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 null 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.
Highlights
estradiol benzoate (EB)-treated wt and PRBKO mice had a greater number of progestin receptors (PRs)-ir cells compared with PRAKO mice (F(2,59) ϭ 5.03, p ϭ 0.01; Fig. 2A), suggesting that PR-A is more strongly induced by EB than PR-B in the ventromedial nucleus of the hypothalamus (VMN)
PR-A is expressed more than PR-B in mouse brain Using PR isoform-specific null mutant mice that express PR-A only (PRBKO) or PR-B only (PRAKO), we found that EB induces differential expression of the PR isoforms in the adult female hypothalamus
The present and novel results that PR-A is expressed more than PR-B in reproductively relevant brain regions provide a mechanism by which progestin action can be modulated in brain
Summary
The sex steroid hormones estradiol and progesterone act in the brain to influence neurogenesis, neuroprotection, sexual differentiation, learning and memory, energy homeostasis, and reproductive behavior and physiology (Simerly, 2005; Brinton et al, 2008; Barha and Galea, 2010; Pfaff et al, 2011; Mani and Oyola, 2012; McCarthy and Nugent, 2013; Bless et al, 2014; Arevalo et al, 2015; Frick, 2015; López and Tena-Sempere, 2015; Willing and Wagner, 2015). In the classic genomic mechanism of action, the steroid binds to its receptor and the activated receptors bind to the promoter region of target genes to mediate gene transcription (Kraus et al, 1994; Stanisicet al., 2010). These receptors can elicit profound effects on behavior and physiology by functioning independent of the ligand on DNA or at the membrane to rapidly activate cytoplasmic signaling pathways (Kelly and Rønnekleiv, 2008; Vasudevan and Pfaff, 2008; Mani et al, 2012; Sinchak and Wagner, 2012). Except for the PR-B upstream sequences (BUS region of ϳ165 aa), both PRs are identical and contain a variable N-terminal regulatory domain, a highly conserved DNA binding domain, a C-terminal ligand-binding domain
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