Credit: Lucia Garcia del Valle Martinez. Copyright: Hubrecht Institute. 21 June 2023 Roundworm research offers new insights into cellular clock Back to news How do cells measure time? That is one of the main unanswered questions in developmental biology. New research by the Korswagen group brings us one step closer to the answer. The researchers studied the timing of cell migration during the development of the roundworm C. elegans. In collaboration with mathematicians from the United States they predicted a mechanism that allows a cell to precisely ‘tell time’ and confirmed these predictions in the lab. The results of the study were published on 15 May 2023 in the scientific journal eLife. During the development of an organism, it is essential that cells execute the right processes at the right time. Individual cells must therefore be able to ‘tell time’ precisely to ensure they divide, specialize or move at the right time, otherwise the organism will not develop properly. How cells can time these processes so precisely, remains largely a mystery. Miniscule worms To study the internal clock of cells, the Korswagen group uses C. elegans: tiny worms of approximately 1 mm in length. Group leader Rik Korswagen explains: “As these are relatively simple organisms, they are very suitable for our research. The adult worms always consist of exactly 959 cells and they all develop in the same way. In this study we looked at the migration of a neuroblast: a precursor of a nerve cell. Each worm has only one of these cells, which eventually splits and develops into two nerve cells. This makes it a lot clearer than in more complex organisms, where many cells are involved that all influence each other.” Schematic representation of a C. elegans worm. The neuroblast moves towards the front of the worm and is represented in different colors, depending on the stage of migration and development. Credit: Korswagen group. Copyright: Hubrecht Institute. On-off switch for migration The researchers studied how the neuroblast moves from the middle of the worm towards the front. “We previously discovered how the cell knows when to stop during this migration. You would perhaps expect that there is some sort of molecular stop sign at its final destination, but we discovered that it is more like an egg timer. The timer starts ticking as soon as the cell starts moving and the cell keeps going until the timer rings. At that moment, a mechanism kicks in that slows the cell down,” says Korswagen. This brake is regulated by a protein on the outside of the cell, a so-called Wnt receptorA protein that serves as a binding place for other proteins. The binding of a protein to the receptor initiates a specific reaction in the cell.. Korswagen: “Just before the cell needs to brake, the production of this receptor suddenly shoots up. It is like an on-off switch for migration. In this new study we have investigated further how this on-off switch works and why it works as it does.” A mathematical model in which the quantity of Wnt receptors (blue) is regulated by an activator (grey) that increases linearly over time. Credit: Korswagen group. Copyright: Hubrecht Institute. Mathematical models in the lab To answer these questions, the researchers collaborated with mathematician Andrew Mugler from the University of Pittsburgh. “This collaboration was possible thanks to a very quantitative technique we use in our lab: smFISH. This technique allows us to precisely count, on the scale of a single neuroblast, how many copies of the Wnt receptor are produced at different timepoints. This type of data can be used by a mathematician,” explains Korswagen. Through mathematical modelling, Mugler and his team showed that the sudden increase in the number of Wnt receptors has a function. It allows the timing to be much more precise than if there were a gradual, linear increase of the receptor. In other words: through this mechanism, the migrating cell knows very precisely when to step on the brakes. Korswagen continues: “They also predicted how such a rapid increase in receptors could be driven. Namely by a linear increase of an activator, a molecule that stimulates the production of the receptor. When the quantity of the activator exceeds a certain threshold, the number of Wnt receptors would suddenly increase and stop the cell from migrating. We took this prediction to the lab, to test in C. elegans if this is indeed how it works, and it is.” An example of results obtained with the technique smFISH. On the left, individual transcripts of the Wnt receptor gene are stained in a single neuroblast, in order to count them (pink). The graph on the right shows a collection of such measurements at different timepoints during migration. From this it can be deduced that the Wnt receptor increases in quantity as migration progresses (read from right to left). Credit: Korswagen group. Copyright: Hubrecht Institute. Interdisciplinary approach According to Korswagen, the strength of this study lies in the collaboration between different disciplines. “The results of models are not always very intuitive, but that is precisely why it provides you with new ideas that you might not otherwise come up with as an experimental biologist. These can then be tested in the lab. I was very pleased to see that the predictions from the models proved to be correct.” The team is already working on follow-up research. “Now that we have shown how a cell can make a very precise clock, we are working on a project proposal to further investigate how all the cogs in that clock work.” This study was funded by the Human Frontier Science Program. Publication Precise temporal control of neuroblast migration through combined regulation and feedback of a Wnt receptor. Erik S. Schild, Shivam Gupta, Clément Dubois, Euclides E. Fernandes Póvoa, Marie-Anne Félix, Andrew Mugler and Hendrik C Korswagen. eLife, 2023. Rik Korswagen is group leader at the Hubrecht Institute and professor of Molecular Developmental Genetics at Utrecht University.
