Nuclear Receptor Coactivators Modulate Hormone-Dependent Gene Expression in Brain and Female Reproductive Behavior in Rats

Abstract

Gonadal steroid hormones act in the brain to elicit changes in gene expression that result in profound effects on behavior and physiology. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Two nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and cAMP response element binding protein-binding protein (CBP), have been shown to act in concert to enhance ER activity in vitro. In the present study, we investigated the function of these important nuclear receptor coactivators in estrogen action in rodent brain. Reduction of SRC-1 and CBP protein in brain disrupted ER-mediated activation of the behaviorally relevant progestin receptor gene. Furthermore, we found that SRC-1 and CBP function in brain to modulate the expression of hormone-dependent female sexual behavior. These findings indicate that these nuclear receptor coactivators function in brain to modulate ER transcriptional activity and the expression of hormone-dependent behavior.

Inhibition of Steroid Receptor Coactivator-1 Blocks Estrogen and Androgen Action on Male Sex Behavior and Associated Brain Plasticity

“…In a previous study that investigated the actions of coactivators for adult sexual behaviors, both SRC-1 and CBP were blocked and only moderate effects were observed on the ability of estrogen to facilitate the lordosis response (intensity only), as well as to induce the expression of the progesterone receptor in female rats (Molenda et al, 2002). Another study, however, demonstrated a profound inhibition of lordosis in female rats treated with SRC-1 antisense (Apostolakis et al, 2002).…”

“…Previous studies have indicated the importance of coactivators for the actions of estrogen on brain and behavior in female rodents during ontogeny and in adulthood (Auger et al, 2000;Molenda et al, 2002). In a previous study that investigated the actions of coactivators for adult sexual behaviors, both SRC-1 and CBP were blocked and only moderate effects were observed on the ability of estrogen to facilitate the lordosis response (intensity only), as well as to induce the expression of the progesterone receptor in female rats (Molenda et al, 2002).…”

“…SRC-1 may also play a role in the estrogenic activation of female sexual behaviors (Molenda et al, 2002). Studies with SRC-1 knock-out mice found no significant effects on female sexual responding, but it was demonstrated that developmental compensation had occurred based on the upregulation of other coactivators (Apostolakis et al, 2002).…”

Trans-activators Regulating Neuronal Glucose Transporter Isoform-3 Gene Expression in Mammalian Neurons

“…Variance in how CREB is being phosphorylated determines those co-regulatory proteins that are recruited to the transcriptional complex. The formation of unique transcriptional complexes may be a mechanism by which CREB can induce different patterns of gene transcription within the brain (58,(61)(62)(63)(64). CBP also increases genomic activity by acetylating histones, leading to a reduction in higher order chromatin structures and making DNA more accessible to transcription factors (65,66).…”

Histone modifications proposed to regulate sexual differentiation of brain and behavior

“…Such mechanisms of transcriptional regulation employed by ERs have been described in neuronal as well as non-neuronal systems [34][35][36][37], and a large number of cofactors involved in ER-mediated transactivation have already been identified [22][23][24][38][39][40]. Among them, nuclear receptor coactivators, SRC and CPB, as well as the corepressor NCoR exhibit sexually dimorphic pattern of expression [41][42][43], and are necessary for the development of sexually dimorphic behaviors in adulthood [42][43][44].…”