By Joseph Milton
The molecular changes that trigger the uterus to start contracting at the beginning of childbirth have been worked out in detail. The research could eventually help the design of therapies to prevent premature birth, a significant cause of infant mortality and disability in developed countries.
There are few effective treatments to block early labor, perhaps in part because the molecular mechanism that underlies the onset of contractions has remained elusive--until now.
Researchers at the University of Texas Southwestern Medical Center in Dallas, led by biochemist Carole Mendelson, analyzed the changes in the expression of different genes in the mouse uterus wall when contractions begin.
The hormone progesterone is known to have an important role in inducing labor in both mice and humans. In mice, the level of progesterone remains high during pregnancy and as it falls, contractions begin. However, in pregnant women, the levels of progesterone remain the same and instead, the sensitivity of progesterone receptors decreases--a change that effectively means the level of circulating progesterone drops, thus causing contractions to start.
In both species, the drop in progesterone leads to changes in the expression of tiny fragments of RNA, called microRNAs
Mendelson and her team have now found that the levels of one group of miRNAs, called the miR-200 family, increase significantly during late pregnancy and in labor. The results are detailed in the November 15 issue of Proceedings of the National Academy of Sciences.
Looking at gene expression levels in samples of mouse uterus, the team uncovered a complex interaction between these miRNAs and two genes called ZEB1 and ZEB2. The two genes are sensitive to progesterone so are active during pregnancy, when levels of the hormone are high. Both the ZEB1 and ZEB2 proteins suppress other genes that encode proteins involved in muscle contraction and labor, such as the oxytocin receptor and connexin-43. The ZEB1 protein also suppresses the production of miR-200 molecules.
When progesterone levels fall before labor, the level of ZEB1 also decreases. That leads to an increase in miR-200 molecules, which suppresses both ZEB1 and ZEB2, and in turn promotes further expression of the miRNAs.
This means that there is insufficient ZEB1 and ZEB2 to suppress the oxytocin receptor and connexin-43 genes associated with contractions, so those genes are up-regulated and labor begins. "There's a double negative feedback loop," says Mendelson.
To ensure that what the researchers saw in mouse tissue was also occurring in humans, they looked at gene expression in cultured human cells from the uterus wall. "This miRNA family is highly conserved between mice and humans and the mechanism also appears to be conserved," explains Mendelson.
Mendelson says that many women go into early labor because bacterial infection leads to inflammation, which can induce labor. And labor itself resembles the body's inflammatory response, she notes, in which foreign material is ejected from the body.
The team then used two mouse models of preterm labor to investigate whether the same changes in miRNAs and ZEB1/2 occur. One model involved treating pregnant mice with labor-inducing hormones, and the other induced an inflammatory response in the mice by exposing tissues to lipopolysaccharide toxins that are normally found in bacterial cell walls.
The researchers found that in both models, levels of the miRNAs, ZEB1/2 and the genes associated with contractions followed the same pattern as in their expression-analysis experiments. "We think that this is the same pathway that is operating in preterm labor," Mendelson says.
Mendelson says it has taken this long to identify the mechanism behind labor partly because researchers were looking for more obvious and specific targets. "ZEB is expressed in a number of different cell types," she says. "It's not something that anyone would normally consider to be uniquely associated with pregnancy and labor, so nobody paid any attention to it."
"We already knew that inflammation was a mechanism for preterm labor," says Phillip Bennett, clinical professor in the department of surgery and cancer at Imperial College London, "but this research adds another piece of the jigsaw as to how inflammation might cause it."
With few available treatments to prevent early labor, Bennett says that a therapy to block the signal is the "holy grail" of preterm labor research. "This work suggests to me that an anti-inflammatory approach might inhibit these particular pathways," says Bennett.
Mendelson thinks that therapies based on suppressing the miRNAs involved may be feasible. She explains that ultimately, she and her team plan to look at miRNA antagonists that interfere with miRNA action in mice. "That's the next area of investigation for us," she says.