Mani S K, Allen J M, Lydon J P, Mulac-Jericevic B, Blaustein J D, DeMayo F J, Conneely O, O'Malley B W
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Endocrinol. 1996 Dec;10(12):1728-37. doi: 10.1210/mend.10.12.8961281.
Using the recently generated mutant mice strain (PRKO) carrying a null mutation for the progesterone receptor (PR) gene by gene targeting, we examined the critical role of PR as a coordinator of key regulatory events involved in the steroid hormone and dopamine-facilitated sexual behavior in female mice. In vitro one-point binding analyses of estradiol benzoate (EB)-induced cellular PRs and immunohistochemistry of PR in the mediobasal hypothalamus demonstrated a reduction in binding in the homozygous females, equivalent to background levels seen in EB-unresponsive tissue. The biochemical findings correlated well with the behavioral observations, with the wild type females exhibiting high levels of lordosis, while the homozygous females showed minimal lordosis in response to mating by male mice. As a critical validation of our earlier studies on ligand-independent activation of PRs by dopamine, we examined the facilitation of sexual behavior by a dopamine agonist in the null mutants. Wild type females having the full complement of PRs exhibited high levels of lordosis, while the homozygous females showed minimal lordosis in response to dopamine. To determine whether this reduced response was due to a general lack of ability to express lordosis, mice were treated with another neurotransmitter, serotonin. No significant difference in the serotonin-facilitated lordosis response was observed between the wild type and the homozygous females. We conclude that multiple signal transduction pathways coexist in the neuroendocrine system for reproductive behavior, with PR acting as a transcriptional mediator for dopamine, as well as progesterone, to achieve integration of neural communication in the central nervous system.
利用最近通过基因靶向技术产生的携带孕酮受体（PR）基因无效突变的突变小鼠品系（PRKO），我们研究了PR作为雌性小鼠甾体激素和多巴胺促进性行为中关键调控事件协调者的关键作用。对雌二醇苯甲酸酯（EB）诱导的细胞PR进行体外单点结合分析以及对中基底下丘脑PR进行免疫组织化学分析，结果表明纯合雌性小鼠的结合减少，相当于在对EB无反应组织中所见的背景水平。这些生化结果与行为观察结果高度相关，野生型雌性小鼠表现出高水平的脊柱前凸，而纯合雌性小鼠在雄性小鼠交配时表现出最小程度的脊柱前凸。作为对我们早期关于多巴胺对PR进行非配体依赖性激活研究的关键验证，我们研究了多巴胺激动剂对无效突变体性行为的促进作用。具有完整PR的野生型雌性小鼠表现出高水平的脊柱前凸，而纯合雌性小鼠对多巴胺的反应则表现出最小程度的脊柱前凸。为了确定这种反应降低是否是由于普遍缺乏表达脊柱前凸的能力，用另一种神经递质血清素对小鼠进行处理。在野生型和纯合雌性小鼠之间，未观察到血清素促进的脊柱前凸反应有显著差异。我们得出结论，神经内分泌系统中存在多种用于生殖行为的信号转导途径，PR作为多巴胺以及孕酮的转录介质，以实现中枢神经系统中神经通讯的整合。
