Conditional Deletion of Bmal1 in Ovarian Theca Cells Disrupts Ovulation in Female Mice
Conditional Deletion of Bmal1 in Ovarian Theca Cells Disrupts Ovulation in Female Mice
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DOI：
10.1210/en.2015-1645
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Sellix, Michael T.
中科院分区：
文献类型：
--
作者：
Mereness, Amanda L.;Murphy, Zachary C.;Sellix, Michael T.
女性生殖生理学中的节律性事件，包括排卵，受到昼夜节律计时系统的严格控制。分子钟是生物钟基因转录因子的反馈环振荡器，决定着下丘脑-垂体-卵巢轴基因表达的节律。由于环境因素（如轮班工作）或生物钟的遗传操纵而导致的昼夜节律紊乱对生育力有负面影响。尽管视交叉上核的中枢起搏器经典地调节排卵的时间，我们已经证明这种节律也依赖于对LH的阶段性敏感性。我们假设这种节律依赖于卵泡特定细胞区室的生物钟功能。为了检验这一假设，我们产生了在卵巢颗粒细胞（GC）（颗粒细胞Bmal 1 KO; GCKO）或卵泡膜细胞（TC）（卵泡膜细胞Bmal 1 KO; TCKO）中缺失Bmal 1基因座的小鼠。生殖周期，排卵前LH分泌，卵巢形态和行为在GCKO或TCKO小鼠中没有明显改变。我们在野生型同窝对照（LC）和GCKO小鼠中检测到对LH的阶段性敏感性，但TCKO小鼠未检测到。这种对LH敏感性的下降与TCKO小鼠卵巢中生育能力受损和LH受体（Lhcgr）mRNA丰度模式改变一致。这些数据表明，TC是一个起搏器，通过调节对LH的阶段性敏感性，促进排卵的时间和幅度。TC时钟可能在昼夜节律紊乱介导的生殖病理学中发挥关键作用，并且可能是由于环境昼夜节律紊乱和/或女性中的生物钟依赖性重编程而导致的不孕症的时间生物学管理的目标。
Rhythmic events in female reproductive physiology, including ovulation, are tightly controlled by the circadian timing system. The molecular clock, a feedback loop oscillator of clock gene transcription factors, dictates rhythms of gene expression in the hypothalamo-pituitary-ovarian axis. Circadian disruption due to environmental factors (eg, shift work) or genetic manipulation of the clock has negative impacts on fertility. Although the central pacemaker in the suprachiasmatic nucleus classically regulates the timing of ovulation, we have shown that this rhythm also depends on phasic sensitivity to LH. We hypothesized that this rhythm relies on clock function in a specific cellular compartment of the ovarian follicle. To test this hypothesis we generated mice with deletion of the Bmal1 locus in ovarian granulosa cells (GCs) (Granulosa Cell Bmal1 KO; GCKO) or theca cells (TCs) (Theca Cell Bmal1 KO; TCKO). Reproductive cycles, preovulatory LH secretion, ovarian morphology and behavior were not grossly altered in GCKO or TCKO mice. We detected phasic sensitivity to LH in wild-type littermate control (LC) and GCKO mice but not TCKO mice. This decline in sensitivity to LH is coincident with impaired fertility and altered patterns of LH receptor (Lhcgr) mRNA abundance in the ovary of TCKO mice. These data suggest that the TC is a pacemaker that contributes to the timing and amplitude of ovulation by modulating phasic sensitivity to LH. The TC clock may play a critical role in circadian disruption-mediated reproductive pathology and could be a target for chronobiotic management of infertility due to environmental circadian disruption and/or hormone-dependent reprogramming in women.