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See detailRapid changes of aromatase activity in discrete brain regions following social interactions
de Bournonville, Catherine ULg; Ball, Gregory, F.; Balthazart, Jacques ULg et al

in Trabajos del Instituto Cajal (2011), LXXXIII

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See detailImportance of steroid receptor coregulators for neuronal phenotype determination: Modulation of steroid action
Charlier, Thierry ULg

in Trabajos del Instituto Cajal (2009), LXXXII

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent ... [more ▼]

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelching, between two different nuclear receptors introduced the notion that common cofactors might be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors, which are now known as coactivators, are involved in chromatin remodeling and stabilization of the general transcription machinery. Since the characterization of the steroid receptor coactivator 1 or SRC-1, more than 100 different cofactors have been identified. Although an increasingly large amount of information has been collected about the in vitro function of these coregulatory proteins, relatively little is known regarding their physiological role in vivo, particularly in the brain. Our laboratory and others have demonstrated the importance of SRC-1 in the differentiation and activation of steroid-dependent sexual behaviors and the related neural genes. In Japanese quail, the inhibition of SRC-1 expression by intracerebroventricular antisense injections blocked the activating effects of exogenous testosterone on male sexual behaviors and the steroid-dependent vasotocine expression and increase of the median preoptic area volume defined by Nissl staining as well as by aromatase immunoreactivity. These data therefore strongly suggested that SRC-1 is required to modulate estrogen receptor dependent gene-expression. It is however interesting to note that steroid receptors and SRC-1 are not always colocalized. For example, both glial cells and neurons in the hippocampus express estrogen receptor alpha but SRC-1 is rarely observed in glia. It is therefore possible that estrogen receptor alpha in glial cell require another coactivator or set of coactivators to induce estrogen-dependent gene transcription. It has been suggested very recently that SRC-1 is associated with neuronal differentiation of neural stem cell derived from the ganglionic eminence of mouse embryos. These stem cells differentiating into glial cell (GFAP-positive) did not express SRC-1. The presence of a specific coactivator could therefore determine a specific cell phenotype (neuronal vs glial). Another coactivator, the coactivator-associated arginine methyl transferase 1 or CARM-1 seems to be important to keep progenitor cells in a dividing state. The inhibition of CARM-1 expression leads to neuronal differentiation. Neurogenesis can therefore offers an excellent model to define the spatio-temporal role of different coactivators. It is indeed possible to study a subset of coactivators associated to various stages phenotype determination (proliferation vs. differentiation). The study of neurogenesis in the dentate gyrus of the hippocampus in female adult rats shows that around 40 % of proliferative cells express SRC-1 or CARM-1. Interestingly, 70% of proliferative cells express SRC-1 but only a very few cells (<5%) express CARM-1. We are currently investigating the temporal pattern of expression of these two coactivators during the neurogenesis in the hilus and dentate gyrus. The expression of the coactivators CARM-1 and SRC-1 is analyzed in proliferating and differentiating cells. We expect that proliferating and differentiating cells will differentially express the two coactivators. It seems that the presence of a precise subset of coactivators could help defining the phenotype of the cell by modulating a specific downstream pathway after steroid receptor activation. The very large number of coactivators and their association into preformed complexes potentially allows the determination of hundreds of different phenotypes. The study of the expression of the coactivator and their function in vivo is required to fully understand steroid action and specificity in the brain. [less ▲]

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See detailModulation of steroid-dependent male sexual behavior and neural gene expression: A role for steroid receptor co-activators
Charlier, Thierry ULg; Ball, Gregory F; Balthazart, Jacques ULg

in Trabajos del Instituto Cajal (2005), 80

One of the best-characterized actions of steroids is the regulation of brain areas involved in endocrine function and in the activation of reproductive behaviors in male and female vertebrates. Progress ... [more ▼]

