Importance of steroid receptor coregulators for neuronal phenotype determination: Modulation of steroid action

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.