A failsafe mechanism keeps fruit fly body symmetry on track

A lot can go wrong as an embryo grows from a fertilized egg into a complex, multicellular organism. In fruit flies, for instance, a handful of different mutations can catastrophically twist the embryo into a corkscrew shape. Corkscrewed embryos always die, but exactly how these mutations cause the twisted body shape hasn’t been clear.

A recent paper in Current Biology found that embryos twist when a genetic system that normally maintains bilateral symmetry breaks down. Without that system, the embryo’s tissue elongates faster on one side of its body than on the other, contorting it into a lethal corkscrew shape. “Fundamentally, the difference between what happens in twisted mutants and normal embryos is the breaking of symmetry,” says biologist Celia Smits, who led the work as a PhD student at Princeton University in New Jersey. The discovery hints that similar systems may be at work in other animals, Smits says—though she hesitates to make the leap to humans, in part because people don’t develop inside an eggshell like fruit flies.

Tasked with understanding the corkscrew trait, Smits imaged the development of several dozen fruit flies in their eggs, both corkscrew mutants and normal embryos, under a light sheet microscope. Unlike a conventional confocal, the light sheet microscope can image “both sides of the embryo at the same time, to see development happening in 3D,” Smits says. Each egg was slightly bigger than a pinhead, roughly jellybean-shaped, and had been genetically engineered with fluorescent molecules to light up all 6,000 of its cells under the scope. A camera inside the microscope recorded each embryo for about an hour, during the exact same phase of development for each one—namely, gastrulation, the early stages of gut formation. This is when the twisting begins in some mutants.

In videos evocative of goo swirling through a lava lamp, the recordings captured cells rearranging within the eggs. In normal embryos, gastrulation begins when the tissue at the posterior end of the body narrows and then pushes inward. The embryo then elongates symmetrically on both sides of its body to help form the hollow tube of the gut. In mutants, rather than elongating symmetrically, one side of the embryo elongated much faster than the other, causing the body to lose bilateral symmetry and corkscrew.

The next question was what had happened genetically. A few different gene systems are associated with the corkscrew shape. Smits imaged flies with mutations in each of these gene systems and found that, at least during gastrulation, only one mutated system led to twisting. It had a defect in the so-called “terminal patterning system,” which directs cells to push into the body from the posterior end of the embryo, forming the gut. These mutants also lacked a gene called scb, Smits found, which encodes a membrane protein that sticks out of the cell. The protein can act as a scaffold that has been shown to help the embryo adhere to the eggshell.

Every time a geneticist sees a defect in symmetry, the error points to “a system that should have been preserving symmetry, but didn’t work perfectly,” says senior author Stanislav Shvartsman, a developmental biologist at Princeton. In normal embryos where the terminal patterning system works correctly, the gut develops with bilateral symmetry. That suggests that something about this genetic pathway maintains symmetry, while mutants cannot.

How exactly the terminal patterning system maintains symmetry in normal embryos is an open question, but Shvartsman and Smits have a theory. The scb protein has been shown to help cells stick to the fruit fly eggshell. In normal embryos, the protein from scb is expressed in an arrowhead shape down the back third of the body. So, perhaps, when normal embryos stray off the midline of symmetrical development, the scb protein helps guide the cells back on track, by gripping the eggshell, almost like bumpers in a bowling alley, Smits says.

Over the last decade, more and more developmental biology studies have explored the interplay between genes and mechanics (in this case, cell adhesion and tissue elongation) to understand how they influence one another in embryo development, says Grigory Genikhovich, a developmental biologist at the University of Vienna. This latest paper offers a case study that’s “very fitting to this general direction,” he says.

Developmental biologist Daniel Grimes at the University of Oregon sees the paper as offering one mechanism by which symmetry is actively maintained in normal fruit flies and lost in mutants. “Random, albeit small, differences between left and right inevitably occur as embryos form, but embryos appear to be set up in such a way to deal with them,” Grimes says. “The mutant conditions in the paper are kind of like a runaway train, where the small left–right differences get worse and worse because the embryo has lost the capacity to deal with those random differences.”

Looking ahead, Smits says one next direction of research is searching for developmental guardrails on bilateral symmetry in other organisms, especially marine species that develop in fluctuating environments. Understanding the mechanisms that suppress errors in embryogenesis, and which organisms are best at recovering from error, might also help predict which will be most resilient to environmental change.

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