine motifs known as LXXLL or NR-Box (4 -8).We became interested in coregulators in particular that influence the transcriptional activity of estrogen receptors (ER). Two related subtypes, ER␣ and ER␤, play crucial roles in sex development and reproduction in multiple physiological processes as well as in cancer (9 -11). Previous research has provided detailed insights into structural and functional aspects of their interplay with coregulators (8,(12)(13)(14). Although agonist binding usually is associated with ER activation caused by coactivator recruitment, regulatory mechanisms have been proposed that could play a role in modulation and feedback control of estrogen signaling (15, 16). Recent work has revealed an unexpected role of the orphan receptor SHP (NROB2) in inhibiting transactivation of ERs (17, 18). Particularly, we have provided evidence that SHP, which consists only of an LBD and thus cannot bind target genes directly, has instead acquired a novel coregulator function by antagonizing the interactions of ERs with associated coactivators (18,19).The closest relati...

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Section: Discussionmentioning

confidence: 99%

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Zhang¹,

Thomsen

Johansson

et al. 2000

Journal of Biological Chemistry

Self Cite

156

127

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“…In particular, ER , which is prominently expressed in several important brain regions, is a likely candidate. The relatively higher affinity of DHEA for ER is also interesting in the light of co-expression of sulphatases (Compagnone et al 1997) and ER at ossification sites in the mouse embryo (Lemmen et al 1999). Local conversion of DHEAS to DHEA could therefore activate ER in these ossification centres.…”

Section: Discussionmentioning

confidence: 99%

“…Both ER and ER are expressed during embryogenesis in many species including Solomon 1994 andCarr 1996. ) humans (Takeyama et al 2001) and mice (Lemmen et al 1999). However, the function of oestrogens and their receptors during normal development of the foetus remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Detection of oestrogenic activity of steroids present during mammalian gestation using oestrogen receptor alpha- and oestrogen receptor beta-specific in vitro assays

Lemmen¹,

Brink²,

Legler³

et al. 2002

Journal of Endocrinology

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Numerous steroid hormones are present in the foetus but their potential to activate oestrogen receptor (ER) and/or is largely unknown. In this study, in vitro assays were developed to rapidly and specifically detect ER or ER activation by these steroid hormones. Our results showed that several oestrogen precursors and androgens are able to activate both ER and ER . Of special interest is that some of these precursors are able to activate ER and ER at concentrations that are present during human gestation. Moreover, some precursors (dehydroepiandrosterone (DHEA) and 17-hydroxylated pregnenolone sulphate) and androgens (5-androsten-3 ,16 ,17 -triol and testosterone) showed a more than 100-fold relative preference for ER transactivation over ER transactivation when compared with 17 -oestradiol. Due to their relatively high levels, the precursor steroids DHEA and pregnenolone may be of particular importance in the regulation of ER activity in vivo. To obtain information about the oestrogenic activity of the total pool of steroid hormones present during mammalian gestation, steroids were extracted from mouse embryos at different prenatal stages and assayed for oestrogenic activity in the established in vitro assays. Oestrogenic activity was detected in steroid extracts from all stages tested. This study has demonstrated that oestrogen receptor agonists are present in the murine embryo and that oestrogen precursors may contribute to the total pool of agonists during foetal life.

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“…25 Before the onset of E2 biosynthesis in the brain that occurs at E18.5, 26-28 mRNA of ERb1 is already expressed in fetal brain as early as at E10.5. 29 ERb1 protein is detected at E12.5, reaches a peak at E18.5 14 and its function can be detected from E14.5. 16 Although ERb1 is essential for neuronal migration and cortical layering, E2 itself does not appear to be necessary as the brain of aromatase knockout (ArKO) mice, which cannot make E2, has not been reported to show major neuronal abnormalities.…”

Section: Introductionmentioning

confidence: 98%

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Sugiyama

Andersson

Lathe³

et al. 2008

Mol Psychiatry

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This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERa and ERb1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERa expression was visible only in the hypothalamic area. Decline in ERb1 expression was slower than that of ERa, and ERa-negative, ERb1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5a-androstane-3b, 17b-diol (3bAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3bAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3bAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3bAdiol, is important in neuronal function in the postnatal brain.

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Expression of estrogen receptor alpha and beta during mouse embryogenesis

Cited by 135 publications

References 8 publications

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors

Detection of oestrogenic activity of steroids present during mammalian gestation using oestrogen receptor alpha- and oestrogen receptor beta-specific in vitro assays

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

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