TY - JOUR T1 - Estradiol preferentially induces progestin receptor-A (PR-A) over PR-B in cells expressing nuclear receptor coactivators in the female mouse hypothalamus JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0012-15.2015 SP - ENEURO.0012-15.2015 AU - Kalpana D. Acharya AU - Sarah D. Finkelstein AU - Elizabeth P. Bless AU - Sabin A. Nettles AU - Biserka Mulac-Jericevic AU - Orla M. Conneely AU - Shaila K. Mani AU - Marc J. Tetel Y1 - 2015/07/31 UR - http://www.eneuro.org/content/early/2015/07/31/ENEURO.0012-15.2015.abstract N2 - 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 (PR). PR 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 if 17β-estradiol benzoate (EB) regulates differential expression of the PR isoforms in the ventromedial nucleus of the hypothalamus (VMN), arcuate nucleus (ARC) and medial preoptic area (MPA), brain regions rich in EB-induced PR. 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-1 (SRC-1) and SRC-2 are important in estrogen receptor (ER)-dependent transcription in brain, including PR induction, we tested if 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, 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.Significance Statement: Progesterone acts in brain to influence neuroprotection, sexual differentiation, cognition, energy homeostasis and reproduction. Many of these effects are mediated through the estradiol-induction of the two progestin receptor (PR) isoforms, PR-A and PR-B, which have distinct functions. However, due to the inability to distinguish these two PR isoforms at the cellular level, it is not known if estradiol differentially induces these isoforms in brain. Using PR isoform specific knock-out mice, we show that estradiol differentially regulates these PR isoforms in a brain region-specific manner. Furthermore, our data suggest that the cofactor, SRC-2, preferentially functions in the estradiol-induction of hypothalamic PR-A, but not PR-B. These findings provide a mechanism by which progestin action in brain can selectively regulate behavior and physiology. ER -