What drives labor onset remains largely unknown. Understanding the molecular mechanisms defining pregnancy duration and preparing the uterus for labor onset can help improve current treatment strategies to promote or halt labor. Biological processes with a ~24-hour cycle called circadian rhythms are generated by endogenous "clock" transcription factors referred to as the molecular clock, which drives daily changes in cellular functions. To understand the role of circadian rhythms in pregnancy, we first characterized how the molecular clock of the reproductive axis adapts to pregnancy and found the molecular clock is upregulated. Next, to understand if the molecular clock helps define pregnancy duration, we analyzed gene expression data from pregnant women. We found that low maternal levels of two clock genes increased the risk of preterm birth 5 fold. As preterm birth is driven by a premature increase in uterine contractions, we then asked how time of day impacted uterine contractile response to oxytocin, a hormone that increases uterine contractions and is widely used to induce labor. As model for human pregnancy, mice presented with daily time windows of increased uterine sensitivity to oxytocin. To determine if the molecular clock drives this daily change in sensitivity to oxytocin, we used conditional knockout mice which had the molecular clock ablated in uterine smooth muscle. These mice lost the daily change in sensitivity to oxytocin-induced contractions and presented stronger spontaneous uterine contractions than controls. In conclusion, we show that circadian rhythms have an important role in regulating pregnancy duration and uterine function, where the uterine molecular clock defines daily time windows of enhanced uterine sensitivity to oxytocin.
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