Cell Division’s Surprise Twist

During the final step of cell division, a ring of proteins pinches the cell in two—a process often likened to a purse string drawing shut. The analogy evokes a picture of thread-like proteins wrapping around the cell’s middle in an orderly fashion. But the mechanics of this “contractile ring”—detailed for the first time in the January 4th issue of Science—turn out to be far more intricate and chaotic.


“The answer—which is very exciting and surprising—is that it’s a completely random, unguided process that works perfectly,” says Thomas D. Pollard, MD, professor of molecular, cellular, and developmental biology at Yale University. His team used a combina- tion of computer modeling and high-res- olution microscopy to show that ring assembly in fission yeast follows a dynamic “search, capture, pull, and release” mechanism. The general principles are likely to be the same in higher organisms, Pollard says.


Simulations of the assembly of the contractile ring in fission yeast: Nodes (red) sprout actin filaments (green) in a random network. Myosin proteins in one node randomly encounter, capture, pull on, and then release actin filaments growing from another node. Repeated iterations of this process eventually draw the nodes together in a ring. Courtesy of Thomas Pollard.Their work follows decades of scientific exploration on the topic, he says. Experiments in the 1970s revealed that myosin and actin—the same proteins that make muscles contract—are key players. Genetic studies later identified a complete “parts list” of proteins required (about 50). Recently, scientists observed that the process begins with a broad band of dots—or “nodes”—appearing around the equator of the cell. Pollard’s team pinpointed the composition of these nodes; among other proteins, they contain formin, which polymerizes actin filaments, and myosin, which interacts with actin.


Their observations suggested a simple and elegant model for ring assembly: Nodes grow actin filaments that are captured by myosins in neighboring nodes to make a continuous chain; then the myosins pull the chain closed. But, a Monte Carlo simulation of the scenario gave disappointing results—instead of forming a ring, the proteins disbanded into isolated clumps. “So we were missing something,” Pollard says.


Back in the lab, they carefully measured the movements of fluorescently tagged actin and myosin using high-resolution time-lapse microscopy in live cells. What they saw was unexpected: “The nodes move around in a completely crazy way,” Pollard says, “They go at almost 360 degrees. They don’t all head to the equator at all. They start and stop.”


This suggested a different model of ring assembly where the nodes form transient rather than permanent connections: nodes sprout actin filaments in random directions; these filaments encounter myosins in nearby nodes; the myosins capture, pull on, and then release the actin. Repeated iterations eventually draw the nodes together in a ring.


“You’d swear after two minutes of this 10-minute process, this thing was never going to get there. Even after five minutes, even after seven minutes, it’s a mess,” Pollard says. “But it turns out that just by this completely random process of searching, getting captured, moving intermittently, and then breaking connections, it always works.”


A simulation of this model formed a virtual ring in the same time it takes a live cell. “The gratifying thing is that not only does it make a ring, but it makes it in 10 minutes—which is actually a big constraint,” Pollard says.


“It’s fascinating work,” comments Alex Mogilner, PhD, professor of neurobiology, physiology and behavior and of mathematics at the University of California, Davis. “I think there will be more surprises in the future,” he says, “but they nailed the essence of what’s going on.”


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