Oestrogen receptor knockout mice: roles for oestrogen receptors alpha and beta in reproductive tissues

Hewitt, Sylvia C.; Korach, Kenneth S.

doi:10.1530/rep.0.1250143

Cited by 225 publications

(88 citation statements)

References 45 publications

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“…Other authors report that only gonadotropes and thyrotropes from pituitaries of OVX KO mice lack Esr1 (Gieske et al 2008, Singh et al 2009). Moreover, the selective lack of Esr1 expression in gonadotropes was confirmed in the present study by: i) the lack of effect of PPT on the number of homogeneous gonadotropes in OVX KO mice, ii) the similar response, in both mouse genotypes, of uterus and vagina to E 2 and PPT but not to DPN treatment (present results, Harris et al 2002, Frasor et al 2003, Hewitt & Korach 2003, iii) the negative feedback of ESR1 activation on LH secretion in both OVX WT and KO mice, and iv) significantly (P!0.05) lower expression of Pgr in OVX KO than in OVX WT mice. Taken in conjunction, these ESR2 in mouse gonadotrope biology findings confirmed, though only in part, the adequacy of the model used to study the effects of specific activation of ESR2 on mouse gonadotropes.…”

Section: Discussionsupporting

confidence: 82%

“…The actions of ESR1 are much better known (Parker 1995) than those of ESR2, which remain elusive (Pettersson & Gustafsson 2001, Imamov et al 2005, Koehler et al 2005, Sugiyama et al 2010. The role played by each ESR isoform in the gonadotrope is currently being studied, in vivo and in vitro, in OVX rats injected with the selective ESR1 and 2 agonists, propylpyrazole triol (PPT) and diarylpropionitrile (DPN), respectively (Sá nchez- Criado et al 2004, Garrido-Gracia et al 2007, and in global or ESR isoform-specific knockout (KO) mice (Dupont et al 2000, Hewitt & Korach 2003, Gieske et al 2008, Singh et al 2009, Kim et al 2011). …”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

et al. 2012

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Estrogen receptor 1 and 2 (ESR1 and 2) mediate estrogen (E) action on gonadotrope function. While much is known about the effects of ESR1 on the gonadotrope, there is still some controversy regarding the effects of ESR2. To investigate the role of ESR2 in the gonadotrope, 45-day-old female mice of two different genotypes were used: wild type (WT) and pituitary (gonadotropes and thyrotropes)-specific Esr1 knockout (KO). All mice were ovariectomized (OVX) and 15 days later injected over 3 days with 2.5 mg 17b-estradiol (E 2 ), 0.2 mg of the selective ESR1 or 2 agonists, propylpyrazole triol and diarylpropionitrile, respectively, or 0.1 ml oil. The day after treatment, anterior pituitary glands were dissected out for evaluation of gonadotrope ultrastructural morphology and pituitary immunohistochemical expression of progesterone receptor (Pgr (Pr)). Blood was collected and serum LH levels were assessed. Activation of ESR1 in WT mice resulted in the following: i) uterine ballooning and vaginal cornification, ii) negative feedback on LH secretion, iii) increased number of homogeneous (functional) gonadotropes, and iv) pituitary Pgr expression (35.9G2.0% of pituitary cells). Activation of ESR1 in KO mice induced normal uterine, vaginal, and LH secretion responses, but failed to increase the number of functional gonadotropes, and induced significantly lower Pgr expression (21.0G3.0% of pituitary cells) than in WT mice. Whilst activation of ESR2 had no significant effects in WT mice, it doubled the number of functional gonadotropes exhibited by KO mice injected with oil. It is concluded that E 2 exerted its action in KO mouse gonadotropes via ESR2.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

et al. 2012

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“…ERa activation was shown to be primarily responsible for the reorganization of the disrupted organelle morphology seen in the gonadotroph after ovariectomy (Sanchez-Criado et al 2006). In addition to ERa knockout (ERaKO) female mice exhibiting complete infertility and lack of ovulation (Dupont et al 2000, Hewitt & Korach 2003, we recently reported that targeted deletion of ERa in the gonadotroph caused infertility in female mice (Gieske et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Identification of estradiol/ERα-regulated genes in the mouse pituitary

