Steroid receptor coactivator-1 (SRC-1) mediates the development of sex-specific brain morphology and behavior

Abstract

Steroid hormone action during brain development exerts profound effects on reproductive physiology and behavior that last into adulthood. A variety of in vitro studies indicate that steroid receptors require nuclear receptor coactivators for efficient transcriptional activity. To determine the functional significance of the nuclear receptor coactivator SRC-1 in developing brain, we investigated the consequence of reducing SRC-1 protein during sexual differentiation of the brain. We report that reducing SRC-1 protein interferes with the defeminizing actions of estrogen in neonatal rat brain. Our data indicate that SRC-1 protein expression is critically involved in the hormone-dependent development of normal male reproductive behavior and brain morphology. Intracellular receptors for steroid hormones constitute a superfamily of transcription factors that includes receptors for estrogens, progestins, androgens, glucocorticoids, thyroid hormone, retinoic acid, and 9-cis retinoic acid along with numerous orphan receptors with as-yet unidentified ligands (1). Spontaneously occurring mutations in steroid receptors or disruptions of normal steroid hormone levels during development have profound and devastating effects on adult reproductive physiology (2-4). However, not all endocrine-related disorders can be explained by disruptions in steroid receptors or hormone levels, and a potential role for an additional class of proteins, nuclear receptor coregulators, has been implicated (5).Steroid hormones act in the brain by binding to intracellular receptors located predominantly in neurons. On ligand binding, the steroid-receptor complex binds to a hormone response element located on DNA (6, 7) where it regulates gene transcription and ultimately neuronal function (7,8). Recent studies reveal that steroid receptors interact with other proteins, nuclear receptor coactivators or corepressors, that increase or decrease their binding and action at the hormone response element, respectively. The first nuclear receptor coactivator to be characterized is steroid receptor coactivator-1 (SRC-1; refs. 9 and 10). The majority of studies to date have used transfection assays in cell culture systems in which large quantities of steroid receptors are expressed to elucidate interactions with coactivators and corepressors. Although this approach is valid, it does not allow for assessment of the in vivo role of nuclear receptor coactivators and their physiological significance, which remain largely unknown at this time. A recent study indicates that peripheral steroid target organs of mice containing a targeted disruption of the SRC-1 gene have a decreased response to steroid hormones (11); however, it is not known whether SRC-1 protein mediates steroid hormone action within the developing brain.To determine the functional significance of SRC-1, we examined the influence of SRC-1 on sexual differentiation of the rodent brain. The developing brain is an exquisitely sensitive target organ for steroid hormones, which differentiate the neural s...

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

“…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 is necessary for the estrogenic defeminization of sexual behavior in male rats and the masculinizing effects of estrogen on the volume of the sexually dimorphic nucleus of the preoptic region (Auger et al, 2000). SRC-1 may also play a role in the estrogenic activation of female sexual behaviors (Molenda et al, 2002).…”

Transactivation Specificity of Glucocorticoid VersusProgesterone Receptors

“…Similar quantitative differences have been noted for other steroid receptors. SRC-1 has a greater effect on ER than AR action in the brain of developing rats (42), which may result from SRC-1 interacting with the ER LBD via the LXXLL motifs of SRC-1 but with the amino-terminal region of AR in a manner that does not depend on the SRC-1 LXXLL motifs (34). SRC-1e interacts with the fragments containing the DNA binding domain and LBD of ER but not of AR (28).…”

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids

“…The p160 coregulator Steroid Receptor Coactivator (SRC-1) is strongly expressed in brain (11), can affect neuronal differentiation (12), and mediates effects of androgens and estrogens in brain areas involved in sexual behavior (13)(14)(15). SRC-1 is a multimodal protein that can also interact with nonnuclear receptor transcription factors (16,17), but to date these have not been shown to be relevant in the brain.…”