How can we maintain the blueprint of an organism for long enough such that it can develop correctly?

What is it about?

Development of an embryo has a lot in common with the construction of a new building. For a building, it is necessary to correctly map its blueprint onto the actual construction site, such that the foundations are laid exactly where they need to be. Similarly, embryos are formed from initially identical cells, but for correct development each cell must activate precisely those genes which are needed at the position occupied by the cell. Such “maps” of gene activity, setting the future body plan, are known as gene expression patterns. In the embryo, just like at a busy construction site, there are many random factors that could disturb or even completely destroy the pattern. We studied how one type of such patterns, known as the “alternating cushions” motif, keeps up its long-term presence even under these challenging conditions. The “alternating cushions” pattern consists of multiple slightly overlapping stripes. The genes activated in each stripe try to block the activity of the genes from their neighboring stripes. This “repulsion” between the genes is necessary for a stripe to form, but the obvious danger is that the stripe squeezed between two neighbors may completely disappear if the “repulsion” is too strong. In a way, these genes behave like people trying to fit on a bench that is slightly too short for all of them. In addition, this bench is very wobbly and shaky, so that it is easy to push someone out when everybody tries to make oneself comfortable. In a real organism, the correct development requires each gene to be active exactly where it is needed. In our metaphor, each person must stay on the bench in their right place for as long as necessary. How long will it take before one of them falls off and the “pattern” formed by all of them is destroyed? What should they do in order to stay on the bench as long as possible? And can they cooperate to prevent one of them falling down? While people would possibly try to hold on to each other, for genes the solution is quite different. We found that in order to stabilize the pattern, the genes must repel not only their immediate neighbors, but also their next-nearest neighbors. Moreover, the proportion between both repulsion forces must be very precisely chosen. In our bench metaphor, it means that the left and right direct neighbors of one person must strongly push away each other behind the backs of the person in the middle. Then, the person in the middle needs a considerably smaller force, to squeeze in between them. When the proportion of forces is just right, not only everyone has enough space, but also they can easier regain balance when randomly shaken. The genes in the “alternating cushions” pattern behave in a very similar way. By combining advanced methods for simulating chemical reactions and a new theoretical model of how gene activity spreads in the tissue, we developed methods to predict this optimal “force” of interaction between the neighboring gene stripes, and to show what happens to the expression patterns if the force is not optimal. We found that with an optimal force, the time for which the patterns remain stable increases by ten to hundred times.

Featured Image

Photo by Phonsay P on Unsplash

Photo by Phonsay P on Unsplash

Why is it important?

Inasmuch as the correct transfer of blueprints onto the layout of a building’s foundations is necessary before any more complex structure can be built, the formation of precise and stable gene expression patterns is necessary for the correct development of organs and limbs. However, unlike a typical building, gene expression patterns are shaped in a volatile environment of biochemical processes, which are, to a high degree, random. In spite of this, these patterns are remarkably precise and reproducible. Certain pattern motifs, such as the “alternating cushions”, are encountered by scientists again and again in various organisms, which suggests that these patterns are preferred for how reliably they form. It is then of fundamental interest to learn what makes these patterns robust. By elucidating how the fine-tuning of interactions between the genes allows the “alternating cushions” pattern to survive longer, we explain why this motif is at work in the early fly embryo and, possibly, other developmental systems.

Perspectives