Imagine a train parked at the station. Passengers climb aboard and find their seats. Conductors move up and down the aisles, checking tickets. But there's a problem—the engineer's watch is broken. As a result, the doors never close, the whistle never sounds, and the train never starts. Something similar occurs in cells when developmental timing is disrupted. Rather than making people late for work, it can mean the difference between maturing into a healthy adult and never growing up at all.
In the worm C. elegans, Cold Spring Harbor Laboratory (CSHL) Professor Christopher Hammell and his team previously discovered how pulses of gene expression drive development. However, the mechanism behind their precise timing remained a mystery. Now, the team has found that a feedback circuit composed of two previously known proteins, MYRF-1 and LIN-42, acts as the worm genome's master developmental clock, scheduling the start and duration of each pulse. This is the first non-repeating biological clock of its kind ever found.
"This is the central clock for all cells in the worm," Hammell explains. "It's responsible for coordinating a finite series of sequential pulses of gene expression that must occur only once, and in order, for proper developmental progression. It's like a ratchet. It turns genes on and off multiple times during development, but ultimately, it's only going in one direction."
Using a combination of classical molecular experiments, DNA and protein sequencing, and the AI tool AlphaFold, the team zeroed in on the key roles MYRF-1 plays in C. elegans development. Remarkably, they found that the protein acts as the starting gun and is essential for the checkpoint at the end of each developmental stage. Once a pulse of gene expression has started, MYRF-1 also activates LIN-42 , which controls the strength and duration of each pulse. When the team blocked MYRF-1, it disrupted the entire developmental cycle.
"We've never seen anything like this before," Hammell says. "MYRF-1 is part of this master regulatory clock for all cells, but it's also acting as a key maker and the master key for each stage of growth. Without the right key for each stage, development hits a wall and can't progress."
The team, which also includes CSHL Director of Research Leemor Joshua-Tor , is now investigating how LIN-42 and MYRF-1 physically interact and how each of these cellular clocks communicates with others during development. Understanding how these clocks operate in sync opens the door for future studies on cellular growth, progression, and differentiation.
"The MYRF-1/LIN-42 circuit runs in all cells," Hammell says. "And every one of these independent cellular clocks appears to be in sync when you watch normal development. But are they communicating with each other? We've never thought deeply about that question before."
Addressing it could one day provide insight into genetic diseases and developmental disorders, helping "pull the train out of the station" for countless lives needlessly cut short.
