Frog builds toes, then legs

Watching gene activity of growing coquí frogs reveals surprising sequence

A small frog appears to jump-start its skeletal development, turning on genes for building feet and toes before bothering to build its legs.

While researchers are still trying to figure out how a clump of cells becomes a wing or flipper or arm, the order of events has been established: The upper arm bone forms first, then the forearm, then the wrist bones, and finally fingers or toes.

But the new research, reported in the July–August Evolution & Development, hints that limb formation may not be so clear-cut.

“This is a very interesting idea,” says developmental geneticist Francesca Mariani, who was not involved with the research. “Maybe limb development has different ways of occurring.”

The evolutionary pathway from ancient fish fins to the structures that today’s creatures use for flying, burrowing, running and jumping has long intrigued scientists. They are still trying to figure out the massive coordination of genes, cells and proteins that it takes to build a fully formed animal. Insights from the frog’s fancy footwork could lead to a greater understanding of the cellular blueprint for all creatures, which one day could lead to therapies for repairing injured tissues.

While revealing an exception to the rule, the new work fits with a model proposed by Mariani in the May 15 Nature. Instead of a single management center that directs limb development from shoulder to fingertip, there might be a control center for areas close to the torso and a separate control center for the more distant structures, like wrists bones and fingers, she suggests.

The frog study “does fit in with the idea that different components of development programs are modular—they can be somewhat separate, potentially,” she says.

Coquí frogs, Eleutherodactylus coqui, are already known for bypassing normal amphibian growth stages. The Coquí is what scientists call a direct developer—it skips the tadpole phase, emerging from the egg as a tiny, fully formed froglet.

“These guys have managed to delete some aspects of the larval stage,” says embryologist Ryan Kerney of DalhousieUniversity in Halifax, Nova Scotia, who conducted the research with Harvard colleague James Hanken.

For years, scientists investigated the development of body parts by tracking the growth of cartilage, the precursor to bone, with a blue stain. But recently, researchers have gone further upstream, looking at the genes and proteins that act as taskmasters coordinating the construction site that is a developing embryo.

The new study follows the activity of three genes known to be involved in skeletal formation. In the coquí frogs, two genes were active in the budding cells that become toes before they were active in the budding cells that become a leg.

While looking at genes and proteins has provided a lot of insight, it isn’t necessarily cut and dried, says Mariani, of the University of Southern California. A gene might be turned on at a certain developmental stage, and then turned on again later for a different task. Mariani isn’t fully convinced that the reported gene activity means the frog’s budding cells are gearing up for making toes.

But she says “this kind of work is really important. It tells you when and where the template becomes established.”

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