MicroRNAs, tiny molecules, act together with hormones to control the start of labour, and this discovery has led researchers to believe that RNA-based drugs could prevent premature labour.
Using pregnant mice as well as human uterine tissue, the researchers at UT Southwestern Medical Center have uncovered a feedback cycle involving microRNAs, proteins called ZEB1 and ZEB2, and the pregnancy-maintaining hormone progesterone, as well as genes and other factors that control contraction of the uterus.
"Our findings indicate that progesterone controls a family of microRNAs whose levels dramatically increase right before labor. At the same time, levels of the microRNAs' targets, the ZEB proteins, decrease. This enables uterine contractions," said Carole Mendelson, senior author of the study.
MicroRNAs interact with other protein-making molecules in cells, helping to fine-tune the expression of networks of genes and control cell function, said Mendelson.
In the new study, the researchers measured microRNA levels in the uteri of mice in mid-pregnancy and near labor. As labor approached, the level of a group of microRNAs called the miR-200 family greatly increased. When the researchers artificially stimulated premature labor, the miR-200 levels also increased.
The miR-200s block the production of two proteins called ZEB1 and ZEB2. In contrast, progesterone directly increases ZEB1 levels.
"We found that during pregnancy, progesterone acts on the feedback loop to keep the microRNA levels down and the ZEBs up," said Nora Renthal, lead author of the study.
"The ZEBs, in turn, inhibit contraction-associate genes. But then, just prior to labor, there's a switch. Progesterone action decreases; the ZEBs are suppressed; the miR-200s increase; and the contraction-associated genes are turned on," said Renthal.
The study appeared in the online issue of the Proceedings of the National Academy of Sciences.