Rumi M A Karim, Singh Prabhakar, Roby Katherine F, Zhao Xiao, Iqbal Khursheed, Ratri Anamika, Lei Tianhua, Cui Wei, Borosha Shaon, Dhakal Pramod, Kubota Kaiyu, Chakraborty Damayanti, Vivian Jay L, Wolfe Michael W, Soares Michael J
Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160.
Endocrinology. 2017 Jul 1;158(7):2330-2343. doi: 10.1210/en.2016-1916.
Estrogens are essential hormones for the regulation of fertility. Cellular responses to estrogens are mediated by estrogen receptor α (ESR1) and estrogen receptor β (ESR2). In mouse and rat models, disruption of Esr1 causes infertility in both males and females. However, the role of ESR2 in reproductive function remains undecided because of a wide variation in phenotypic observations among Esr2-mutant mouse strains. Regulatory pathways independent of ESR2 binding to its cognate DNA response element have also been implicated in ESR2 signaling. To clarify the regulatory roles of ESR2, we generated two mutant rat models: one with a null mutation (exon 3 deletion, Esr2ΔE3) and the other with an inframe deletion selectively disrupting the DNA binding domain (exon 4 deletion, Esr2ΔE4). In both models, we observed that ESR2-mutant males were fertile. ESR2-mutant females exhibited regular estrous cycles and could be inseminated by wild-type (WT) males but did not become pregnant or pseudopregnant. Esr2-mutant ovaries were small and differed from WT ovaries by their absence of corpora lutea, despite the presence of follicles at various stages of development. Esr2ΔE3- and Esr2ΔE4-mutant females exhibited attenuated preovulatory gonadotropin surges and did not ovulate in response to a gonadotropin regimen effective in WT rats. Similarities of reproductive deficits in Esr2ΔE3 and Esr2ΔE4 mutants suggest that DNA binding-dependent transcriptional function of ESR2 is critical for preovulatory follicle maturation and ovulation. Overall, the findings indicate that neuroendocrine and ovarian deficits are linked to infertility observed in Esr2-mutant rats.
雌激素是调节生育能力所必需的激素。细胞对雌激素的反应由雌激素受体α（ESR1）和雌激素受体β（ESR2）介导。在小鼠和大鼠模型中，Esr1的破坏会导致雄性和雌性不育。然而，由于Esr2突变小鼠品系之间的表型观察存在很大差异，ESR2在生殖功能中的作用仍未确定。独立于ESR2与其同源DNA反应元件结合的调节途径也与ESR2信号传导有关。为了阐明ESR2的调节作用，我们构建了两种突变大鼠模型：一种是无效突变（外显子3缺失，Esr2ΔE3），另一种是框内缺失，选择性破坏DNA结合结构域（外显子4缺失，Esr2ΔE4）。在这两种模型中，我们观察到ESR2突变的雄性具有生育能力。ESR2突变的雌性表现出规律的发情周期，可以被野生型（WT）雄性授精，但不会怀孕或假孕。尽管存在处于不同发育阶段的卵泡，但Esr2突变的卵巢较小，且与WT卵巢不同，没有黄体。Esr2ΔE3和Esr2ΔE4突变的雌性表现出排卵前促性腺激素激增减弱，并且对在WT大鼠中有效的促性腺激素方案没有排卵反应。Esr2ΔE3和Esr2ΔE4突变体中生殖缺陷的相似性表明，ESR2的DNA结合依赖性转录功能对于排卵前卵泡成熟和排卵至关重要。总体而言，这些发现表明神经内分泌和卵巢缺陷与Esr2突变大鼠中观察到的不育有关。
