New research shows that a tiny piece of RNA has an essential role in ensuring that embryonic tissue segments form properly.
The study, conducted in chicken embryos, determined that this piece of RNA regulates cyclical gene activity that defines the timing of the formation of tissue segments that later become muscle and vertebrae.
Genes involved in this activity are turned on and off in an oscillating pattern that matches the formation of each tissue segment. If the timing of these genes' activity doesn't remain tightly regulated, the tissue either won't form at all or will form with defects.
One gene long associated with this segmentation "clock" is called Lfng. Researchers established in this study that a single microRNA - a tiny segment of RNA that has no role in producing any protein - is key to turning off Lfng at precisely the right time as tissues form in this oscillating pattern.
When the microRNA was deleted or manipulated so that it wouldn't bind when it was supposed to, the oscillatory pattern of the genetic clock was broken and tissue development was abnormal.
"It's a big deal to find that a single interaction between a microRNA and its target has this very profound effect when you interfere with its function," said Susan Cole, associate professor of molecular genetics at The Ohio State University and lead author of the study. "There are very few cases where interfering with just one microRNA during development can make this much of a difference. But here, this regulation is so tight that this turns out to be incredibly important.
"We don't think this is exclusive to chickens because the site where the microRNA binds to the RNA segment produced by Lfng is found in chickens, humans, mice and zebrafish."
A better understanding of these segmentation clocks could lead to new ways to treat certain human conditions that are traced to embryonic development. Defects in the clock are implicated in vertebral malformations, and the correct patterning of the nervous system and blood vessels depends on proper timing of the earliest stages of development.
The research is published in the journal Developmental Cell.
This work focuses on the formation of somites, which are tissue segments in the mesoderm of embryos that give rise to the ribs, vertebrae and muscle in all vertebrates, including humans.
Within the segmentation clock, genes are turned on and make RNA, and resulting proteins then turn off the genes, and so on, and the pattern repeats until all necessary somites are formed. Experts in tissue segmentation liken the oscillating cycle of gene activation and de-activation that cells go through before they form somites to the wave that fans perform in a stadium.
The downward part of the cycle - when the wave fans are seated - is just as critical as the upward cycle, when fans are standing. This means the RNA that genes make on their way up must be destroyed so the genes can be turned off. Existing mathematical models of the segmentation clock suggest that the half-life of RNA is tightly controlled, but can't say how.