Kim¹,

Gieske²,

Trudgen³

et al. 2011

Journal of Endocrinology

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Estrogen acts to prime the pituitary prior to the GnRHinduced LH surge by undiscovered mechanisms. This study aimed to identify the key components that mediate estrogen action in priming the pituitary. RNA extracted from the pituitaries of metestrous (low estrogen) and proestrus (high estrogen) stage mice, as well as from ovariectomized wildtype and estrogen receptor a (ERa) knockout mice treated with 17b-estradiol (E 2 ) or vehicle, was used for gene expression microarray. Microarray data were then aggregated, built into a functional electronic database, and used for further characterization of E 2 /ERa-regulated genes. These data were used to compile a list of genes representing diverse biological pathways that are regulated by E 2 via an ERa-mediated pathway in the pituitary. This approach substantiates ERa regulation of membrane potential regulators and intracellular vesicle transporters, among others, but not the basic components of secretory machinery. Subsequent characterization of six selected genes (Cacna1a, Cacna1g, Cited1, Abep1, Opn3, and Kcne2) confirmed not only ERa dependency for their pituitary expression but also the significance of their expression in regulating GnRH-induced LH secretion. In conclusion, findings from this study suggest that estrogen primes the pituitary via ERa by equipping pituitary cells with critical cellular components that potentiate LH release on subsequent GnRH stimulations.

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“…In the uterus, ESR1 is the predominant isoform and its presence is necessary for reproductive functions (Couse & Korach 1999; Matthews & Gustafsson 2003). Indeed, mice null for Esr1 are infertile in contrast to Esr2 KO mice (Hewitt & Korach, 2003), due in part to the failure of the uteri to properly develop (Couse et al . 1995).…”

Section: Introductionmentioning

confidence: 99%

Response of adult mouse uterus to early disruption of estrogen receptor-α signaling is influenced by Krüppel-like factor 9

Simmons¹,

Pabona²,

Zeng³

et al. 2010

Journal of Endocrinology

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Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-a (ESR1) signaling is well acknowledged to mediate early events in tumor initiation, mechanisms contributing to sustained ESR1 activity later in life and leading to induction of oncogenic pathways remain poorly understood. We had shown previously that the transcription factor Krüppel-like factor 9 (KLF9) represses ESR1 expression and activity in Ishikawa endometrial glandular epithelial cells. We hypothesized that KLF9 functions as a tumor suppressor, and that loss of its expression enhances ESR1 signaling. Here, we evaluated the contribution of KLF9 to early perturbations in uterine ESR1 signaling pathways elicited by the administration of synthetic estrogen diethylstilbestrol (DES) to wild-type (WT) and Klf9 null (KO) mice on postnatal days (PNDs) 1-5. Uterine tissues collected at PND84 were subjected to histological, immunological, and molecular analyses. Compared with WT mice, KO mice demonstrated larger endometrial glands and lower endometrial gland numbers; DES exposure exacerbated these differences. Loss of KLF9 expression resulted in increased glandular ESR1 immunoreactivity with DES, without effects on serum estradiol levels. Quantitative RT-PCR analyses indicated altered expression of uterine genes commonly dysregulated in endometrial cancers (Akt1, Mmp9, Slpi, and Tgfb1) and of those involved in growth regulation (Fos, Myc, Tert, and Syk), with loss of Klf9, alone or in concert with DES. Our data support a molecular network between KLF9 and ESR1 in the uterus, and suggest that silencing of KLF9 may contribute to endometrial dysfunctions initiated by aberrant estrogen action.

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Oestrogen receptor knockout mice: roles for oestrogen receptors alpha and beta in reproductive tissues

Cited by 225 publications

References 45 publications

Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

Identification of estradiol/ERα-regulated genes in the mouse pituitary

Response of adult mouse uterus to early disruption of estrogen receptor-α signaling is influenced by Krüppel-like factor 9

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