Regulatory mechanisms of expression of nuclear receptor coactivators in motoneurons

雄性大鼠球海绵体脊髓核的运动神经元支配着与阴茎相连的会阴横面肌球海绵体和提肛肌。它们含有雄激素受体（AR），在交配行为中起重要作用，这对循环雄激素水平的变化很敏感。众所周知，雄激素首先通过与AR结合，然后通过雄激素-AR复合物与DNA上作为转录因子的雄激素反应元件相互作用来调节基因表达。近年来研究表明，核受体共调节因子是核受体有效转录调控所必需的共激活因子或共抑制因子。为了阐明共调节因子的调控机制，我们通过免疫组织化学方法研究了雄激素是否调节了年轻成年雄性大鼠（2月龄）SNB运动神经元中环AMP反应元件结合蛋白（CREB）、CREB结合蛋白（CBP）和类固醇受体共激活因子-1 （SRC-1）等共调节因子的表达。在完整雄性大鼠中，强烈的CREB、CBP和SRC-1免疫反应仅限于细胞核，而不局限于SNB运动神经元的核仁。去势后雄激素的减少没有引起这些共调节因子的表达变化。这些结果表明雄激素可能不参与这些共调节因子在SNB运动神经元中的表达。另一方面，老龄动物（22月龄）的细胞核中CREB免疫反应强度、SNB运动神经元中CREB免疫阳性核数和血浆雄激素水平均明显低于幼龄动物。CREB在老年SNB运动神经元中的表达显著下降，提示随着年龄的增长，c- amp介导的SNB系统基因表达调节发生了变化。血浆雄激素水平的下降可能与这种现象无关。

Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) of male rats innervate the perineal striated muscles bulbocavernosus and levator ani that attach to the penis.They contain androgen receptors (AR) and have an important role in copulatory behavior, which is sensitive to alterations in circulating levels of androgen. It is well known that androgen regulates gen expression first by binding to AR and then by interaction of androgen-AR complex with androgen response elements on the DNA that act as transcriptional factors. Recently it has been shown that there are nuclear receptor coregulators are coactivators or corepressors that are required by nuclear receptors for efficient transcriptional regulation. To clarify regulatory mechanisms of coregulators, we examined whether androgen regulates expression of coregulators such as cyclic AMP response element-binding protein (CREB), CREB-binding protein (CBP) and steroid receptor-coactivator-1 (SRC-1) in the SNB motoneurons in young adult male rats (2 months of age) by immunohistochemistry. In intact male rats, intense CREB, CBP and SRC-1 immunoreactivity were confined to the cell nucleus, but not to the nucleolus of SNB motoneurons. Androgen withdrawal by castration did not induce any changes in expression of these coregulators. These results indicate that androgen may not participate in expression of these coregulators in SNB motoneurons. On the other hand, in aged animals (22 months of age), the intensity of CREB immunoreactivity in the nuclei, number of CREB immunopositive nuclei of the SNB motoneurons and plasma levels of androgen in aged animals were significantly reduced as compared with young ones. A marked decline in expression of CREB in the aged SNB motoneurons suggest alternation of c-AMP-mediated regulation of gene expression in the SNB system with advancing age. A decline in plasma levels of androgen may not be involved in the phenomenon.