Acute disruption of select steroid receptor coactivators prevents reproductive behavior in rats and unmasks genetic adaptation in knockout mice.
Acute disruption of select steroid receptor coactivators prevents reproductive behavior in rats and unmasks genetic adaptation in knockout mice.
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DOI：
10.1210/mend.16.7.0877
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发表时间：
2002-07
影响因子：
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通讯作者：
E. M. Apostolakis;Meera Ramamurphy;Dan Zhou;S. Oñate;B. O’Malley
中科院分区：
文献类型：
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作者：
E. M. Apostolakis;Meera Ramamurphy;Dan Zhou;S. Oñate;B. O’Malley
雌激素和孕激素对发育和生殖有着重要的影响。在体外，类固醇受体辅激活因子（SRC）是与DNA结合的类固醇受体相互作用以增强其转录效率的核蛋白。我们研究了SRC-1、SRC-2和SRC-3的反义寡核苷酸对雌性性行为和类固醇受体介导的转录的影响。克隆大鼠（r）SRC-1、rSRC-2和rSRC-3基因。我们的研究结果表明，SRC-1和SRC-2的反义核酸（AS）对雌激素诱导的生殖行为有显著的抑制作用，而SRC-3则无此作用。重要的是，性行为通过雌激素受体α（ER α）依赖性转录而不是孕激素受体（PR）依赖性转录减弱，因为E不能诱导内侧基底下丘脑中PR含量的合成，并且在rSRC-1-AS-和rSRC-2-AS-处理的组织中，腹内侧核中的免疫反应性PR被耗尽，而不是rSRC-3-AS-处理的，用E致敏的大鼠。与ER α诱导的转录中断一致，单独高剂量E和表皮生长因子不能诱导用rSRC-1-AS或SRC-2-AS处理的雌性的性行为。免疫反应性SRC-1和SRC-2，但不是SRC-3，蛋白质丰富的腹内侧核，从而表明，下丘脑类固醇受体的生物活性选择性地调节特定SRC的区域分布。由于SRC-1基因敲除小鼠的生殖功能仅有轻微损失，因此测试了在发育期间发生遗传适应的可能性。小鼠（m）SRC-1-AS抑制野生型的脊柱前凸，但不能抑制SRC-1基因敲除小鼠的脊柱前凸，而mSRC-2-AS抑制两种基因型的行为。mSRC-3-AS对两种基因型均无影响，SRC-3敲除小鼠表现出完全的感受性。总的来说，这些发现清楚地表明在完整的女性大脑中SRC-1和SRC-2对ER α依赖性功能的双重调节。在SRC-1的遗传（但非急性）缺失中，SRC-2的上调在雌性发育期间充当关键的适应机制。
Estrogen (E) and progesterone exert profound influence on development and reproduction. In vitro, steroid receptor coactivators (SRCs) are nuclear proteins that interact with DNA-bound steroid receptors to potentiate their transcriptional efficiency. We examined the effects of antisense oligonucleotides to SRC-1, SRC-2, and SRC-3 on female sexual behavior and steroid receptor-mediated transcription. Rat (r) SRC-1, rSRC-2, and rSRC-3 genes were cloned. Our results reveal a significant inhibitory effect by antisense (AS) to SRC-1 and SRC-2, but not SRC-3, on hormone-induced reproductive behavior. Importantly, sexual behavior was attenuated through estrogen receptor alpha (ERalpha)-dependent, rather than progesterone receptor (PR)-dependent, transcription, as E failed to induce the synthesis of PR content in the medial basal hypothalamus, and immunoreactive PR in the ventromedial nucleus were depleted in tissue from rSRC-1-AS- and rSRC-2-AS-treated, but not rSRC-3-AS-treated, rats primed with E. Consistent with interruption of ERalpha-induced transcription, high dose of E and epidermal growth factor alone failed to induce sexual behavior in females treated with either rSRC-1-AS or SRC-2-AS. Immunoreactive SRC-1 and SRC-2, but not SRC-3, proteins were abundant in the ventromedial nucleus, thus demonstrating that the biological activities of hypothalamic steroid receptors are selectively regulated by regional distribution of specific SRCs. As SRC-1 knockout mice have only a slight loss in reproductive function, the possibility that genetic adaptation occurs during development was tested. Mouse (m) SRC-1-AS suppressed lordosis in wild-type, but not SRC-1, knockout mice, whereas mSRC-2-AS suppressed behavior in both genotypes. mSRC-3-AS had no effect in either genotype, and SRC-3 knockout mice exhibited full receptivity. Collectively, the findings clearly implicate dual regulation of ERalpha-dependent function by SRC-1 and SRC-2 in the intact female brain. In the genetic, but not acute, absence of SRC-1, up-regulation of SRC-2 serves as a critical adaptive mechanism during female development.