Novel mechanism to steer cell identities gives clue on how organisms develop

"We set out from a curious observation in the nematode worm C. elegans," explains Luisa Cochella. "We noticed that the gene mir-791 was expressed specifically in neurons we knew were responsible for the detection of carbon dioxide." The tiny worm is a common model organism because its anatomy and cell functions are very well-understood and can be observed easily under a microscope. When the worms detect carbon dioxide, they start moving in a characteristic way, giving the scientists an easy tool to indirectly "watch" molecular processes by observing the worms' behaviour.

When the scientists removed mir-791 from the worms, the animals had trouble responding to carbon dioxide. Normally, mir-791 prevents the expression of two genes exclusively in the neurons that detect carbon dioxide, while these same two genes are expressed in pretty much all other cells of the worm. When this repression mechanism fails, the carbon dioxide sensing neurons do not work properly and animals cannot respond adequately to an environmental cue that, in its natural environment, could determine whether the worm lives or dies. The question how the identity of cells is determined in the course of their development, however, goes far beyond nematodes -- it is a fundamental question in biology.

The cells that form our bodies belong to hundreds of different cell types that are shaped by the combinations of genes they express. For example, hemoglobin is produced in red blood cells where it is necessary for oxygen transport, while neurotransmitter receptors are made in neurons where they allow these cells to communicate with each other. On the other hand, a number of genes that are required for more common functions of cells are expressed by most, if not all cells. These are called ubiquitous genes.

In rare cases, ubiquitous genes are not expressed in a specific cell type, where reduced levels of these genes are necessary for the correct function of this particular cell type. The unique properties of a cell can therefore not only be specified by the genes it expresses, but also by the genes it prevents from being expressed. However, the mechanisms that underlie the highly specific repression of genes in some cells have remained puzzling, which is why this study is important.

What was characterised as a developmental mechanism could also be relevant for evolution. The responses of different animals to carbon dioxide vary a lot -- some are attracted to it because it is linked to food sources, others flee from it because carbon dioxide is often high in environments with little oxygen. "Given this, our work has the additional implication that microRNAs may be good candidates to give species new tools to adapt to different environments," says Cochella, who points at the known fact that microRNAs evolve faster than the bigger protein-coding genes.

The IMP, with 15 groups focusing on a diversity of fundamental research questions, provided the perfect place for Cochella and her team to carry out this study. The collaboration with co-author Manuel Zimmer, who has long established ways to quantitatively measure behavioural responses in C. elegans, was instrumental to this project.

In addition, this study provides insight into understanding microRNA functions. "In C. elegans there are between 150 and 200 miRNAs but we only know the functions of 25 or so of them," says Cochella. This is not only true for the worm, a similarly low fraction of miRNAs has been characterized out of the hundreds found in humans, even though as a whole, miRNAs are essential for animal development and function. This study hints at why miRNA functions have been difficult to uncover: many miRNAs may be only expressed in restricted cell types and finding their functions may require methods as precise as those used in the worm to know exactly which and how cells are affected.