Pituitary Gonadotroph Estrogen Receptor-α Is Necessary for Fertility in Females

Gieske, Mary C.; Kim, Hyun Joon; Legan, Sandra J.; Koo, Yongbum; Krust, Andrée; Chambon, Pierre; Ko, CheMyong

doi:10.1210/en.2007-1084

Cited by 68 publications

(74 citation statements)

References 31 publications

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“…In addition, the results indicated similar Esr2 expression in gonadotropes of both OVX KO and WT mice. 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.…”

Section: Discussionmentioning

confidence: 96%

“…Forty-five-day-old Esr1 fl/fl with WT phenotype and pituitary-specific aGSU-Cre:Esr1 fl/fl mice, referred to here as KO mice, were used (Gieske et al 2008). KO mice were generated following a previously published strategy (Dupont et al 2000, Gieske et al 2008.…”

Section: Animals and General Conditionsmentioning

confidence: 99%

“…At the pituitary level, the effects of E on the gonadotrope are exerted through activation of the complete gonadotrope ESR orchestra (Alonso et al 2006). Rat and mouse gonadotropes express both ESR1 and 2 isoforms (Wilson et al 1998, Sánchez-Criado et al 2005, Gieske et al 2008. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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%

“…This study investigated the effects of specific ESR1 and 2 activation on gonadotrope ultrastructural morphology and pituitary immunohistochemical (IHC) Pgr expression in OVX wild-type (WT) and pituitary (gonadotrope and thyrotrope)-specific Esr1 KO mice (Gieske et al 2008). The effects of ESR agonists (17b-estradiol (E 2 ), PPT, and DPN) on uterus and vagina and on LH release were also evaluated.…”

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: Discussionmentioning

confidence: 96%

Section: Animals and General Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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Generation of Cyp17iCre transgenic mice and their application to conditionally delete estrogen receptor alpha (Esr1) from the ovary and testis

Bridges

Koo

Kang

et al. 2008

Genesis

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A transgenic mouse line that expresses iCre under regulation of the Cytochrome P 450 17α-hydroxylase/17, 20-lyase (Cyp17) promoter was developed as a novel transgenic mouse model for the conditional deletion of genes specifically in the theca/interstitial cells of the ovary and Leydig cells of the testis. In this report we describe the development of Cyp17iCre mice and the application of these mice for conditional deletion of the estrogen receptor alpha (Esr1) gene in the theca/ interstitial and Leydig cells of the female and male gonad, respectively. These mice will prove a powerful tool to inactivate genes in the gonad in a cell-specific manner.Targeted gene deletion has become a powerful tool in the study of gene function with the utilization of this technology leading to marked progress in our understanding of both physiological and pathophysiological systems. The ovary is one organ where targeted genetic deletion has proven fruitful with the establishment of transgenic mice with Cre expression targeted to granulosa cells (Lécureuil et al., 2002), somatic cells (Bingham et al., 2006) and the oocyte (Lan et al., 2004;Lewandoski et al., 1997). However, our understanding of ovarian function cannot advance at optimal pace without a tool to specifically delete genes of interest from the other major endocrine cell population of the ovary, the theca/interstitial cells. Hence, our primary goal was to develop the mice necessary to allow the specific deletion of genes in the theca/interstitial cells of the ovary and in this report we describe the generation of such a line of transgenic mice, with codon-improved Cre (iCre) driven by the promoter to Cytochrome P 450 17α-hydroxylase/17, 20-lyase (Cyp17).Cytochrome P 450 17α-hydroxylase/17, 20-lyase, the product of Cyp17 gene expression, plays a major role in the control of sex steroid hormone synthesis by mediating the17α-hydroxylation of pregnenolone or progesterone to dehydroepiandrostenedione or androstenedione, respectively. In the female mouse, Cyp17 expression is primarily restricted to the ovary and placenta (Su et al., 2002) and within the ovary, Cyp17 is abundant in the gonadotropin-primed theca/interstitial cell population, but not the granulosa cells or oocyte (Zhang et al., 2001), making it ideal for iCre targeting. Furthermore, coincident to the need of a transgenic mouse line with iCre targeted to the theca/interstitial cells, is one also designed to allow the deletion of Leydig cell specific genes from the male gonad. Fortunately, the specificity of Cyp17 expression to the Leydig cells of the testis (Zhang et al., 2001) makes this line of mice also ideal as a tool to inactive genes specifically within that endocrine population of cells. Hence, this report was widened as a functional characterization of these mice inclusive to both the sexes.Three lines of Cyp17iCre founder mice were generated (A, B and C) by pronuclear injection of a KpnI/SalI DNA fragment derived from a Cyp17iCre expression plasmid (Figure 1). Then, to facilitate expression analys...

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Generation and characterization of an estrogen receptor alpha‐iCre knock‐in mouse

Park

Chen

Koo

et al. 2017

Genesis

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Summary Two estrogen receptors, ESR1 and ESR2, are responsible for the classical actions of estrogens in mammalian species. They display different spatiotemporal expression patterns and nonoverlapping functions in various tissues and physiological conditions. In this study, a novel knock-in mouse line that expresses codon-improved Cre recombinase (iCre) under regulation of the natural Esr1 promoter (Esr1–iCre) was developed. Functional characterization of iCre expression by crossing them with reporter lines (ROSA26-lacZ or Ai9-RFP) showed that iCre is faithfully expressed in Esr1-lineage cells. This novel transgenic mouse line will be a useful animal model for lineage-tracing Esr1-expressing cells, selective gene ablation in the Esr1-lineage cells and for generating global Esr1 knockout mice.

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Pituitary Gonadotroph Estrogen Receptor-α Is Necessary for Fertility in Females

Cited by 68 publications

References 31 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

Generation of Cyp17iCre transgenic mice and their application to conditionally delete estrogen receptor alpha (Esr1) from the ovary and testis

Generation and characterization of an estrogen receptor alpha‐iCre knock‐in mouse

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