Nuclear Receptor Coactivators Are Coexpressed with Steroid Receptors and Regulated by Estradiol in Mouse Brain

Abstract

Background/Aims: The steroid hormones, including estradiol (E) and progesterone, act in the brain to regulate female reproductive behavior and physiology. These hormones mediate many of their biological effects by binding to their respective intracellular receptors. The receptors for estrogens (ER) and progestins (PR) interact with nuclear receptor coactivators to initiate transcription of steroid-responsive genes. Work from our laboratory and others reveals that nuclear receptor coactivators, including steroid receptor coactivator-1 (SRC-1) and SRC-2, function in brain to modulate ER-mediated induction of the PR gene and hormone-dependent behaviors. In order for steroid receptors and coactivators to function together, both must be expressed in the same cells. Methods: Triple-label immunofluorescence was used to determine if E-induced PR cells also express SRC-1 or SRC-2 in reproductively relevant brain regions of the female mouse. Results: The majority of E-induced PR cells in the medial preoptic area (61%), ventromedial nucleus of the hypothalamus (63%) and arcuate nucleus (76%) coexpressed both SRC-1 and SRC-2. A smaller proportion of PR cells expressed either SRC-1 or SRC-2, while a few PR cells expressed neither coactivator. In addition, compared to control animals, 17β-estradiol benzoate (EB) treatment increased SRC-1 levels in the arcuate nucleus, but not the medial preoptic area or the ventromedial nucleus of the hypothalamus. EB did not alter SRC-2 expression in any of the three brain regions analyzed. Conclusions: Taken together, the present findings identify a population of cells in which steroid receptors and nuclear receptor coactivators may interact to modulate steroid sensitivity in brain and regulate hormone-dependent behaviors in female mice. Given that cell culture studies reveal that SRC-1 and SRC-2 can mediate distinct steroid-signaling pathways, the present findings suggest that steroids can produce a variety of complex responses in these specialized brain cells.

Effects of gonadal steroids and of estrogen receptor agonists on the expression of estrogen receptor alpha in the medial preoptic nucleus of female rats

“…The fact that this repressive action disappears when both ERs are simultaneously activated suggests a higher transcriptional activity of the ERa. The possible functional consequences of these effects are difficult to predict as MPN neurons are interconnected in a complex network system and it is known that the activation of ERa by estradiol activates a plethora of downstream pathways that modulate the expression of other receptor systems, like l-opioid receptors (Micevych et al, 2003), and cause the differential expression of several hormone receptors and co-activators (Micevych and Sinchak, 2008;Tognoni et al, 2011). …”

Convergence of Multiple Mechanisms of Steroid Hormone Action

“…In order for SRC-1 and SRC-2 to function with steroid receptors in brain, both the coactivator and receptor must be expressed in the same cells. In support, SRC-1 and SRC-2 are expressed in the majority of estradiol-induced PR cells in regions involved in metabolism and behavior, including the ventromedial hypothalamus (VMH), medial preoptic area and arcuate nucleus in rodents [35,49]. A variety of studies reveal that steroids influence the expression of these coactivators in brain [35,43,50-52].…”

“…In support, SRC-1 and SRC-2 are expressed in the majority of estradiol-induced PR cells in regions involved in metabolism and behavior, including the ventromedial hypothalamus (VMH), medial preoptic area and arcuate nucleus in rodents [35,49]. A variety of studies reveal that steroids influence the expression of these coactivators in brain [35,43,50-52]. Moreover, protein-protein interactions studies reveal that SRC-1 and SRC-2 from rodent brain physically associate with ER and PR in a receptor subtype- and brain region-specific manner [53,54].…”

Steroid receptor coactivator 2 modulates steroid‐dependent male sexual behavior and neuroplasticity in Japanese quail (Coturnix japonica)

“…Interestingly, about 90% of progesterone receptor‐positive cells in the VMN co‐express SRC‐1 (Tetel et al. 2007) and over 60% of progesterone receptor‐positive cells in the VMN express both SRC‐1 and SRC‐2 (Tognoni et al. 2011).…”

“…Both coactivators are expressed in the same brain nuclei, including those involved in the control of sexual behavior (Apostolakis et al 2002;Nishihara et al 2003) and both SRC-1 and SRC-2 are involved in the estrogen-dependent expression of PR in female rat VMN (Apostolakis et al 2002;Molenda et al 2002). Interestingly, about 90% of progesterone receptor-positive cells in the VMN co-express SRC-1 ) and over 60% of progesterone receptor-positive cells in the VMN express both SRC-1 and SRC-2 (Tognoni et al 2011). Similarly, our data show that SRC-1 and -2 are both implicated in the control of testosterone-dependent aromatase expression in the POM (present data and Charlier et al 2005).…”