Rethinking progesterone regulation of female reproductive cyclicity
Rethinking progesterone regulation of female reproductive cyclicity
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DOI：
10.1073/pnas.1601825113
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发表时间：
2016-04-12
影响因子：
11.1
通讯作者：
Soares, Michael J.
中科院分区：
文献类型：
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作者：
Kubota, Kaiyu;Cui, Wei;Soares, Michael J.
孕激素受体（PGR）是一种配体激活的转录因子，在调节女性生育力中起关键作用。通过使用药理学抑制剂和遗传操作，使用小鼠诱变，已经了解了很多PGR信号传导的作用。在Pgr基因座的一个无效突变的大鼠的特点，迫使重新检查孕酮在调节女性生殖周期的作用。我们使用基因组编辑生成了两种Pgr突变大鼠模型。在这两种情况下，缺失产生无效突变，由无义移码和终止密码子的出现引起。与Pgr基因敲除小鼠相似，Pgr基因敲除大鼠由于性行为、排卵和子宫内膜分化缺陷而不育。然而，与所报道的Pgr信号传导中断的雌性小鼠的表型相反，Pgr缺失雌性大鼠表现出稳健的发情周期。周期性变化的阴道细胞学，子宫组织学，血清激素水平，和车轮运行活动是明显的PGR空雌性大鼠，类似于野生型对照。此外，外源性孕酮治疗抑制野生型雌性大鼠的发情周期，但在PGR无效的雌性大鼠。如前所述，药理学拮抗作用支持PGR信号传导在调节排卵促性腺激素激增中的作用，这一结果与使用PGR信号传导的基因消融的实验不同。总之，我们的研究结果在PGR无效大鼠挑战目前的假设，并提示生殖周期的激素控制的重新评估。
The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity.