Edited by Lukas Breitzler
Billions of years ago, in the primordial waters of early life, life consisted entirely of single cells. Organisms could only reproduce by making identical copies of themselves. It worked—but it came with serious limitations. If a cell carried mutations in its genome, each division would propagate them, slowly degrading the genome with each new generation. Life also lacked diversity which made it susceptible to attack. If a virus or parasite threatened one cell, it could threaten them all. Cells therefore evolved a trick that would form one of the foundations on which complex life evolved: they learned to fuse with other cells and combine their DNA—a process called cell-fusion. Billions of years later, a version of cell-fusion still happens during sexual reproduction in many animals, and even in humans.
Researchers in the Vještica lab study this ancestral process in Schizosaccharomyces pombe—a type of yeast widely used as a research organism in modern biology. When observed under one of the lab’s high-resolution microscopes, it looks deceptively simple. Two rod-shaped cells meet, their tips dissolve, and their contents merge into one. Yet hidden inside that smooth sequence is an enormous amount of molecular traffic. The genetic material or DNA (residing in a part of the cell called nucleus) need to be converted to messengers called RNA. This messages then need to be sent outside of the nucleus where they are translated to dictate which proteins to produce. Some of these messages will be stabilized while others will be destroyed, and proteins need to be turned on or off at exactly the right moment.
“We want to understand how a cell completely rewires its gene expression program from the moment when cells fuse” explains Ayokunle Araoyinbo, who carried out this project in the Vještica lab. How is all of this coordinated so precisely, and what happens when it goes wrong? A new publication by the lab now uncovered that a protein—Mei2—once thought to work only in one part of the cell actually has a surprising second job elsewhere.
Scientists had long thought of Mei2 as a kind of switch that tells yeast cells when to start reproduction. Cells without Mei2 won’t reproduce, and cells with prematurely active Mei2 start reproducing too early. Previously it was thought that Mei2 did most of its work in the nucleus—the cell’s control center. But when researchers in the Vjestica lab tagged Mei2 with a bright fluorescent protein and watched its movement under a high resolution microscope, they saw something unexpected: during fertilization, Mei2 didn’t only stay in the nucleus. They noticed it also gathered in molecular structures called P-bodies, small droplets inside cells that were previously thought of as generic storage bins or recycling centers for RNA.
“Even when we forced Mei2 into the nucleus using our genetic tools, we could see it leaving the nucleus and decorating P-bodies as soon as cells fused” said Ayokunle.
Now that the researchers saw Mei2 drawn to these structures, two interesting questions emerged. Why was Mei2 drawn to these P-bodies? And what were they doing when cells fused that made them such hotspots for Mei2?
To answer the first question, the researchers turned to proteins that work like an on-off switch for Mei2. They created yeast strains in which one part of this switch, called Mei3, was intentionally disabled and watched how Mei2 moved inside the cell. Without Mei3, Mei2 stayed inactive—and importantly—it never moved into P-bodies. This revealed something important. The same signal that activates Mei2 also controls where it goes.
But to understand what Mei2 was actually doing in P-bodies, the team had to go beyond watching and start testing. They genetically engineered yeast strains carrying different versions of Mei2. Some variants could no longer switch on properly, some could no longer latch onto the RNA molecules that they usually interact with, and some could not longer travel to certain parts in the cell. By comparing how these modified Mei2 proteins behaved, the team could pinpoint which features of Mei2 were essential for the early steps of cell-fusion. These experiments revealed that Mei2 uses different “parts” of itself for different steps. One region helps it grab onto specific RNA messages and transport them outside the nucleus, another regulates whether an RNA message is converted into proteins.
One result especially unveiled that P-bodies are far from passive structure that happen to collect Mei2. Normally, cells with prematurely active versions of Mei2 will attempt to reproduce too early, usually with fatal consequences. But when the researchers disrupted a core component of P-bodies, even this version of Mei2 stopped causing harm. The cells survived. This showed that P-bodies are essential partners that enable Mei2 to perform its function during Schizosaccharomyces pombe‘s sexual reproduction.
On paper, yeast sexual reproduction could not seem further from human development. Yet the principles uncovered in this study shed light one of biology’s most important transitions.
By probing this process using high resolution microscopes and clever genetic engineering, the Vjestica lab shows that the decisions cells make depend not just on the genes they carry, but also on how they manage the products of those genes. “The core idea is that cells don’t just turn genes on and off at the level of RNA production,” Ayokunle notes. “The integrity of a cell indeed relies on where an RNA goes, how long they stay there, and which proteins accompany them. Granules like P-bodies are central to that logic.”
By working in a system where this entire process can be filmed and perturbed in single cells, the Vještica lab can dissect this logic in detail.