Importance of steroid receptor coactivators in the modulation of steroid action on brain and behavior

Steroid receptors such as estrogen and androgen receptors are nuclear receptors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent protein 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 may be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors or coregulatory proteins are functionally divided into coactivators and corepressors and are involved in chromatin remodeling and stabilization of the general transcription machinery. Although a 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. For example, we report that the inhibition of SRC-1 expression blocks the activating effects of exogenous testosterone on male sexual behaviors and increases the volume of the median preoptic area. Other coactivators are likely to be involved in the modulation in vivo of steroid receptor activity and it seems that the presence of a precise subset of coactivators could help define 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.