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Estradiol Preferentially Induces Progestin Receptor-A (PR-A) Over PR-B in Cells Expressing Nuclear Receptor Coactivators in the Female Mouse Hypothalamus(1,2,3).

Acharya KD, Finkelstein SD, Bless EP, Nettles SA, Mulac-Jericevic B, Conneely OM, Mani SK, Tetel MJ - eNeuro (2015)

Bottom Line: Estrogens act in brain to profoundly influence neurogenesis, sexual differentiation, neuroprotection, cognition, energy homeostasis, and female reproductive behavior and physiology through a variety of mechanisms, including the induction of progestin receptors (PRs).Interestingly, the intensity of PR-A immunoreactivity correlated with SRC-2 expression in the VMN, providing a potential mechanism for selective ER-mediated transactivation of PR-A over PR-B in a brain region-specific manner.In summary, these novel findings indicate that estrogens differentially regulate PR-A and PR-B expression in the female hypothalamus, and provide a mechanism by which steroid action in brain can selectively modulate behavior and physiology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Program, Wellesley College , Wellesley, Massachusetts 02481.

ABSTRACT
Estrogens act in brain to profoundly influence neurogenesis, sexual differentiation, neuroprotection, cognition, energy homeostasis, and female reproductive behavior and physiology through a variety of mechanisms, including the induction of progestin receptors (PRs). PRs are expressed as two isoforms, PR-A and PR-B, that have distinct functions in physiology and behavior. Because these PR isoforms cannot be distinguished using cellular resolution techniques, the present study used isoform-specific mutant mice that lack PR-A or PR-B for the first time to investigate whether 17β-estradiol benzoate (EB) regulates the differential expression of the PR isoforms in the ventromedial nucleus of the hypothalamus (VMN), arcuate nucleus, and medial preoptic area, brain regions that are rich in EB-induced PRs. Interestingly, EB induced more PR-A than PR-B in all three brain regions, suggesting that PR-A is the predominant isoform in these regions. Given that steroid receptor coactivator (SRC)-1 and SRC-2 are important in estrogen receptor (ER)-dependent transcription in brain, including PR induction, we tested whether the expression of these coactivators was correlated with PR isoform expression. The majority of EB-induced PR cells expressed both SRC-1 and SRC-2 in the three brain regions of all genotypes. Interestingly, the intensity of PR-A immunoreactivity correlated with SRC-2 expression in the VMN, providing a potential mechanism for selective ER-mediated transactivation of PR-A over PR-B in a brain region-specific manner. In summary, these novel findings indicate that estrogens differentially regulate PR-A and PR-B expression in the female hypothalamus, and provide a mechanism by which steroid action in brain can selectively modulate behavior and physiology.

No MeSH data available.


A–C, Estradiol induces PR-A and PR-B in a brain region-specific manner. Estradiol induces PR-A and PR-B in the VMN (A), but not in the ARC (B) or MPA (C), of PRBKO and PRAKO mice. *p < 0.05, for differences between vehicle and EB groups within each genotype; #p < 0.05, for differences between EB-treated genotypes.
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Figure 2: A–C, Estradiol induces PR-A and PR-B in a brain region-specific manner. Estradiol induces PR-A and PR-B in the VMN (A), but not in the ARC (B) or MPA (C), of PRBKO and PRAKO mice. *p < 0.05, for differences between vehicle and EB groups within each genotype; #p < 0.05, for differences between EB-treated genotypes.

Mentions: To investigate the effects of EB on the expression of PR-A and PR-B in the hypothalamus, we compared the number of PR-ir cells of EB-primed PRAKO and PRBKO mice with that of vehicle controls. The wt mice were used to examine the effects of EB on total PR expression. Consistent with previous studies in mice and rats (MacLusky and McEwen, 1980; Parsons et al., 1980; Blaustein and Turcotte, 1989; Lauber et al., 1991; Turcotte and Blaustein, 1993; Moffatt et al., 1998; Kudwa and Rissman, 2003; Tognoni et al., 2011), EB induced PRs in the MPA, VMN, and ARC of wt mice (Fig. 1E), while little to no PR-ir cells were observed in vehicle controls (Fig. 1A). EB induced the expression of PRs in the hypothalamus of wt, PRAKO, and PRBKO female mice in a region- and isoform-specific manner. In the VMN, the number of PR-ir cells was increased in EB-primed mice in all three genotypes (F(1,59) = 42.31, p = 0.001; Figs. 1E,I,M, 2A), but not in vehicle controls. Interestingly, EB-treated wt and PRBKO mice had a greater number of PR-ir cells compared with PRAKO mice (F(2,59) = 5.03, p = 0.01; Fig. 2A), suggesting that PR-A is more strongly induced by EB than PR-B in the VMN.