One of the best-characterized actions of steroids is the regulation of brain areas involved in endocrine function and in the activation of reproductive behaviors in male and female vertebrates. Progress in the understanding of the mechanisms that control the expression of the eukaryotic genome by nuclear receptors has brought forward the importance of steroid receptor coactivators in mediating efficient gene transcription. However, little is know about the specific physiological requirements of these coactivators in vivo. In Japanese quail, testosterone treatment of castrated males restores the full copulatory behavior and increases the volume of the sexually dimorphic medial preoptic nucleus (POM) to the level observed in intact males [1]. Testosterone also affects a number of sexually dimorphic neurochemical characteristics such as the vasotocineric innervation of the septum and meadial preoptic nucleus [2]. The quail therefore provides an excellent model to study steroid-dependent sexual behavior and the associated neuroplasticity and should provide insights into the modulation of steroid action by steroid receptor coactivators. The present studies were focused on the steroid receptor co-activator-1 (SRC-1), which was already shown to be involved in the process of sexual differentiation of brain and behavior in rats [3]. We first amplified by RT-PCR from quail brains a 3,411bp fragment highly homologous with the chicken (94.5%) and mammalian (70%) SRC-1 and designed digoxigenin-labeled oligonucleotides for in situ hybridization. A broad distribution of SRC-1 transcripts was observed throughout the male quail brain. A particularly dense coactivator expression was observed in limbic (e.g. POM, nucleus striae terminalis) and mesencephalic (e.g. substantia grisea centralis) nuclei associated with the control of male sexual behavior [4]. Because male and female quail exhibit a very pronounced sexual dimorphism in the steroid-dependent mechanisms that activate male-typical copulatory behavior, we investigated the potential role of SRC-1 in the sexually differentiated responses to steroids by quantifiying the SRC-1 mRNA by real time quantitative polymerase chain reaction (qPCR) and the corresponding protein by western blot (WB). Contrary to previous results, which had identified a higher SRC-1 mRNA expression in the POM of males compared to females [4], we found in two separate experiments that sexually mature females had higher concentrations of SRC-1 in the preoptic area-hypothalamus (HPOA) compared to males. Additional studies should be carried out to identify the origins of this discrepancy but seasonality and time of the day when brains were collected are potentially involved. We also quantified the SRC-1 mRNA and protein in the preoptic area-hypothalamus (HPOA) of castrated males treated or not with testosterone. SRC-1 mRNA was increased by testosterone in two independent experiments but not in a third one. This difference is likely due to the differential manipulations of the birds during these experiments. Birds had been repeatedly handled to test their sexual behavior in the first experiment and we showed that stress tends to decrease the coactivator expression in the male HPOA. This interpretation is strengthened by recent work in rats indicating that stress regulates SRC-1 expression in hypothalamus and hippocampus [5]. More surprisingly, we found a significant correlation between the expression of SRC-1 and the time of the day when birds were killed in the optic lobes, hippocampus and hindbrain. The expression of SRC-1 in the optic lobes increased throughout the day, independently of sex, testosterone treatment or stress. In the hippocampus and hindbrain, the coactivator concentration varied in opposite directions during the morning and afternoon and reached respectively its lowest or highest concentration around the middle of the day, here again independently of sex, stress and hormonal treatment. Together, these data support the idea that SRC-1 is not constitutively expressed but regulated by steroids, stress and possibly other unidentified factors. Differential controls also appear to take place in specific brain nuclei and these differential controls should be further analyzed by immunohistochemistry and in situ hybridization. A second part of our work was dedicated to the study of the physiological significance of SRC-1 whith the use of daily intra-cerebroventricular injections of modified antisense (AS) oligonucleotides (Locked nucleic acid LNA) to disrupt SRC-1 expression in the POM. AS injections significantly reduced the expression of male copulatory behavior in response to exogenous testosterone compared to control animals (Ctrl group) that received the vehicle alone or scrambled (SC) oligonucleotides. Moreover, sexual behavior was restored and even enhanced within 48 hours after interruption of AS injection (ASSC group). Western blot analysis confirmed the decrease of SRC-1 expression in AS animals and demonstrated an over-expression of the coactivator in ASSC animals. The effects of SRC-1 knock down on behavior was related to a reduced POM volume defined by Nissl-staining and aromatase immunohistochemistry. The aromatase index, indicative of the relative amount of aromatase in the POM as well as the vasotocinergic innervation of this nucleus were higher in the Ctrl group. Taken together, these findings indicate that SRC-1 functions as a critical regulatory molecule in the brain to modulate steroid-dependent gene transcription and behavior. The study of the modulation of nuclear receptors activity by different co-regulatory proteins is still in its infancy. Abnormal co-activator expression or function is currently being linked to some endocrine/neurological disorders in humans and it is thus critical to understand how co-activator expression and function are controlled in the developing as well as in the adult brain. [less ▲]

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See detailRapid changes in production and behavioral action of estrogens
Balthazart, Jacques ULg; Baillien, Michelle; Charlier, Thierry ULg et al

in Trabajos del Instituto Cajal (2005), 80

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