Almost 700 years ago, a Dutch naturalist envisioned a fish with arms that would enable it to climb out of the water, setting the stage for terrestrial life. Now, it turns out, his fantasy had roots in reality. Researchers studying skeletons of the finger-size zebrafish have discovered mutants that grow extra bones in their front fins. The mutations unleash the same sets of genes that give rise to our own forearms, demonstrating that—even early in animal evolution—the potential for making landfall was already in place.
“The formation of an extra bone is quite spectacular,” says Marie-Andrée Akimenko, a developmental biologist at the University of Ottawa who was not involved with the work. “This is an important breakthrough to understand the fin to limb transition.”
Researchers have long been intrigued by the seemingly great leap that landed animals on terra firma. How could fins turn into limbs? Paleontologists study fossils to find out, but M. Brent Hawkins, a postdoc at Harvard Medical School, found clues while studying the development of zebrafish.
Hawkins had recently joined a lab at Boston Children’s Hospital that was mutating the DNA of zebrafish to create skeletal abnormalities. Usually mutations cause bones to disappear or misform, and the idea was to find the genes behind similar abnormalities in humans. So, Hawkins was astonished to find a fish with extra bone—two bonus bits in their front, or pectoral, fins.
Intrigued, he began to use the gene editor CRISPR to figure out which stretches of DNA were involved. Hawkins discovered two mutated genes, vav2 and waslb, on two different chromosomes that independently added bones to the fins. And they didn’t just create the bones themselves: The mutations also made the blood vessels, joints, and muscles needed to make the bones work, he and his colleagues report today in Cell. The fish’s development “follows a very similar process to the formation one of the long bones in our arm,” Akimenko says.
Both genes code for proteins that are part of a pathway that controls the activity of the so-called Hox11 proteins, Hawkins found. In mammals, these proteins guide the formation of the two bones of the forearm. In fish, Hox11 is normally suppressed by these other proteins, but when they are mutated, the body starts to build a forearm. “These mutations reawakened a developmental pathway in zebrafish that was hidden,” says Frank Tulenko, an evolutionary developmental biologist at Monash University.
Until now, few scientists could have guessed that vav2 and wasl play a role in bone formation. That they do is “changing the paradigm on limb development and evolution,” says Renata Freitas, a developmental biologist at the University of Porto who calls the study a “landmark.”
The genetic pathway itself is likely ancient. The fact that it exists in zebrafish, which come from a branch of fish that split off more than 400 million years ago from the branch that led to land animals, suggests the pathway was present in the ancestor of almost all modern bony fish. Once in place, the pathway likely helped with the transition from sea to land, says Peter Currie, an evolutionary developmental biologist at Monash University.
“It is becoming increasingly appreciated that the fins of fish are more similar to our limbs than formerly believed,” says Gage Crump, a developmental biologist at the University of Southern California. And similarities between land and water animals may be even more widespread. “A lot of things we think are just in land animals are also in fish,” he says. Some genes making it possible to breathe air, for example, seem to date back to very early fish ancestors, he notes. The early Dutch naturalist would be pleased.
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