Estradiol Preferentially Induces Progestin Receptor-A (PR-A) Over PR-B in Cells Expressing Nuclear Receptor Coactivators in the Female Mouse Hypothalamus(1,2,3).

Acharya KD, Finkelstein SD, Bless EP, Nettles SA, Mulac-Jericevic B, Conneely OM, Mani SK, Tetel MJ - eNeuro (2015)

A–C, Estradiol induces PR-A and PR-B in a brain region-specific manner. Estradiol induces PR-A and PR-B in the VMN (A), but not in the ARC (B) or MPA (C), of PRBKO and PRAKO mice. *p < 0.05, for differences between vehicle and EB groups within each genotype; #p < 0.05, for differences between EB-treated genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596027&req=5

Figure 2: A–C, Estradiol induces PR-A and PR-B in a brain region-specific manner. Estradiol induces PR-A and PR-B in the VMN (A), but not in the ARC (B) or MPA (C), of PRBKO and PRAKO mice. *p < 0.05, for differences between vehicle and EB groups within each genotype; #p < 0.05, for differences between EB-treated genotypes.
Mentions: To investigate the effects of EB on the expression of PR-A and PR-B in the hypothalamus, we compared the number of PR-ir cells of EB-primed PRAKO and PRBKO mice with that of vehicle controls. The wt mice were used to examine the effects of EB on total PR expression. Consistent with previous studies in mice and rats (MacLusky and McEwen, 1980; Parsons et al., 1980; Blaustein and Turcotte, 1989; Lauber et al., 1991; Turcotte and Blaustein, 1993; Moffatt et al., 1998; Kudwa and Rissman, 2003; Tognoni et al., 2011), EB induced PRs in the MPA, VMN, and ARC of wt mice (Fig. 1E), while little to no PR-ir cells were observed in vehicle controls (Fig. 1A). EB induced the expression of PRs in the hypothalamus of wt, PRAKO, and PRBKO female mice in a region- and isoform-specific manner. In the VMN, the number of PR-ir cells was increased in EB-primed mice in all three genotypes (F(1,59) = 42.31, p = 0.001; Figs. 1E,I,M, 2A), but not in vehicle controls. Interestingly, EB-treated wt and PRBKO mice had a greater number of PR-ir cells compared with PRAKO mice (F(2,59) = 5.03, p = 0.01; Fig. 2A), suggesting that PR-A is more strongly induced by EB than PR-B in the VMN.

Bottom Line: Estrogens act in brain to profoundly influence neurogenesis, sexual differentiation, neuroprotection, cognition, energy homeostasis, and female reproductive behavior and physiology through a variety of mechanisms, including the induction of progestin receptors (PRs).Interestingly, the intensity of PR-A immunoreactivity correlated with SRC-2 expression in the VMN, providing a potential mechanism for selective ER-mediated transactivation of PR-A over PR-B in a brain region-specific manner.In summary, these novel findings indicate that estrogens differentially regulate PR-A and PR-B expression in the female hypothalamus, and provide a mechanism by which steroid action in brain can selectively modulate behavior and physiology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuroscience Program, Wellesley College , Wellesley, Massachusetts 02481.

ABSTRACT
Estrogens act in brain to profoundly influence neurogenesis, sexual differentiation, neuroprotection, cognition, energy homeostasis, and female reproductive behavior and physiology through a variety of mechanisms, including the induction of progestin receptors (PRs). PRs are expressed as two isoforms, PR-A and PR-B, that have distinct functions in physiology and behavior. Because these PR isoforms cannot be distinguished using cellular resolution techniques, the present study used isoform-specific mutant mice that lack PR-A or PR-B for the first time to investigate whether 17β-estradiol benzoate (EB) regulates the differential expression of the PR isoforms in the ventromedial nucleus of the hypothalamus (VMN), arcuate nucleus, and medial preoptic area, brain regions that are rich in EB-induced PRs. Interestingly, EB induced more PR-A than PR-B in all three brain regions, suggesting that PR-A is the predominant isoform in these regions. Given that steroid receptor coactivator (SRC)-1 and SRC-2 are important in estrogen receptor (ER)-dependent transcription in brain, including PR induction, we tested whether the expression of these coactivators was correlated with PR isoform expression. The majority of EB-induced PR cells expressed both SRC-1 and SRC-2 in the three brain regions of all genotypes. Interestingly, the intensity of PR-A immunoreactivity correlated with SRC-2 expression in the VMN, providing a potential mechanism for selective ER-mediated transactivation of PR-A over PR-B in a brain region-specific manner. In summary, these novel findings indicate that estrogens differentially regulate PR-A and PR-B expression in the female hypothalamus, and provide a mechanism by which steroid action in brain can selectively modulate behavior and physiology.

No MeSH data available.